CRO Vol 28 Number 1 by MediConcept

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Clinical & Refractive Optometry

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VOLUME 28, NUMBER 1, 2017

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In Vivo Ocular Surface Osmolarity in a Dry Eye Population Vogt-Koyanagi-Harada Syndrome Ocular and Oral Mucous Membrane Pemphigoid Common Ocular Disorders in the Pediatric Population Ophthalmic Artery Steal

Clinical &Refractive Optometry

Editorial Board • Volume 28, Number 1, 2017 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 Rhéaume, 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.

HOLD THE DATES

A SYMPOSIUM ON THE DIAGNOSIS, TREATMENT & MANAGEMENT OF OCULAR SURFACE DISEASE

OSD

2017

presented by

Clinical & Refractive Optometry in collaboration with

Optometry Giving Sight May 26-27, 2017 Toronto, Ontario THIS MEETING WILL BE ACCREDITED FOR 7 HOURS OF COPE CE CREDIT

Clinical & Refractive Optometry

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

Contents • Volume 28, Number 1, 2017

SCIENTIFIC STUDY 3 In Vivo Ocular Surface Osmolarity in a Dry Eye Population Richard L. Maharaj, OD INTRODUCTION: The lacrimal functional unit (LFU) is a system of anatomical, physiological and biochemical mechanisms working in concert to maintain homeostasis at the ocular surface. When any component of this system becomes unstable or dysfunctional, the resultant cascade can affect ocular surface and if corrective measures are not taken, can cause significant discomfort, pain and visual disturbances for a given patient. Dry eye disease (DED) is the result of dysfunction of the LFU and affects between 5% to 30% of adults over age 50 according to the TFOS Dry Eye Workshop.

CE CREDIT ARTICLES 8 Vogt-Koyanagi-Harada Syndrome: A Case Study Len Ferguson, OD ABSTRACT: Vogt-Koyanagi-Harada (VKH) syndrome is considered to be a multisystem autoimmune and ethno-specific inflammatory disorder whose primary ocular manifestations consist of bilateral granulomatous panuveitis, choroiditis, and exudative retinal detachments. This case study involves a younger male patient of mixed ethnic background who presented with acute phase ocular findings without any prior history of VKH.

Ocular and Oral Mucous Membrane Pemphigoid: An Intimate Association Leonid Skorin Jr., OD; Jennifer Keller, OD; Gary Jernberg, DDS ABSTRACT: Mucous membrane pemphigoid (MMP) is a multiorgan system disease affecting any mucous membrane within the body. The ocular and oral structures are commonly affected, either individually or simultaneously. Ocular manifestations include symblepharon and corneal keratinization. Oral involvement includes painful blisters and bleeding gingiva.

Common Ocular Disorders in the Pediatric Population David P. Sendrowski, OD; Robert W. Lingua, MD ABSTRACT: While most young children and infants are referred to the eye care physician with isolated ophthalmic problems for assessment and possible treatment, a smaller percentage will harbor serious ocular pathology which may be associated with co-existing systemic or neurologic abnormalities. Infant and early childhood development can be profoundly influenced by disorders of the visual system. The eye care physician should be aware of these common ocular pathologies for potential treatment options and urgency of referral if required by the condition.

The Journal is made available to all optometrists on www.crojournal.com. 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 © 2017 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.

Ophthalmic Artery Steal Joyce Hsieh, OD; Pauline F. Ilsen, OD ABSTRACT: The optometrist needs to be aware of the potential manifestations of ophthalmic artery steal and its appropriate management, both ocular and systemic. Timely diagnosis by an eyecare specialist can play a crucial role in reducing patient mortality.

ISSN: 2371-7017; Date of Issue: February 2017

Courtesy of: Dr. David Sendrowski and Dr. Robert Lingua

Scientific Study In Vivo Ocular Surface Osmolarity in a Dry Eye Population Richard L. Maharaj, OD, FAAO Clinical Director, eyeLABS Optometry and Center for Ocular Surface Disease Associate Clinical Adjunct Faculty, University of Waterloo School of Optometry

INTRODUCTION The lacrimal functional unit (LFU) is a system of anatomical, physiological and biochemical mechanisms working in concert to maintain homeostasis at the ocular surface.1 When any component of this system becomes unstable or dysfunctional, the resultant cascade can affect ocular surface and if corrective measures are not taken, can cause significant discomfort, pain and visual disturbances for a given patient. Dry eye disease (DED) is the result of dysfunction of the LFU and affects between 5% to 30% of adults over age 50 according to the TFOS Dry Eye Workshop.2

TEAR OSMOLARITY In 1978, Dr. Jeff Gilbard wrote about tear osmolarity as a clinical indicator of dryness in a small study of 36 samples.3 The concept of hyperosmolarity was eventually integrated into the clinical definition of DED in 2007 based on the TFOS Dry Eye Workshop.2 Tear film hyperosmolarity has been used as a DED metric in numerous publications including landmark studies by Tomlinson (2008) and Lemp (2011).4,5 At the time, the prevailing and sole commercial device available to measure osmolarity was TearLab® (TearLab Corp, San Diego, CA). This system measures the electrical impedance of a 50 hL sample collected from temporal location of the meniscus of the tear film to quantify osmolarity ex vivo.6 A new osmometer known as the i-Pen® (I-MED Pharma Inc., Montreal QC), is now commercially available for clinical use. Like previous systems, it measures electrical impedance, but does so in vivo which results in the ability to assess ocular surface osmolarity more rapidly than current commercially available systems. Measuring

tear osmolarity through the tissues of the palpebral conjunctiva is not novel and has been previously shown as an effective method of measuring osmolarity in vivo. A flexible conductimetric sensor fabricated using microelectronic techniques is small and flexible enough to be placed on the peri-ocular surface to measure the electrical conductivity of tear fluid in vivo.7 As with any new diagnostic device however, interpretation of a new measure comes from studying clinical use and outcomes. As such, this prospective observational case study sought to examine the meaning of ocular surface osmolarity through the lens of this new device in comparison to accepted metrics of the tear film and ocular surface: corneal staining, tear break-up time, Ocular Surface Disease Index (OSDI), Standard Patient Evaluation of Eye Dryness (SPEED) and Schirmer volume testing.

METHODS This prospective observational case series involved 48 randomly selected patients measured bilaterally (n=96) presenting to a referral center for ocular surface disease. Patients ranged from age 27 to 88, 28 (58%) females and 20 (42%) males (average age 59.2 ± 15.6). Subjects of this study were excluded if contact lenses were used within 24 hours of testing, had an active ocular infection, had undergone ocular surgery or changed systemic medicine in the previous 30 days. Subjects presented to the clinic for a single visit which involved the following diagnostic protocol based on common tests for dry eye disease8: 1. 2. 3. 4.

R. Maharaj — Clinical Director, eyeLABS Optometry and Center for Ocular Surface Disease, Brampton, ON; Associate Clinical Adjunct Faculty, University of Waterloo School of Optometry, Waterloo, ON Correspondence to: Dr. Richard Maharaj, 7900 Hurontario, Suite 406, Brampton, ON L6Y 0P6; E-mail: rmaharaj@eyelabs.ca Disclosure: This study was supported by an unrestricted educational grant by I-MED Pharma Inc., Montreal QC This article has been peer reviewed.

Ocular Surface Disease Index and Standard Patient Evaluation of Eye Dryness (SPEED) Osmometric testing using i-Pen® Schirmer (without anesthetic) Tear break-up time (TBUT) using fluorescein (NaFl) (10 minutes after Schirmer) Corneal and conjunctival staining (Oxford staining protocol)

Steps 1 through 3 were performed by a trained ophthalmic technician with steps 4 and 5 by the attending clinician who was blinded from the previous steps findings.

In Vivo Ocular Surface Osmolarity in a Dry Eye Population — Maharaj

Table I Cut-off values for Dry Eye Disease tests (Binary score of 1 or 0 were applied for values beyond cut-off)

Table II Sensitivity and specifity of ocular surface osmolarity at specified cut-offs

DED Test

Cut-off Value

OSDI SPEED Oxford Staining TBUT Schirmer

>12 >6 >I <10 s <18 mm

Ocular Surface Osmolarity (mOsm/L) 286 290(i) 308 311

Sensitivity

Specificity

93.2% 91.8% 87.7% 86.3%

42.9% 71.4% 85.7% 100%

i = highest sensitivity and specificity combination between normal and DED patients

Table III Sensitivity and specificity values of non-osmolarity tests Test

Sensitivity

Specificity

TBUT Oxford Staining OSDI SPEED Schirmer

91.8% 58.8% 100% 89.1% 40.2%

5.9% 62.5% 16.1% 22.3% 53.1%

The study was designed to assess the sensitivity and specificity of ocular surface osmolarity against a composite of common tests for dry eye disease. As such, the investigator compared osmolarity against a composite of each metric in a binary format to determine the cut-off between a ‘normal’ subject and ‘mild’ DED as noted by the Dry Eye Workshop Scale2 (Table I). Similar to Lemp’s work in 2011, each metric was mapped to this binary score of 1 or 0 so as not to create more weight to any one metric depending on the disease severity.5 Thus, disease severity and etiology were not considered in this study. Subjects presenting with 3 or more subnormal test outcomes were classified as having at minimum mild DED (classified as the binary score of “1” for yes and “0” for no). The absolute osmolarity and an inter-eye osmolarity difference of > 8 mOsm/L were compared to the binary composite DED score. The > 8 mOsm/L value is based on the observation made by Lemp et al.5

RESULTS In this study’s cohort, the prevalence of DED based on greater than 3 positive non-osmolarity test outcomes was 76.0%. Osmometric readings > 290 mOsm/L (which is the upper range of blood plasma and serum osmolarity) had 91.8% sensitivity and 71.4% specificity which was the greatest sensitivity and specificity range of all other tests (Table II). TBUT yielded 91.8% sensitivity with only 5.9% specificity, while Oxford staining yielded the lowest sensitivity at 58.8% (Table III). When removed from the analysis, inter-eye difference was shown to have a large impact on testing sensitivity, particularly at values over 290 mOsm/L (Table IV). The average inter-eye difference for values > 7 mOsm/L was 23.1 ± 16.5 and values < 8 mOsm/L was 3.1 ± 1.9. The sensitivity of an inter-eye difference > 7 mOsm/L alone was 84.9%. This is consistent with findings by Lemp.5

Clinical and Refractive Optometry 28:1, 2017

Table IV Sensitivity of ocular surface osmolarity without inter-eye difference consideration Ocular Surface Osmolarity (mOsm/L) 286 290 308 311

Sensitivity 70.0% 57.5% 23.3% 15.1%

The mean osmolarity above the 290 mOsm/L cut-off was 307.8 ± 16.4 and below this cut-off the mean was 281.9 ± 9.0 mOsm/L. Further analysis demonstrated a positive relationship between absolute inter-eye osmolarity difference and both standardized symptom measures, OSDI and SPEED with an R2=0.526 and R2=0.531, respectively however this was not statistically significant (p=0.05) (Figs. 1, 2). As noted with sensitivity testing, inter-eye difference showed the strongest relationship to symptom severity when compared to average subject osmolarity (mean of OD and OS). The osmolarity values found in this small observational study seem to be lower than those observed in previous studies, notably the frequently cited Lemp paper in 2011 which showed the value of 308 mOsm/L as being the intersecting osmolarity between normal and DED subjects.5 The in vivo method of measurement and sample cohort are the two most plausible explanations for this difference, which will be further discussed below.

DISCUSSION Previous studies have reported a range in tear osmolarity cut-off between normal and DED patients from 304 to 316 mOsm/L depending on the study in question.3,5 Based on the results from this cohort, and using a novel method of in vivo electrical impedance, findings suggest that ocular surface osmolarity cut-offs may be lower than previously reported when using the i-Pen® osmometer. The results raise questions as to why this shift to lower osmolarity range is noted using an in vivo technique. Some of the possible differences could be related to the site of sampling. The i-Pen®, when used as directed, takes a

Fig. 1 The absolute inter-eye difference in osmolarity (mOsml/L) between OD and OS versus Ocular Surface Disease Index (OSDI)

Fig. 3 The vicious circle of pathology of dry eye disease as proposed by Badouin (2016).15

measurement of the central palpebral conjunctival surface, while the TearLab® system takes samples peripherally. While looking at this question, it is important to consider a small single cohort from a focused demographic both geographically and pathologically may influence the results. Given that the patient base was from a referral dry eye clinic however, one would expect findings to skew to higher osmolarity measures rather than the lower shift noted in the results. The lower cut-off (290 mOsm/L) found in this study may be explained by the measuring method (in vivo) compared to previous studies (ex vivo). The purpose of this paper is to consider a hypothesis based on homeostasis of the ocular surface as it relates to human reference fluid, namely blood plasma. Human plasma has an osmolarity range from 275-295 mOsm/L and the osmolarity of human serum has been reported to

Fig. 2 The absolute inter-eye difference in osmolarity (mOsml/L) between OD and OS versus Standard Patient Evaluation of Eye Dryness (SPEED) score

be 289 mOsm/L (281-297 mOsm/L).9,10 There is a direct link between blood (plasma and serum) osmolarity and tear film osmolarity as observed in a recent publication which studied the effect of hemodialysis on tear osmolarity. It was observed that the tear osmolarity decreased in a statistically significant manner (p=0.0001) from 314 to 301 mOsm/L from before to immediately after hemodialysis.9,11 Tear hyperosmolarity has been shown to trigger a breakdown in ocular surface homeostasis at levels above 300 mOsm/L. The method of collection and testing for many of the aforementioned studies however uses the TearLab® system, which relies on an aliquot of 50 hL from the tear meniscus which is then transferred to a testing chip ex vivo. This being the first study examining findings from osmolarity measures taken in vivo, it is possible that these measures are a closer representation of ocular surface osmolarity due to the elimination of variables like sample transfer, temperature variations, location of sampling, sample volume and humidity variations, which are factors using ex vivo systems. Ex vivo systems like TearLab® have been critiqued mainly due to high variability of the readings that could be instrument and/or sampling technique dependent.12,13 Corneal nociceptors, particularly those involved in sensing evaporation and hyperosmolarity have a pivotal role to play in the homeostasis of the LFU. The cornea contains three basic types of nociceptors which include mechanoreceptors, polymodal receptors and cold receptors. Polymodal receptors make up 70%, and are stimulated by mechanical forces, pH, osmolarity and heat.14 A plausible question is at what threshold do the polymodal nociceptors signal the dry eye alarm as postulated by Rosenthal?14 Considering the human blood plasma/serum range of 275-297 mOsm/L, it may be that triggering of this alarm occurs when the ocular surface osmolarity differs sufficiently from serum osmolarity so as to signal apoptotic stress. The trigger of hyperosmolar stress could vary from person to person depending on the difference between blood and tear osmolarity. Certainly, further

In Vivo Ocular Surface Osmolarity in a Dry Eye Population — Maharaj

studies would be needed to draw this conclusion, however this theory could explain the range in hyperosmolarity we see in prospective studies and meta-analyses such as Lemp and Tomlinson.4,5 Continuing with this hypothesis, the observed cut-off between normal and mild DED noted in this study’s cohort of 290 mOsm/L may be lower due to the lack of variables with the i-Pen® in vivo method of measurement and therefore being more representative of true ocular surface osmolarity. With sensitivity of 91.8% and specificity of 71.4%, it would seem that this lower threshold is in fact reasonable and can be explained by current understanding of the interaction between ocular surface osmolarity and corneal nociceptor stimuli. What is consistent with previous studies is that the inter-eye osmolarity variability has significant sensitivity at 84.9% independent of average eye osmolarity. In line with polymodal nociceptor stimulation, if triggering the dry eye alarm requires an osmolar point-of-reference, then the inter-eye difference in osmolarity could also serve as that reference. In anticipation of the DEWS II report, a newer understanding of the immunophysiology and biochemistry of DED are evolving. Badouin has postulated his ‘Vicious Circle’ theory (Fig. 3), in which we start to see the cyclical nature of dry eye, rather than the conventional Aqueos Deficient Dry Eye (ADDE) versus Evaporative Dry Eye (EDE) binary pathways in the past.15 What remains constant however is the role of tear and cell hyperosmolarity as an influencer in this vicious circle which drives the cycle forward. The findings of this report warrant further multicenter trials to shed a new light on this familiar metric. This paper does not in any way suggest that the data results should become a new standard, but rather a signal to study the unifying measure of ocular surface osmolarity sufficiently and with a wider lens, using this new in vivo technique, perhaps evolving what has previously been accepted as fact. ❏

Clinical and Refractive Optometry 28:1, 2017

REFERENCES 1.

4. 5.

8. 9.

10. 11.

12. 13. 14. 15.

Stern ME, Schaumburg CS, Dana R, et al. Autoimmunity at the ocular surface: pathogenesis and regulation. Mucosal Immunology 2010; 3: 425-442. TFOS: The epidemiology of dry eye disease: report of the Epidemiology Subcommittee of the International Dry Eye WorkShop. Ocul Surf 2007; 5(2): 93-107. Gilbard JS, Farris RL, Santamaria J. Osmolarity of tear microvolumes in keratoconjunctivitis sicca. Arch Ophthalmol 1978; 96(4): 677-687. Khanal S, Tomlinson A, McFadyen A, et al. Dry eye diagnosis. Invest Ophthalmol Vis Sci 2008; 49(4): 1407-1414. Lemp MA, Bron AJ, Baudouin C, et al. Tear osmolarity in the diagnosis and management of dry eye disease. Am J Ophthalmol 2011; 151(5): 792-798. Sullivan BD, Whitmer D, Nichols KK. An objective approach to dry eye disease severity. Invest Ophthamol Vis Sci 2010; 51(12): 6125-6130. Ogasawara K, Mitsubayashi K, Tsuru T, Karube I. Electrical conductivity of tear fluid in healthy persons and keratoconjunctivitis sicca patients measured by a flexible conductimetric sensor. Graefe's Arch Clin Exp Ophthalmol 1996; 234(9): 542-546. Korb DR. Survey of preferred tests for the diagnosis of the tear film and dry eye. Cornea 2000; 19(4): 483-486. Khajuria A, Krahn J. Osmolality revisited--deriving and validating the best formula for calculated osmolality. Clin Biochem 2005; 38(6): 514-519. Blood - Physicochemical Data, Documenta Geigy, Scientific Tables. 1970. p. 557. Taskapili M, Serefoglu Cabuk K, Aydin R, et al. The effects of hemo-dialisys on tear osmolarity. J Ophthalmol 2015; 2015: 170631. Khanal S, Millar TJ. Barriers to clinical uptake of tear osmolarity measurements. Br J Opthalmol 2012; 96(3): 341-344. Szczensa-Iskander DH. Measurement variability of the TearLab osmolarity system. Cont Lens Anterior Eye 2016; 39(5): 353-358. Rosenthal P, Borsook D. The corneal pain system. Part I: the missing piece of the dry eye puzzle. Ocul Surf 2012; 10(1): 2-14. Baudouin C, Messmer EM, Aragona P, et al. Revisiting the vicious circle of dry eye disease: a focus on the pathophysiology of meibomiangland dysfunction. Br J Ophthalmol 2016; 100(3): 300-306.

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Clinical & Refractive Optometry is pleased to present this continuing education (CE) article by Dr. Len Ferguson entitled Vogt-Koyanagi-Harada Syndrome: A Case Study. In order to obtain a 1-hour Council of Optometric Practitioner Education (COPE) approved CE credit, please refer to page 15 for complete instructions.

Vogt-Koyanagi-Harada Syndrome: A Case Study Len Ferguson, OD

ABSTRACT Vogt-Koyanagi-Harada (VKH) syndrome is considered to be a multisystem autoimmune and ethnospecific inflammatory disorder whose primary ocular manifestations consist of bilateral granulomatous panuveitis, choroiditis, and exudative retinal detachments. This case study involves a younger male patient of mixed ethnic background who presented with acute phase ocular findings without any prior history of VKH. Initial clinical presentation and follow-up was documented with fundus photography and Spectral Domain OCT. Topical and systemic medical treatment was conducted over the course of several months as he continued with oral corticosteroid and immunosuppressant therapy, as well as intermittent topical treatment for anterior uveitis. While prompt diagnosis and treatment of VKH frequently results in stable visual outcomes, long-term functional loss can be a potential risk in this disorder.

INTRODUCTION Vogt-Koyanagi-Harada (VKH) syndrome presents systemically with a pattern suggestive of a T-cell-mediated autoimmune disorder directed against uveal, dermal, and meningeal melanocytes that is genetically influenced and is race dependent.1 Somewhat biased toward females, VKH predominately affects individuals with darker skin pigmentation, such as Hispanics, Asians, Native Americans, Middle Easterners, and Asian Indians, but not blacks of sub-Saharan African descent.2 Its chief systemic manifestations are dermatologic and neurologic, including

L. Ferguson â&#x20AC;&#x201D; Private Practice, Lethbridge, AB Correspondence to: Dr. Len Ferguson, 517-4th Avenue South, Lethridge, AB T1J 0N4; E-mail: drlen@shaw.ca No grants or financial disclosures are applicable. This article has been peer reviewed.

Clinical and Refractive Optometry 28:1, 2017

alopecia, poliosis, vitiligo, CNS meningeal lesions, auditory, and ocular signs.2 Other autoimmune conditions are known to be associated with the VKH syndrome, including hypothyroidism, diabetes, and autoimmune polyglandular syndrome type 1.3 VKH accounts for 1% to 4% of uveitis cases in tertiary referral centers in the United States4 and as many as 9.2% of cases in Japan.5 As a granulomatous inflammatory disorder, the precise mechanism that prompts the autoimmune attack is poorly understood. Some authors have speculated that cutaneous injury could elevate sensitization to melanocytic antigens,6 others have postulated a systemic immune response to viral infection.7 The medical literature in fact support the contention that ocular signs and symptoms can be preceded by headache, aseptic meningitis, tinnitus, or symptoms resembling those of influenza.8 The four clinical stages of VKH are outlined in Table I. VKH typically presents in the anterior chamber as a granulomatous inflammatory process that can include keratic precipitates on the corneal endothelium.9 The posterior segment is generally considered to be chiefly affected by a diffuse, sometimes severe, choroiditis in both eyes. Indocyanine green imaging classically demonstrates uneven filling of dye in the arterial phase with a generalized irregular hypofluorescence in the later venous phase. Sporadic signs of exudative retinal detachments secondary to the choroiditis are often detected, seen either as undulating subretinal fluid accumulations or as frank bullous detachments.10 The primary ocular pathogenesis in the VKH syndrome is thought to involve the choroid, with minimal involvement of the retinal vasculature. In fact, fluorescein

Table I The four clinical phases of VKH Stage 1 Prodromal: tends to mimic signs and symptoms of a viral infection Stage 2 Uveitic: bilateral uveitis, papillitis, and serous retinal detachment Stage 3 Convalescent: retinal depigmentation Stage 4 Recurrent: repeating patterns of uveitis and other ocular complications

Fig. 1 (A) External photo of the right eye at initial presentation. (B) External photo of the left eye at initial presentation.

Fig. 2 45 degree fundus photo of the right eye at initial presentation. Multiple bands of retinal striae occupy regions superior and inferior to the macula. The optic nerve appears well-perfused with crisp neural rim borders nasally but a subtle blurring temporally. Retinal vasculature appears to be within normal limits apart from a superior arcade artery.

Fig. 3 45 degree fundus photo of the left eye at initial presentation. Retinal striae are almost absent, with good nerve head vascular perfusion and crisp borders. No changes were observed in the retinal vasculature.

angiographic studies have failed to reveal any anomalies of retinal vessels, at least when studied in the acute presenting phase. Relatively few patients are followed with retinal angiography over the long term for chronic disease. It is well known that the leading cause of decreased vision in retinal disease is cystoid macular edema, yet in VKH this is relatively uncommon. In fact, the precise way in which uveitis elicits fluid accumulation in retinal extracellular spaces remains poorly understood. Some compromise must necessarily take place in either the outer blood-retina barrier (tight junctions in the RPE cells) or in the inner blood-retina barrier (tight junctions in the retinal vascular endothelial cells). Finally, the choroid can potentially factor into longstanding, chronic VKH through neovascular invasion of the retina that can eventually lead to disciform scarring.11

CASE REPORT This 22-year-old male had an ethnic background consisting of both Japanese and Aboriginal Canadian heritage. He was unaware of any immediate family member with notable ocular or systemic medical conditions. His medical history was negative for any systemic conditions, medications, or illicit substances. Three days prior to the initial assessment, the patient had been experiencing progressively worsening signs of redness with symptoms of floaters and photophobia starting in his right eye. His vision started to deteriorate in the right eye and was described as â&#x20AC;&#x153;looking through an after image.â&#x20AC;? Soon thereafter, similar signs and symptoms emerged in the left eye. Vision was becoming blurry to the point that driving was difficult and reading printed material was a strain. He admitted to having slept in his

Vogt-Koyanagi-Harada Syndrome: A Case Study â&#x20AC;&#x201D; Ferguson

Fig. 4 Right eye: EDTRS grid thickness values (above, left) showing central subfield of 390 microns, and colour-grade thickness map (above, right) demonstrating regions of serous retinal detachment (shown as white). The outer inferior EDTRS subfield is 725 microns in thickness.

Fig. 5 Horizontal B-scan of the right macula at initial presentation showing fovea (yellow arrow), four small multilobular exudative detachments (white arrows) and two larger serous retinal detachments (red arrows). The neurosensory layers above the SRD show diffuse edema without any cystoid pockets of fluid.

Fig. 6 Vertical B-scan taken temporal to the right fovea showing a large neurosensory detachment inferiorly (I) and a smaller detachment superiorly (S). The Cirrus SLO (scanning laser ophthalmoscope, inset) indicates scan registration with a teal line. Note that portions of the RPE continue to be attached to Bruchâ&#x20AC;&#x2122;s membrane (red arrows).

Fig. 7 The left central subfield thickness in the left eye was 286 microns with two subtle areas of serous neurosensory detachment (red arrows).

Fig. 8 Horizontal B-scan of the left eye at initial presentation showing two subtle neurosensory detachments (white arrows). Foveal contour is intact with an absence of overt cystoid macular edema.

contact lenses two weeks ago, and made an appointment for an eye exam thinking that his contact lenses were the source of the problem.

CLINICAL ASSESSMENT This patient presented for assessment wearing sunglasses to alleviate his photophobia. Pinhole visual acuities were found to be OD 6/30 (20/100) and OS 6/24 (20/80). Extraocular muscle movements and pupil responses were unremarkable OU, as were applanation intraocular pressures. Slit lamp examination revealed bilateral

Clinical and Refractive Optometry 28:1, 2017

circumferential conjunctival hyperemia (Fig. 1A, B) and grade 2+ anterior uveitis. Dilated fundus examination of the right posterior pole revealed paramacular retinal striae with serous retinal detachment superiorly, supranasally, and inferiorly, all within a 1-3 disc diameter proximity to the fovea (Fig. 2). The right optic nerve head and retinal vasculature appeared to be unremarkable apart from a subtle blurring of the disc margin nasally. Low-grade vitreous haze was suggestive of posterior uveitis. Reduced signs were apparent in the left posterior pole, with only subtle retinal striae observed supranasally and just inferior to the fovea (Fig. 3). No abnormalities were demonstrated in either the optic nerve head or the retinal vasculature. There was an absence of overt vitreous haze in the left eye.

OCT ASSESSMENT Cirrus Spectral Domain OCT (Zeiss, Dublin, CA) was used to assess the retinal architecture through dilated pupils. The 512X128 Macular Cube scan of the right eye laid out the primary areas of serous retinal detachment in the ILM-RPE thickness map. The central EDTRS subfield thickness was 390 microns (Fig. 4), over 75% thicker than normal. Small regions of detachment shown in white on the thickness map were seen supratemporal and

Fig. 9 Right eye at three weeks post-treatment with oral corticosteroids showing nearly complete resolution of the previous retinal striae. Note the absence of any retinal reflex from camera flash.

Fig. 10 Left fundus showing retinal reflexes (white arrows).

supranasal to the fovea. A much larger detachment was mapped out inferiorly, with an average EDTRS outer subfield thickness of 725 microns. Analysis of the foveal B-scan revealed the presence of a foveal contour (Fig. 5) with no sign of cystoid macular edema. Several small multilobular detachments could be discerned temporal to the fovea, with two larger detachments located subfoveally and nasally. Another vertical B-scan taken temporal to the fovea gave further clinical insight into the extent of the uveitic serous retinal changes (Fig. 6). OCT assessment of the left eye was much less remarkable, with the 512X128 Macular Cube scan revealing only two subtle areas of retinal elevation (Fig. 7) within the 6 mm by 6 mm scan grid. The central subfield thickness was almost 100 microns less than in the right eye, measuring 286 microns. A horizontal B-scan through the left fovea demonstrated a fairly well-preserved foveal contour with an absence of intraretinal cystoid fluid and confirmation of the histological location of the serous detachments (Fig. 8).

funduscopy revealed an absence of vitreous haze and a much flatter retina in the right eye, with virtually a complete resolution of the previous retinal striae (Fig. 9). The left fundus also exhibited a resolution of the striae with the presence of retinal reflexes indicative of a drier retina (Fig. 10). Cirrus OCT imaging of the right macula confirmed a significant improvement in the serous detachments, with the central subfield improving from 390 to 307 microns (Fig. 11). The outer inferior EDTRS subfield corresponding to the largest measured detachment improved from 725 to 306 microns. Histologically, the B-scan revealed an extensive but subtle residual neurosensory elevation (Fig. 12). The restoration of a normative foveal contour corresponded with the improvement in visual function, from 6/30 (20/100) to 6/18-3 (20/60-3). While the OS central subfield remained essentially static, the mid-nasal EDTRS subfield decreased from 358 to 320 microns, showing some resolution of the uveitic serous lesion (Fig. 13). A similar impression can be drawn from the macular B-scan (Fig. 14), where the functional improvement from 6/24 (20/80) to 6/9 (20/30) could be inferred from the structural improvement. Two months after initial presentation, daily dosage of 50 mg oral prednisone and azathioprine were maintained. The gentleman felt encouraged by the improvement in his vision, especially in the left eye. BCVAs were found to be: OD 6/12+2 (20/40+2) and OS 6/7.5- (20/25-). Both eyes demonstrated a complete resolution of the serous retinal elevations, with fully normalized foveal contours and central subfield values within normal limits (Figs. 15, 16). Recent medical assessment by his family physician did not yet reveal any systemic VKH markers. At the six month follow-up after several months on treatment with

TREATMENT AND FOLLOW-UP The patient was started on topical atropine 1.0% b.i.d. OU and prednisolone acetate 1.0% for his anterior uveitis and referred to a retinal subspecialist, who prescribed oral prednisone 50 mg and azathioprine (Imuran®) 50 mg for the VKH choroiditis and conducted appropriate follow-up. The next available optometric follow up was in three weeks’ time. Following upon treatment with oral medications, his best-corrected visual acuities (BCVAs) were now found to be: OD 6/18-3 (20/60-3) and OS 6/9 (20/30). SLE demonstrated white conjunctivae and no discernable anterior chamber activity, OU. Dilated

Vogt-Koyanagi-Harada Syndrome: A Case Study — Ferguson

Fig. 11 OCT thickness map data for the right eye three weeks posttreatment. Note that the outer inferior EDTRS subfield (306 m) is less than half of the thickness at initial presentation (725 m).

Fig. 12 Horizontal B- scan of the right macula showing residual subretinal space and normalized foveal contour.

Fig. 13 Cirrus OCT thickness map data for the left eye three weeks’ post-treatment.

Fig. 14 Left macular B-scan demonstrates a residual subtle subfoveal neurosensory elevation.

Fig. 15 Right eye two months post-treatment. Central subfield is normalized at 220 microns.

Fig. 16 Left eye two months post-treatment. Central subfield is normalized at 235 microns.

cyclosporin 100 mg b.i.d. in addition to azathioprine 50 mg b.i.d., the BCVAs were improved to: OD 6/6-2 (20/20-2) and OS 6/6-4 (20/20-4).

The first attempt to establish diagnostic criteria for Vogt-Koyanagi-Harada disease occurred in 1978 at the annual meeting of the American Uveitis Society. The VKH patient must not have had any previous ocular trauma or surgery and must have at least one clinical finding from the following group of signs: 1) bilateral chronic iridocyclitis; 2) posterior uveitis, including exudative retinal detachment; 3) pigmentary posterior pole changes known as, ‘sunset glow’ fundus; 4) neurological symptoms of tinnitus, stiff neck, headache, or cerebrospinal fluid pleocytosis (elevated leukocyte count); and 5) dermatological signs such as vitiligo, poliosis, or alopecia13 (Table II). Some researchers have tended to use the term, ‘Harada’s disease’ to describe ocular findings of VKH with an absence of neurological

DISCUSSION VKH syndrome was first described by a Persian physician (Ali-ibn-Isa 940-1010A.D.) who reported poliosis in association with inflammation of the eyes.12 Schenkl reported this association again in 1873, and in 1892 by Hutchinson. These disorders described in greater detail by Vogt, Koyanagi and Harada were combined by Babel in 1932, who suggested that these medical signs were manifestations of the same disease process. Since then, the uveomeningo-encephalitic disorder has come to be known as Vogt-Koyanagi-Harada syndrome.

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Table II Differential diagnosis of VKH Sympathetic ophthalmia Posterior scleritis Uveal effusion syndrome Sarcoidosis Primary intraocular B-cell lymphoma

and cutaneous markers, as was observed in the case study of this paper. The use of this term, along with, ‘incomplete’ or ‘atypical’ VKH is gradually becoming discouraged as VKH becomes better defined and recognized in the medical literature. As integumentary changes are expected to be a latter-course sign of VKH, it was not unusual for this study’s patient to initially present without them. Ocular findings within 3 to 4 weeks from the acute stage of clinical presentation are of particular importance in VKH. A patient’s visual acuity at one month’s posttreatment has been shown to be a strong predictor of long-term VA following treatment. Eyes with VA better than 6/60 (20/200) at one month were shown to maintain at least 6/12 (20/40) acuity after three years.14 In this study, VA at three weeks’ post-treatment was: OD 6/18-3 (20/60-3) and OS 6/9 (20/30), implying a favorable long-term prognosis. Visual outcomes have improved over recent years with the combination of oral corticosteroids and immunosuppressants such as azathioprine. By inhibiting purine formation and therefore DNA synthesis, azathioprine stalls the formation of fastgrowing T-cells and B-cells that are implicated in autoimmune disorders. VKH over the long term will manifest a bilaterality in flare-ups of both anterior uveitis and choroiditis. Independent from these unpredictable events, the posterior pole over time will demonstrate pigmentary changes that can be unique to VKH. Generalized RPE clumping, as an example of a less specific sign, was observed in this case study some three months after initial presentation (Fig. 17). The Sugiura sign, or ‘sunset glow fundus,’ is unique to VKH,15 and is a form of depigmentation that presents as a kind of ‘ocular vitiligo.’ It is expected to emerge after several years subsequent to initial diagnosis. Another generalized pigmentary finding is nummular hypopigmented choroidal scars that are erroneously referred to as Dalen-Fuchs nodules. Despite the implementation of new treatment protocols, slightly more than half of the patients who present with acute phase signs of VKH still proceed to develop chronic disease.16 Whereas acute phase patients may manifest systemic findings of auditory and CNS anomalies, chronic or recurrent phase findings of vitiligo (patchy skin hypopigmentation) and poliosis (hypopigmentation of hair, eyebrows, and eyelashes) are more typical. One study uncovered a connection between the

Fig. 17 Diffuse pigmentary clumping changes emerging in the right eye three months after initial presentation.

emergence of vitiligo and visual field loss secondary to chorioretinal degeneration.14 Due to the necessity of systemic corticosteroid use, VKH patients also face the possibility of visual field loss as a comorbidity secondary to glaucoma. Recurrent panuveitic events over the long term constantly predispose the VKH patient to reduced acuity due to macular edema. VKH in fact can be a relentless autoimmune condition in over half of affected individuals with eventual vision loss due to subretinal fibrosis, choroidal neovascular membranes, epiretinal membrane, pigmentary degeneration, and chorioretinal atrophy.17 The recent emergence of effective VEGF blockade therapy has helped reduce vision loss as a complication of choroidal neovascular membrane formation, and the judicious use of immunomodulatory drugs such as azathioprine has been shown to preserve vision in relentless VKH cases. A commonly accepted treatment protocol for acute phase VKH or for a patient naïve to the condition is highdose oral corticosteroids followed by a slow tapering over a 3 to 6 month period. Immunosuppressive medications are sometimes used as adjunct therapies, or if the patient demonstrates intolerance or resistance to oral steroids. The goal in acute treatment is to gain control of the regions of inflammation and minimize complications. Long-term treatment strategy focuses on intermittent control of flare-ups, with almost no data in the literature detailing how VKH responds over extended time lines. Whether therapy involves topical, oral, or intravenous corticosteroids, cyclosporine, antimetabolites, and alkylating agents, the most efficacious treatment with the least long-term risk of complications is yet unknown.2

CONCLUSION Vogt-Koyanagi-Harada syndrome is a multisystem autoimmune disorder that challenges health care

Vogt-Koyanagi-Harada Syndrome: A Case Study — Ferguson

providers on virtually every continent to provide an accurate assessment of signs and symptoms, thereby enabling prompt topical and systemic treatment. Although the clinical picture of VKH is well established, little is known about its pathogenesis. At the point of acute onset presentation, slit lamp examination to uncover anterior chamber findings is essential, and Optical Coherence Tomography can demonstrate a powerful clinical utility by harmonizing retinal architecture findings with functional visual acuity. As vision improves in response to therapy, there is a corresponding quantifiable change in the retinal tissues. The optometrist and ophthalmologist is well-advised to educate his or her patient concerning the longterm probability of repeated flare-ups of iritis and/or choroiditis. The patient in this study had been seen on repeated occasions following initial diagnosis, and is likely expected to present in the future with complaints of bilateral red eyes and photophobia over the long term. Clinically, there is evidence supporting the concept of ongoing choroidal inflammation even after high-dose corticosteroid therapy followed by apparent ocular quiescence. This implies that initial therapy may not be sufficient to completely eradicate choroidal inflammation in a significant percentage of patients. Adequate optometric management of the VKH patient over time necessitates timely communication with both the family doctor and retinal subspecialist as the disease moves forward. ❏

3. 4.

5. 6. 7.

8. 9. 10. 11. 12. 13. 14. 15.

REFERENCES 1. 2.

Moorthy RS, Inomata H, Rao NA, et al. Vogt-KoyanagiHarada syndrome. Surv Ophthalmol 1995; 39(4): 265-292. Read, RW, Holland, GN, Rao, NA, et al. Revised diagnostic criteria for Vogt-Koyanagi-Harada disease: report of an international committee on nomenclature. Am J Ophthalmol 2001; 647-652.

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16. 17.

Jaggarao N, Voth D, Jacobsen J. The Vogt-KoyanagiHarada syndrome: Association with hypothyroidism and diabetes mellitus. Postgrad Med J 1989; 65: 587-588. McCannel CA, Holland GN, Helm CJ, et al. Causes of uveitis in the general practice of ophthalmology. UCLA Community-Based Uveitis Study Group. Am J Ophthalmol 1996; 121: 35-46. Shimizu K. Harada’s, Behcet’s, Vogt-Koyanagi syndromes—are they clinical entities? Trans Am Acad Ophthalmol Otolaryngol 1973; 77: OP281-OP290. Rathinam SR, Namperumalsamy P, Nozik RA, Cunningham ET. Vogt-Koyanagi-Harada syndrome after cutaneous injury. Ophthalmology 1999; 106: 635-638. Bassili SS, Peyman GA, Gebhardt BM, et al. Detection of Epstein-Barr virus DNA by polymerase chain reaction in the vitreous from a patient with Vogt-Koyanagi-Harada syndrome. Retina 1996; 16: 160-161. Beniz J, Forster DJ, Lean JS , Smith RE, Rao NA. Variations in clinical features of the Vogt-Koyanagi-Harada syndrome. Retina 1991; 11: 275-280. Nussenblatt RB, Palestine AG. The Vogt-Koyanagi-Harada syndrome (uveomeningitic syndrome). In: Ryan SJ, ed. Retina, 2nd ed. St Louis: Mosby, 1994: 1737-1743. Oshima Y, Harino S, Hara Y. Indocyanine green angiographic findings in Vogt-Koyanagi-Harada disease. Am J Ophthalmol. 1996; 122: 58-66. Vasconcelos-Sanos DV, Sohn EH, Sadda S, et al. Retinal pigment epithelial changes in chronic Vogt-KoyanagiHarada disease. Retina 2010; 30(1): 33-41. Pattison EM. Arch Neurol 1965; 12: 197-205. Snyder DA, Tessler HH. Vogt-Koyanagi-Harada syndrome. Am J Ophthalmol 1980; 90: 69-75. Soon-Phaik C, Aliza J, Bacsal K. Prognostic Factors of Vogt-Koyanagi-Harada Disease in Singapore. Am J Ophthalmol 2009; 147: 154-161. Inomata H, Rao NA. Depigmented atrophic lesions in sunset glow fundi of Vogt-Koyanagi-Harada disease. Am J Ophthalmol 2001; 131: 607-614. Chee SP, Jap A, Bacsal K. Spectrum of Vogt-KoyanagiHarada disease in Singapore. Int Ophthalmol 2007; 27: 137-142. Bykhovskaya I, Thorne JE, Kempen JH, Dunn JP, Jabs DA. Vogt-Koyanagi-Harada disease: clinical outcomes. Am J Ophthalmol 2005; 140(4): 674-678.

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QUESTIONNAIRE Vogt-Koyanagi-Harada Syndrome: A Case Study Len Ferguson, OD 1. ❑ ❑ ❑ ❑

Which of the following profiles best describes an individual suffering from Vogt-Koyanagi-Harada (VKH) syndrome? Japanese male Israeli female Caucasian female African-American male

2. ❑ ❑ ❑ ❑

All of the following are indications of VKH syndrome, EXCEPT: Poliosis Vitiligo Lupus erythematosus Alopecia

3. ❑ ❑ ❑ ❑

In VKH syndrome, ocular signs and symptoms can be preceded by all of the following, EXCEPT: Aseptic meningitis Tinnitus Headache Migraine with aura

Vogt-Koyanagi-Harada Syndrome: A Case Study — Ferguson

All of the following statements about VKH syndrome are true, EXCEPT: Its primary ocular pathogenesis is thought to involve the choroid Retinal involvement is minimal Autoimmune disorder accounts for 75% of cases Posterior uveitis is characteristic of the condition

5. ❑ ❑ ❑ ❑

The patient in this Case Report initially presented with all of the following signs and symptoms, EXCEPT: Ocular redness Diplopia Floaters Photophobia

6. ❑ ❑ ❑ ❑

In the Case Report presented, the patient’s first clinical assessment revealed all of the following, EXCEPT: Elevated intraocular pressure OU Bilateral circumferential conjunctival hyperemia Grade 2+ anterior uveitis Normal extraocular muscle movements

7. ❑ ❑ ❑ ❑

In the Case Report presented, what were the patient’s best-corrected visual acuities? 6/4 (20/15) OU 6/18-3 (20/60-3) OD; 6/9 (20/30) OS 6/12 (20/40) OU 6/15 (20/50) OU

8. ❑ ❑ ❑ ❑

The patient in this Case Report was treated with all of the following, EXCEPT: Atropine 1.0% b.i.d. OU Latanoprost 0.005% OS Prednisolone acetate 1.0% Azathioprine 50 mg

9. ❑ ❑ ❑ ❑

All of the following statements about VKH syndrome over the long term are true, EXCEPT: It may be accompanied by bilateral flare-ups of anterior uveitis Generalized retinal pigment epithelial (RPE) clumping may occur It may be accompanied by “sunset glow” fundus Once symptoms have resolved, choroiditis is unlikely to recur

10. Treatment of acute-phase VKH for a patient naïve to the condition typically involves all of the following, EXCEPT: ❑ Ribavirin 200 mg t.i.d. ❑ High-dose oral corticosteroids ❑ Immunosuppressive agents ❑ Intravenous corticosteroids

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Clinical & Refractive Optometry is pleased to present this continuing education (CE) article by Dr. Leonid Skorin Jr., Dr. Jennifer Keller and Dr. Gary Jernberg entitled Ocular and Oral Mucous Membrane Pemphigoid: An Intimate Association. In order to obtain a 1-hour Council of Optometric Practitioner Education (COPE) approved CE credit, please refer to page 21 for complete instructions.

Ocular and Oral Mucous Membrane Pemphigoid: An Intimate Association Leonid Skorin Jr., OD, DO, MS, FAAO, FAOCO Jennifer Keller, OD; Gary Jernberg DDS, MS

ABSTRACT Mucous membrane pemphigoid (MMP) is a multi-organ system disease affecting any mucous membrane within the body. The ocular and oral structures are commonly affected, either individually or simultaneously. Ocular manifestations include symblepharon and corneal keratinization. Oral involvement includes painful blisters and bleeding gingiva. We present two cases of ocular mucous membrane pemphigoid which each initially presented with oral lesions. These cases highlight the importance of a thorough case history and multi-system awareness for non-specific conjunctivitis symptoms. It also demonstrates the importance of multidisciplinary cooperation to arrive at an appropriate diagnosis and management of MMP.

INTRODUCTION Mucous membrane pemphigoid (MMP) is an autoimmune disease characterized by autoantibody deposition to the basement membrane zone (BMZ) of mucous membranes and skin. All mucous membranes are subject to mucocutaneous blisters, but common sites include the oral cavity, conjunctiva, nose, respiratory tract, and gastrointestinal tract. MMP can remain relatively mild if limited to oral and nasal mucosa. However, life threatening complications can exist if these vesicular lesions extend to the respiratory tract.1,2 L. Skorin, Jr. — Consultant, Community Division of Ophthalmology, Mayo Clinic Health System, Albert Lea, MN; Assistant Professor of Ophthalmology, Mayo Clinic College of Medicine, Rochester, MN; J. Keller — Vision Source Park Rapids & Walker Eye Clinics, Park Rapids, MN; G. Jernberg — Private practice limited to periodontics, Mankato, 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 any of the material mentioned in this article. This article has been peer reviewed.

Ocular involvement is present in 80% of patients with MMP.1 It traditionally presents in the older population between 60 and 70 years old. Ocular MMP is progressive in nature causing cicatrization of conjunctival tissue, keratinization of the cornea, and scarring of the tissues. Due to the rareness of the disease (1 in 20,000) it is often overlooked and consequently treatment is put off until further into the disease process.3 If left untreated, blindness can occur. It has been found that 45.5% of patients who had oral and ocular disease remained undiagnosed for more than 12 months.4 Due to the high risk of blindness from ocular complications of MMP, once ocular signs become present immunosuppressive drug therapy is indicated.1,5

CASE REPORT 1 A 75-year-old female presented with a chief concern of her left lower eyelid turning inward and rubbing against her eye (Fig. 1). She had a history of spastic entropion which was relieved with botulinum toxin injections into the orbicularis oculi muscle of her left lower eye lid. She reported sharp pain, redness and photophobia in her left eye. She had a longstanding severe amblyopia in the right eye. Upon further investigation, she also stated that she had recently developed problems with her gums, including pain and bleeding of her gingiva. Her presenting visual acuities were 6/122 (20/400) in the right eye and 6/6 (20/20) in the left eye. Her pupils were equal, round and reactive to light, with no afferent pupillary defect. Examination of the anterior segment of her left eye revealed symblepharon formation of the

Fig. 1 Entropion of the left lower eyelid.

Ocular and Oral Mucous Membrane Pemphigoid — Skorin et al

Fig. 2 Symblepharon formation between palpebral and bulbar conjunctiva of the left lower lid.

Fig. 3 High magnification photo of symblepharon.

palpebral conjunctiva to the bulbar conjunctiva (Figs. 2, 3). Her left lower eyelid was also turning inward on itself, suggesting entropion. Her cornea was clear with no defects. All other ocular structures of the anterior segment were within normal limits. All structures of her anterior segment of her right eye were normal. The posterior segments of both of her eyes were unremarkable. We referred our patient to an oral and maxillofacial surgeon for a biopsy of her gingival. Tissue samples were taken from her left lower anterior gingiva. Pathologic investigation showed a linear deposition of IgG and C3 at the basement membrane zone, as well as scattered IgM and IgA in the submucosal areas. The results were suggestive of mucous membrane pemphigoid. She was started on medical therapy of 40 mg prednisone by mouth once per day and 1000 mg of mycophenolate mofetil by mouth twice a day. Since this patient had severely reduced vision in her right eye due to amblyopia, and her ocular symptoms from mucous membrane pemphigoid were manifesting in her left eye, she was instructed to remain on the medication until her ocular and oral symptoms became stable.

predominantly plasmocytic inflammation, necrosis and increased vascularity (Fig. 4). These findings suggested possible benign mucous membrane pemphigoid. The patient was referred to ophthalmology for ophthalmic evaluation. The patientâ&#x20AC;&#x2122;s chief ocular concern was watery eyes. The findings from his previous ocular exams were unremarkable. His presenting visual acuities were 6/6 (20/20) in the right eye and 6/7.5 (20/25) in the left eye with habitual correction. His pupils were equal, round, and reactive to light with no afferent pupillary defect. His confrontation fields were full to finger count. His ocular pressures were 14 mmHg in both eyes. Biomicroscopic examination of the anterior segment of both his eyes was unremarkable, revealing no symplepharon, hyperemia, trichiasis or blepharitis. A Schirmers tear test measured 7 mm in the right eye and 13 mm in the left eye. His tear beak-up time measured 5 seconds in the right eye and 7 seconds in the left eye. Funduscopic examination of his posterior segment was unremarkable. The patient was diagnosed with MMP based on the previous biopsy, with no evidence of ocular involvement. He was also diagnosed with dry eye syndrome. He was given Blink and Soothe artificial tears and instructed to use them two to four times a day to reduce dry eye symptoms and to sufficiently lubricate the ocular tissues to prevent any keratinization. The patient was instructed to return to the clinic if the dry eye symptoms persisted. Otherwise he was scheduled for annual medical eye examinations.

CASE REPORT 2 A 65-year-old male presented to his periodontist with complaints of painful oral lesions which had been persistent for one month. He reported that approximately two weeks after his oral lesions appeared, lesions also appeared on his forearms. After clinical investigation, it was determined the oral lesions were ulcerated gingiva throughout the maxillary and mandibular region. The lesions were biopsied and sent to an oral pathologist. The results from pathology revealed partially ulcerated mucosal fragments. The epithelium of the sample was characterized by spongiosis and exocytosis with focal vacuolar degeneration suggesting an intense chronic

Clinical and Refractive Optometry 28:1, 2017

OCULAR MANIFESTATIONS Patients with ocular MMP typically present with a nonspecific conjunctivitis including redness, foreign body sensation, epiphora, and decreased vision. The chronic

Fig. 4 Gingival biopsy demonstrating splitting of basement membrane. Photo courtesy of Michael D. Rohrer DDS, MS

Fig. 5 High-magnification photo of gingival tissue biopsy showing high concentration of lymphocytes, trace eosiniphils and neutrophils. Photo courtesy of Michael D. Rohrer DDS, MS

inflammatory nature of the disease causes fibrotic changes to the conjunctival tissue, lids, and cornea. Conjunctival changes result in fornix shortening, flattening of the plica and keratinization of the caruncle, and symblepharon formation. Lid involvement includes meibomian and lacrimal duct obstruction, trichiasis, blepharitis, sicca syndrome, and ankyloblepharon. Detrimental damage to the cornea results in mechanical abnormalities of the lids causing exposure as well as general dryness. Damage to the limbus causes stem cell destruction exposing the vulnerable cornea to keratinization and vascularization. End-stage ocular MMP is characterized by a complete symblepharon between bulbar and palpebral conjunctiva with extensive corneal opacification.5

ORAL MANIFESTATIONS OF MMP The oral mucosa is often the first site affected by MMP, most commonly presenting as desquamative gingivitis. If the lesions remained isolated to the mouth, the disease tends to have a less severe systemic course.6 The patient will typically present with pain, dysphagia, and peeling of the oral mucosa. Painful blisters may present on any mucosal surface within the oral cavity. These blisters often rupture, leaving behind irregular scar tissue on the gingiva, lips, or inner lining of the mouth.

to the inflamed tissue, taking care to avoid causing any additional scar tissue. Pathologic examination will exhibit a loss of epithelium of the tissue, causing separation of the basement membrane from underlying tissue (Fig. 4). This split of histological layers will cause a deposition of eosinophils, lymphocytes and neutrophils in the lamina propria, which indicate the presence of both acute and chronic inflammation6 (Fig. 5). A direct immunofluorescence assay will show a linear deposit of IgG and C3 along the basement membrane zone.

RELATIONSHIP BETWEEN ORAL AND OCULAR MMP The multi-system nature of mucous membrane pemphigoid emphasizes the need to understand what organ systems are most commonly affected. According to a recent study by Thorne et al., in patients that presented with nonocular involvement, the oropharynx (90.2%) was the most commonly affected site and upon further investigation, the conjunctiva (60.1%) was also found to be affected.1 For those patients who had ocular MMP at presentation, other non-ocular involvement such as the oropharynx was involved up to 82.4% of the time.1 These findings demonstrate the close nature of MMP between the oral and ocular structures. Patients that presented with oral MMP only, had a 4% per year risk of developing ocular involvement, indicating the importance of routine follow-up by eye care professionals.1

DIAGNOSIS There are many other diseases that can mimic MMP including pseudopemphigoid, lichen planus, erythema multiforme, and systemic lupus erythematosus. The only way to definitively diagnose MMP is with a biopsy and histopathological investigation of any blistering lesion. The best technique to acquire a sample is to biopsy a vesicle while avoiding any eroded tissue. If multiple lesions are present, it is best to take samples adjacent

TREATMENT OF MMP Treatment of MMP can be very challenging. Patients with MMP tend to be older making their immune system more vulnerable to inflammatory disease. Secondly, diagnosis of MMP is often delayed. This results in the disease often being identified in an advanced state which requires aggressive, long term systemic immunosuppressant therapy. Lastly, the immunosuppressant agents used for treatment

Ocular and Oral Mucous Membrane Pemphigoid â&#x20AC;&#x201D; Skorin et al

have many significant side effects. In some cases the risk of the medication alone is enough to deter the patient from therapy.3 Treatment of MMP should not be taken lightly, and it is important to have a way to assess if the disease is progressing or remitting. Rowsey, Macias-Rodriguez and Cukrowski have developed a method of measuring the conjunctiva to monitor the progression of MMP.7 They suggest pulling down the lower lid until there is enough traction on the globe for it to move downward. The measurement is taken (in millimeters) from the lower limbus to the posterior edge of the retracted eyelid. Three measurements should be taken in three different positions of gaze; one with the patient looking directly up, one looking up and to the right, and one looking up and to the left. The average measurement of a normal conjunctiva at each of these measurements is 15 mm. The study suggests summing the three measurements (normal would be 45 mm). If a patient loses a cumulative of 3 mm compared to a previous visit, it is suggestive of disease progression and manipulation of medical therapy may be warranted. Topical treatment for ocular MMP has been shown to be ineffective at controlling the disease process, thus requiring systemic immunosuppressive drug therapy. The preferred therapy of MMP is an initial combination therapy of 2 mg/kg/day cyclophosphamide and 1 mg/kg/day of oral predisone, followed by a tapering of the prednisone over three to four months and maintaining cyclophosphamide for 12 to 18 months. This method of treatment has been successful in controlling the disease progression as well as creating drug-free remissions of MMP.2 Other systemic immunosuppressant medications used for MMP therapy include dapsone, methotrexate, and mycophenolate.

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These immunosuppressant agents can have serious side effects. Cyclophosphamide most commonly causes leukopenia, but can also induce thrombocytopenia, hemorrhagic cystitis, liver toxicity, meningitis, and secondary malignancies.2,3 Prednisone also has side effects including hypertension, gastrointestinal hemorrhages, myocardial infarction, and other very serious complications. Thorne et al. found that with full consent of complications of therapy, 98% of patients with ocular MMP still chose to be treated with this therapy.1 Careful observation of potential drug-induced side effects and co-management with the primary care physician, ophthalmologist, and dentist are critical to maintain sight, decrease morbidity, and adjust therapy as needed. â??

REFERENCES 1. 2. 3.

5. 6. 7.

Thorne J, Anhalt G, Jabs D. Mucous membrane pemphigoid and pseudopemphigoid. Ophthalmology 2003; 111: 45-52. Thorne J, Woreta F, Jabs D, et al. Treatment of ocular mucous membrane pemphigoid with immunosuppresive drug therapy. Ophthalmology 2008; 115: 2146-2152. Miserocchi E, Balatzis S Roque M, et al. The effect of treatment and its related side effects in patients with severe ocular cicatricial pemphigoid. Ophthalmology 2002; 109: 111-118. Higgins G, Allan R, Hall R, et al. Development of ocular disease in patients with mucous membrane pemphigoid involving the oral mucousa. Br J Ophthalmol 2006; 90: 964-967. Kanski JJ. Clinical Ophthalmology: A Systematic Approach. 6th ed. Butterworth Heinemann, 2007: 235-237. Scully C, Muzio L. Oral mucosal disease: mucous membrane pemphigoid. Br J Oral Maxillofacial Surgery 2008; 46: 358-366. Rowsey J, Macias-Rodriguez Y, Cukrowski C. A new method for measuring progression in patients with ocular cicatricial pemphigoid. Arch Ophthalmol 2004; 122: 179-184.

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QUESTIONNAIRE Ocular and Oral Mucous Membrane Pemphigoid: An Intimate Association Leonid Skorin Jr., OD, DO, MS, FAAO, FAOCO; Jennifer Keller, OD; Gary Jernberg, DDS, MS 1. ❑ ❑ ❑ ❑

In what percentage of patients is there ocular involvement with mucous membrane pemphigoid (MMP)? 40% 60% 75% 80%

2. ❑ ❑ ❑ ❑

Which of the following patient profiles best describes an individual with MMP? 25-year-old male 30-year-old female 65-year-old female 80-year-old male

3. ❑ ❑ ❑ ❑

In what percentage of patients with oral and ocular MMP is diagnosis delayed for more than one year? 25% 45.5% 60% 75%

Ocular and Oral Mucous Membrane Pemphigoid — Skorin et al

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In Case Report 1, the patient initially presented with all of the following symptoms, EXCEPT: Hyperlacrimation Redness Sharp pain Photophobia

5. ❑ ❑ ❑ ❑

In Case Report 2, what were the patient’s presenting visual acuities? 6/6 (20/20) OD; 6/7.5 (20/25) OS 6/9 (20/30) OD; 6/6 (20/20) OS 6/4.5 (20/15) OD; 6/9 (20/30) OS 6/12 (20/40) OD; 6/7.5 (20/25) OS

6. ❑ ❑ ❑ ❑

In Case Report 2, which of the following was the patient’s primary complaint? Photophobia Migraine Watery eyes Sharp pain

7. ❑ ❑ ❑ ❑

All of the following are characteristics associated with ocular MMP, EXCEPT: Decreased vision Foreign body sensation Dry eye Epiphora

8. ❑ ❑ ❑ ❑

All of the following are oral manifestations of MMP, EXCEPT: Peeling of the oral mucosa Dysphagia Pain Abscess

9. ❑ ❑ ❑ ❑

All of the following diseases can mimic MMP, EXCEPT: Lichen planus Erythema multiforme Pseudopemphigoid Herpes simplex

10. ❑ ❑ ❑ ❑

What amount of cumulative loss of conjunctiva compared to a previous visit indicates progression of MMP? 1 mm 2 mm 3 mm 4 mm

28:1, 17

4. ❑ ❑ ❑ ❑

Clinical and Refractive Optometry 28:1, 2017

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Clinical & Refractive Optometry is pleased to present this continuing education (CE) article by Dr. David P. Sendrowski and Dr. Robert W. Lingua entitled Common Ocular Disorders in the Pediatric Population. In order to obtain a 1-hour Council of Optometric Practitioner Education (COPE) approved CE credit, please refer to the page 30 for complete instructions.

Common Ocular Disorders in the Pediatric Population David P. Sendrowski, OD, FAAO; Robert W. Lingua, MD

ABSTRACT While most young children and infants are referred to the eye care physician with isolated ophthalmic problems for assessment and possible treatment, a smaller percentage will harbor serious ocular pathology which may be associated with co-existing systemic or neurologic abnormalities. Infant and early childhood development can be profoundly influenced by disorders of the visual system. The eye care physician should be aware of these common ocular pathologies for potential treatment options and urgency of referral if required by the condition. The attention span of both infants and young children is quite limited and the eye care physician must conduct and accurate examination for these ocular disorders in a relatively brief period of time. Special exam techniques which are of particular importance and use in the diagnosis and management of these ocular disorders are discussed in this article.

INTRODUCTION Primary eye care physicians address ocular disease disorders in the adult population on a routine basis in their offices. Far less commonly, the pediatric ocular disease presents and may give concern of an ocular disorder which may be a harbinger of a more serious condition and that should not be missed on examination. Subjective tests routinely utilized in the adult exam may be difficult to perform or unreliable in pediatric patients. Additionally, a D.P. Sendrowski — Full Professor/Chief of Service, Ophthalmology Consultation/Chronic Care Service, Marshall B. Ketchum University, Southern California College of Optometry, Fullerton, CA; R.W. Lingua — Clinical Professor in Ophthalmology, Gavin Herbert Eye Institute, University of California, Irvine, CA Correspondence to: Dr. David P. Sendrowski, Marshall B. Ketchum University, Southern California College of Optometry, 2575 Yorba Linda Boulevard, Fullerton, CA 92831-1699; E-mail: dsendrowski@ketchum.edu The authors have no financial or proprietary interest in any of the material mentioned in this article. This article has been peer reviewed.

child’s ability to maintain concentration for only brief periods of time compounds the difficulty of making an accurate diagnosis. The collaborative article you are about to read reviews common ocular disorders that the eye care physician may encounter within the pediatric population. Common pitfalls the practitioner may face and the decision-making process one might utilize with this particular patient population will also be discussed.

INFECTIONS OF THE EYE AND ANTERIOR ADENEXA Red eye is by far one of the more common reasons for the first encounter between a pediatric patient and an eye care physician. Conjunctivitis is a very common ocular disease in this patient population. The Weiss Study from 1993 was an excellent overview of pediatric conjunctivitis.1 Although some pathogens have changed, for the most part 80% of conjunctivitis in the pediatric population is bacterial while only 13% was shown to be of viral origin. The remaining etiologies were allergic and chemical in nature. Practitioners should examine the lower cul-de-sac for signs of injection, as well as the presence or absence of discharge, and/or foreign bodies. Bacterial infections produce a yellowish-green discharge while viral infections produce a more watery type. Both types of infections (viral and bacterial) can cause lid swelling and the lids to be glued shut upon awakening. Adenoviral infections can also be accompanied by a tender swelling of the lymph nodes in front of the ear (pre-auricular adenopathy). Cat-scratch fever (leptospirosis) following singular or multiple infected cat claw injuries can be a common cause of ocular glandular syndrome in young children.2 Examination of the back of the hands and arms for the development of pustules near the site of a cat scratch can be extremely diagnostic.3 Bacterial pathogens most commonly encountered today are streptococcal, staphylococcal, and moraxella in species types.4 Therefore, the physician must keep the treatment geared toward gram positive coverage when choosing a topical medication. Viral infections more commonly fall into the adenoviral variety which may be associated with a concurrent or antecedent upper

Common Ocular Disorders in the Pediatric Population — Sendrowski, Lingua

respiratory infection.5 Examination may reveal an inferior palpebral follicular reaction which is consistent with the viral pathogen. Fluorescein staining is an essential part of any conjunctivitis workup, especially in those considered viral, to rule out active Herpes virus keratopathy. If suspicion is high, start the patient on an oral acyclovir suspension, and refer for further testing. A majority of bacterial infections respond extremely well to topical fourth generation fluoroquinolones which have the added advantage of less frequent administration and shorter duration of use (i.e., moxifloxacin, azasite, gatifloxacin). Older topical antibiotics can still be used as there is a tendency toward low morbidity of conjunctivitis and many pathogens are still responsive to these older antibiotic preparations (i.e., Polysporin, erythromycin and polytrim). Insurance providers and uninsured patients may request a cheaper drug alternative. Viral infections are usually self-resolving requiring the need for symptomatic relief rather than therapeutic intervention. Non-preserved artificial tears kept in a cool place and cool compresses are commonly utilized for this task. For the more symptomatic patient, topical nonsteroidal anti-inflammatory medications (NSAIDs) can be applied sparingly, as excessive use has been reported to cause corneal melt. One caveat the physician should remember is that adenoviral infections easily transfer to other members of the family especially siblings. Hand washing, especially before and after eye drop administration, is recommended.5 Caution should be given to the parent regarding the sharing of pillows, towels and items that may have the potential for eye contact with other family members. Reduction of community spread is accomplished by restricting the child from school, community, or family activities where spreading might occur. Allergic agents are numerous but when encountered in the pediatric population, they are commonly seen in the spring and fall. Ocular tissues are less injected and inflamed as with bacterial and viral infections, and knuckle rubbing by the child is more commonly seen than in the adult, along with the complaint of itching. Conjunctival chemosis may also be more prominent in these cases. Treatment of allergic conjunctivitis is best achieved with the use of topical combination medications (i.e., Pataday, Lastacaft and Bepreve) for ease of use and rapid reduction of ocular itch and conjunctival chemosis. When resistant to topical mast cell-antihistamine combinations, topical steroids may be required for symptomatic relief in advanced vernal conjunctivitis, and to avoid formation of shield ulcers.6 Phlectenular disease, which was relatively common when tuberculosis was prevalent, is uncommon in developed countries like the United States.7 Children still bear the burden of the patient population that will develop

Clinical and Refractive Optometry 28:1, 2017

phlectenular disease from severe staphylococcus lid infections. The disease delineates itself as a unilateral conjunctival inflammation with an elevated nodule in the interpalpebral area of the conjunctiva or cornea. The nodule is very responsive to topical corticosteroid therapy and represents a classic type IV delay hypersensitivity (Gell-combs) reaction.7 Chemical conjunctivitis is commonly associated with a history of swimming pool use. Most often, the inferior half of the eye is red and injected while the upper half is spared. This is probably a result of pooling of the chlorine into the inferior cul-de-sac location. A common pitfall by the examiner is to disregard the cornea evaluation or staining which in some cases may reveal “corneal burn” if extensive chemical contact has occurred. Mild chemical damage to the cornea may be managed with a combination approach of topical cycloplegics, antibiotics and NSAIDs. Without corneal involvement, chemical conjunctivitis is best healed with irrigation via cool, non-preserved artificial tears kept in a cool location such as a pantry or refrigerator. In cases of punctuate epithelial keratitis, topical ointment is preferred for the first 48 hours. Finally, a group of conjunctividies occurring after birth commonly referred to as “ophthalmia neonatorum” requires mentioning. The most common method of prophylaxis is instillation of erythromycin ointment at birth.8 Pathogens that may encounter the eye during passage through the birth canal include neisseria gonorrhea, chlamydial trachomatis and herpes simplex virus.8 These ocular infections arise within the first several days to months after birth, however, as in the case of chlamydia, may present later and if untreated, may lead to a serious chlamydial pneumonitis. They commonly appear in the sequence that is stated above with neisseria gonorrhea being the earliest to manifest,7 but any suppurative conjunctivitis seen in the immediate post-natal period needs cultures, and referral is recommended for systemic involvement. All three pathogens should be tested for in a laboratory series. This should be requested by the eye care physician as part of the ocular work-up.

PEDIATRIC LID INFECTIONS After conjunctivitis, lid infections are the second most common type of periocular infections found in children. Acute hordeolum in children presents suddenly and is very elusive as to the causative pathogen.9 Hordeolum usually increases rapidly over several days. Tender to palpation and localized inflammation in the lid gives the physician excellent physical clues to the etiology to a single infected sebaceous gland. Aggressive use of warm compresses and topical antibiotics (i.e., azithromycin) or antibiotic/steroid combination for reduction of inflammation is commonly utilized as the first therapeutic

Fig. 1 Six-year-old male with early right orbital cellulites secondary to streptococcal infection of the upper respiratory system. Note early conjunctival edema and erythema.

Fig. 2 Five-month-old male with nasal lacrimal obstruction (NLO) causing mucopurulent discharge from inferior puncta. Orbit and lids remain uninvolved from the blockage at this time.

management.9 If the hordeolum fails to respond to hygiene and topical therapy, the patient can be started on systemic antibiotics with good soft tissue penetration (e.g., cephalexin). Due to the risk of progression to peri-orbital tissues or frank orbital cellulitis, failure to respond to oral agents within 48 hours requires prompt referral and the patient should be referred and set-up for incision and drainage of the lid lesion. A more worrisome and often feared infection is orbital cellulites (Fig. 1). The preseptal type is localized to the ocular tissues anterior to the orbital septum. Pediatric preseptal cellulitis is commonly associated with trauma to the lid tissues or a localized infectious/ inflammatory disease (i.e., sinusitis), the latter to a greater degree. The physician’s exams reveal a diffusely swollen and erythematous eyelid which is warm and tender to palpation. The child maintains good acuity and painless ocular motility. Pupils are normal to light response, and proptosis and fever are absent. One must always consider gram positive pathogens as the causative pathogen, making oral cephalosporins and fortified penicillins a first choice of therapeutic intervention by the practitioner. Infections that fail to respond to initial therapy require further laboratory and orbital image investigations, with modification to the therapeutic management being used to treat the infection (Fig. 1). Viral pathogens are less common but may also affect the lid. Herpes Simplex presents with acute swelling, erythema and vesicle eruptions on the eyelids.10 If the child is older they may report a tingling or tenderness to the affected lid area as well. Parent(s) should be queried about this symptom as well. Oral antivirals are commonly used as initial treatment. Once the clinical diagnosis is made, treatment should be initiated as soon as possible. The physician should always consider oral suspensions when treating pediatrics to make administration more tolerable for both patient and parent. Finally, human papilloma virus in the form of Molluscum contagiosum (MC) can also frequent the lid of the pediatric patient.11 These small, isolated umbilicated lesions are found along the periocular skin area. When

squeezed, a “cheesy” like substance manifests itself from the center of the lesion. If an MC occurs close to a lid margin, a follicular conjunctivitis can occur from dissemination of the molluscum bodies onto the ocular surface. Treatment of MC can be accomplished in several ways. The more common treatment options include: simple excision, incision and curettage, or cryosurgery. The patient is followed up every 2 to 4 weeks until the conjunctivitis resolves which often takes 4 to 6 weeks.11

NASOLACRIMAL DUCT OBSTRUCTION Children with congenital obstruction of the nasolacrimal duct (NLD) will present within the first few months of life with what appears to be bacterial conjunctivitis with a copious mucoid discharge. Frequently, the eyelids are matted shut upon awakening in the AM. With pressure on the nasolacrimal sac, a yellow discharge can be produced in evidence of distal obstruction (Fig. 2). Spontaneous opening of the obstruction (i.e., valve of Hasner) in the first year of life is common, and treatment in the interim consists of measures to prevent peri-orbital cellulitis. Frequent lid hygiene and topical antibiotics twice a day are recommended. Because of the long course of treatment, any topical steroid preparation is to be avoided due to the reported association with secondary glaucoma. Nasolacrimal duct obstruction may be partial, and the presenting complaint can be one of tearing whenever there is a condition that encourages evaporative ear loss, like fans, or when it is windy. If the obstruction does not clear spontaneously, surgical probing of the duct can be considered (Fig. 3); 1) urgently, in the presence of recurrent, severe peri-ocular cellulitis; or 2) electively, after one year of life, when the risks of anesthesia are less.

PEDIATRIC OCULAR TRAUMA The most common mechanism of injury in the pediatric population is blunt trauma. In one study, it accounted for 65% of emergency room admittances.12 Sporting activities were the more common cause of blunt trauma in the 5 to 14 year age group.12

Common Ocular Disorders in the Pediatric Population — Sendrowski, Lingua

Fig. 3 Inferior punctal dilation with lacrimal probe in a one-year-old infant. In the NLO patient, the procedure is done prior to opening the valve of Hasner with a Bowman probe.

Fig. 4 Sodium fluorescein stain (pooling) of a corneal abrasion from an unknown foreign body in a three-year-old patient.

In any history of trauma to the eye involving a fast moving object, penetration of the globe has to be presumed, until successfully ruled out, with a thorough dilated fundus exam. Innocent-appearing lacerations of the conjunctiva may be all that remain after penetration of the sclera with a sharp object. Corneal staining is first performed, followed by IOP determination and dilated indirect ophthalmoscopy. Imaging of the eye and orbit is suggested where penetration is suspected but unconfirmed by ocular exam. When there is evidence of globe penetration, the eye is shielded, followed by immediate referral to the ER.

will usually not tolerate procedures “in-office” and may require mild sedation in order to work on removing the foreign body without excessive eye or body movement.

TRAUMATIC CORNEAL ABRASION Topical antibiotics, either as an ointment (erythromycin) or drops (fluoroquinolones) every 2-4 hours, are sufficient. Some doctors choose to patch, while others choose to place a bandage contact lens. In either case, it is necessary to check the cornea daily until re-epithelialization is complete. If the abrasion was due to a tree branch or other plant matter, concern exists for fungal contamination, and ciprofloxin ointment every two hours is recommended.13 If the pediatric patient requires a contact lens (postsurgical), anti-pseudomonal coverage is important, and again, ciprofloxin ointment every two hours is needed. In the latter two cases, patching of the eye, creating an anaerobic environment, is discouraged. Oral suspension of ibuprofen can assist in pain control (Fig. 4). Corneal foreign bodies with a deep rust ring may require removal with a burr. If the foreign body is located within the visual axis and involves the corneal stroma, post removal scarring may be a serious and visually threatening complication. A referral for deep debridement and antibiotic prophylaxis along with judicious steroids may be best option for these patients. Pediatric patients

Clinical and Refractive Optometry 28:1, 2017

TRAUMATIC HYPHEMA If a complete (“eight ball”) eye presents, referral is suggested for hospitalization and consideration of surgical wash-out, and management of secondary iritis and glaucoma. In the case of minor anterior segment bleeding following trauma, much controversy still exists in regard to rest, patching and topical medications. The risk of an extensive, often greater re-bleed 3 to 4 days following trauma requires close monitoring in the office. It is difficult to differentiate floating blood cells from those due to anterior segment trauma and secondary iritis. Often in the presence of floating cells, treatment includes steroids empirically for 5 to 7 days. Atropine 1% daily is used to immobilize the pupil and discourage re-bleeding. Daily evaluation of IOP, anterior chamber reaction and blood level in the anterior chamber are required to prevent a vision threatening complication of hyphema in the first week of care. Once past the re-bleed risk period of five days, treatment continues on a less frequent basis until the chamber is clear and the pressure is normal. Angle recession glaucoma can follow blunt trauma and therefore gonioscopy and IOP check are recommended three months post injury.14

TRAUMATIC IRITIS Blunt injury to the eye or orbit may result in signs and symptoms of pain, redness, photophobia and tearing, all suggestive for traumatic iritis. Complete exam including dilated fundus exam rules out accompanying retinal injury

Fig. 5 Leukocoria in a four-month-old male patient from a congenital cataract. Parent had noted the condition several days earlier.

Fig. 6 Binocular indirect ophthalmoscopic view of a three-month-old infant with retinopathy of prematurity (ROP). Retinal assessment is vital for infants with sudden acquired strabismus or leukocoria.

in the form of detachment or commotion retinae. Cycloplegics and steroids remain the mainstay of treatment, although the use of steroids should be accompanied by an antibiotic if there is an associated corneal abrasion. Minor superficial abrasions of the lids and adnexa can be treated with topical bacitracin ophthalmic ointment, as skin preparations obtained OTC can irritate the eye if it is rubbed between the lids. All invasions of the skin should be searched for foreign material. Insect bites can result in severe edema of the periocular structures and should be evaluated to rule out potentially necrotizing tissue as the result of spider bites. Chemical injury may be severely vision disabling, especially with the availability of alkaline household cleaning agents. The container should always be examined by the doctor and ph testing performed.14 Acid injuries to the cornea form a barrier making penetration of the acid more difficult. Mild acidic burns to the cornea can be treated similarly to corneal abrasions and respond well to this therapeutic management. Alkaline burns (i.e., lye, ammonia) are the most dangerous agents as they penetrate the cornea rapidly.15 Immediate topical anesthesia is used, followed by sweeping of the conjunctival fornices to remove any undissolved particulate matter prior to copious irrigation. At least one litre of irrigation is recommended, after placement of a pediatric lid speculum.15 The child/infant may need to be immobilized by parent(s) or staff for this procedure. If fluorescein staining reveals corneal involvement, immediate referral is recommended. Care must be taken to not confuse a 100% corneal epithelial abrasion which appears uniform with nonstaining, as Bowman’s takes up fluorescein poorly. Cyanoacrylate (“Super glue”) may stick the lashes together, but rarely damage the cornea beyond an abrasion. Lashes may need to be cut to allow the eye to open for a

complete eye exam. Lashes typically re-grow in 2-3 weeks. Thermal injuries (e.g., cigarette burn) fortunately are superficial and can be treated like a corneal abrasion.16 Frequently, the fast eyelid closure will result in first- or second-degree burns of the eyelid skin.16 First-degree erythema can be treated with topical ointments. Due to the thin eyelid skin, second-degree burns can rapidly progress to third degree and result in lid deformity. Therefore in cases of second-degree burn (blister), referral is suggested. Instillation of a topical analgesic agent (i.e., Voltaren, Bromfenac) may calm down the pediatric patient.

NON-ACCIDENTAL TRAUMA Unfortunately, cases continue to present as a result of inflicted injury. In the infant, children can present with confusing histories of “having fallen from the changing table” with extensive periocular injury and lethargy. Dilated fundus exam may reveal retinal hemorrhages. In any instance of suspected child abuse the examining physician is required by law to immediately contact social services.17 The child is taken from the guardians until a complete work up is performed, while hospitalized, including retinal consultation, MRI, CT scans and longbone studies. This approach is taken to prevent any episode of repeat trauma which carries a 50% mortality rate.18 The AAO position paper can be accessed online and should be downloaded for office referral and in-service training.17 The triad of intracranial hemorrhage, multilayered retinal hemorrhages, and/or skeletal fractures, makes the diagnosis of non-accidental trauma highly likely.18 All of your staff need to be on the alert for such conditions as the initial examining physician is directly liable for any secondary injury to the patient, if appropriate referral is overlooked.18

Common Ocular Disorders in the Pediatric Population — Sendrowski, Lingua

PEDIATRIC CATARACTS Cataracts are a common and treatable ocular disorder in children. The reported incidence of infantile cataracts ranges from 1 to 13 per 10,000 live births.19 The most useful classification of pediatric cataracts is by their location and clinical appearance. Detection of cataracts is made visually by the pediatrician in the newborn using a direct ophthalmoscope to look for a red reflex in the undilated pupil. Parents sometimes detect cataracts if their location is more anterior (polar cataract) or if they note a change in light reflex in the pupil (leukocoria) (Fig. 5). Utilizing the same technique, the eye care physician can attempt to view the fovea through a suspected cataract in the child. If the examiner can view the fovea through the cataract with an undilated pupil, it is likely that the infant will develop good vision and surgery can be deferred. Retinoscopy may also be employed in decisionmaking for cataract referral. If it is possible to determine an accurate retinoscopy through an undilated pupil in the infant with a congenital cataract, it is safe to defer surgery. If, on the other hand, it is not possible to determine an accurate retinoscopy result, surgery may be indicated. Examination of the posterior segment through a dilated pupil is also important to rule out congenital anomalies (i.e., ROP, tumors, vitreous opacities) (Fig. 6). If visualization of the posterior pole is not possible because of the cataract, ultrasound is another viable option to view the posterior pole. Normal neonates may not develop good fixation and following responses until 2 to 3 months of age so careful clinical examination is the most important determinant in a visually significant cataract in the new born.20 Since cataracts may progress, serial examinations in the first several years are important to reassess the visual significance of a congenital cataract.20 Amblyopia treatment may be required prior to and after cataract extraction in the treatment of amblyopia, a condition which is a major challenge in many cases of pediatric cataracts. The most profound amblyopia associated with pediatric cataracts is the deprivation type, which is most devastating in eyes with unilateral congenital cataracts.21 The challenge to the eye care physician is to detect unilateral or bilateral congenital cataracts early which could potentially produce deprivational amblyopia, and to determine if surgery needs to be performed in the early years of life. Partial lenticular opacities may not require surgical intervention until years later if good visual stimulation is maintained in the childâ&#x20AC;&#x2122;s developing eye. Strabismus is another cause of amblyopia, and is commonly associated with cataracts in the pediatric population. Most, if not all, patients with visually significant unilateral, congenital cataracts have strabismus.21 The deviation persists even after surgical intervention and post-operative efforts to visually rehabilitate the eye

Clinical and Refractive Optometry 28:1, 2017

should be attempted. In children with bilateral cataracts, the prevalence of strabismus is also high, ranging from 40% to 90%.21 This is especially true if cataract surgery was performed early.20 Among those patients with strabismus from bilateral cataracts, amblyopia occurs in approximately 50% of cases.22

PEDIATRIC GLAUCOMA Glaucoma in the pediatric population is uncommon.23 Once diagnosed, glaucoma control becomes a lifelong goal, considering the myriad patient problems one encounters with adult glaucoma. It has the added complication of having to include parents and care givers into the treatment mix. Pediatric glaucoma can be divided into two main categories: primary and secondary.24 The primary group is sub-classified according to the presence or absence of associated systemic or other significant ocular anomalies. The secondary group is classified according to its etiologies. Key features in the pediatric glaucoma evaluation include the appropriate medical and family history of the child, which can be essential for the diagnosis. The ophthalmic exam should include a general inspection of the external eye to rule out corneal enlargement (megalocornea) and possible opacification. Evaluation of the anterior segment can be achieved with a hand-held biomicroscope or 20 D lens and a light source such as a transilluminator. Additionally, the normal glaucoma and evaluation techniques of tonometry, gonioscopy (which may need to be done under light anesthesia utilizing a direct gonioscopy technique), and fundus examination, which includes retinal nerve fiber layer (RNFL) assessment as well as assessment of the optic nerve head (ONH). In this group, anterior chamber evaluation and tonometry are essential in the care of any pediatric glaucoma patient. The eye care physician should keep in mind that the differential diagnosis of pediatric glaucoma is that primary congenital glaucoma is a disease of exclusion. The child should have no other systemic or ocular disorders. Sequentially measured elevated intraocular pressures are good evidence of glaucoma. The medical treatment for children with glaucoma is acetazolamide.25 Acetazolamide, at doses of 10 to 15 mg/kg/day orally, is safe to use in the short term and reduces the pressure by about one-third. Its use can result in metabolic acidosis and may also be associated with hypernea, diminished appetite and general fatigue symptoms.25 Surgically, goniotomy is the most successful procedure for infantile primary congenital glaucoma.26 If intraocular pressure is still elevated after goniotomy, trabeculotomy is indicated for continued pressure lowering and is a very successful procedure. Patients who are poor candidates for goniotomy or trabeculotomy usually receive implant surgery.

In summary, pediatric glaucoma is an uncommon but important cause of blindness in childhood. Visual prognosis for treated patients with pediatric glaucoma has been improving. However, late diagnosis can result in permanent or severe visual loss.

CONCLUSION The eye care practitioner plays a vital role in the health and ocular well-being of the pediatric population. Apart from the ability to treat the ocular maladies that present in the office, the ocular physician can also be the first health care provider the child encounters. This can leave a lasting life-long impression on the patient. In pediatric cases, there are significant differences with respect to examination techniques and reliability of subjective testing, as well as with the types of diseases encountered, their manifestations and their potential for impact on the developing child. The ocular physician may find that with a little patience and reasoning, they may have just found a life-long patient for their practice. â??

REFERENCES 1. 2.

7. 8.

Weiss A, Brisner JH, Nazar-Stewart V. Acute conjunctivitis in childhood. J Ped 1993; 122: 10-14. Slater LN, Welch DF, Bartonella, including CAT-scratch disease: In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Disease, 6th ed. Philadelphia: Churchill Livingstone Elsevier, 2005; Chap. 232 pp. 1741-1758. Jerris RC, Regnery RL. Will the real agent of cat-scratch fever please stand up. Annu Rev Microbiol. 1996; 50: 707-725. Teoh DL, Reynolds S. Diagnosis and management of pediatric conjunctivitis. Pediatric Emerg Care 2003; 19: 48-55. Chadberry IE, Schnitzler P, Geiss HK, et al. An outbreak of epidemic keratoconjunctivitis in a pediatric unit due to adenovirus type 8. Infection Common Hosp Epidemiology 2003; 24: 514-519. Avunduk AM, Avunduk MC, Dayanir V, et al. Pharmacological mechanism of topical lodoximide treatment in vernal keratoconjunctivitis. Ophthalmic Res 1998; 30: 37-43. Jackson WB. Blepharitis: Current strategies for diagnosis and management. Can J Ophthalmol 2008; 43(2): 170-179. Darville T. Chlamydial trachomatis infections in neonates and young children. Semin Pediatric Infectious Disease 2005; 16: 235-244. Girner LB. Periorbital and orbital infections. Pediatric Infectious Disease J 2002; 21: 1157-1158.

10. Liesegang TJ. Epidemiology of ocular herpes simplex: Natural history in Rochester, Minn. 1950 through 1982. Arch Ophthalmol 1989; 107: 1160-1165. 11. Dohil MA, Lin P, Lee J. et al. The epidemiology of Molluscum Contagiosum in children. J Am Acad Dermatol 2006; 54: 47-54. 12. Vinger PF. Ocular injuries and appropriate protection. Focal Points: clinical modules for ophthalmologists. Am Acad Ophthalmol 1997; 15: 8. 13. La Sage N, Verreault R, Rochette L. Efficiency of eye patching for traumatic corneal abrasions: a controlled clinical trial. Ann Emergency Med 2011; 38: 129-134. 14. Ramasubramanian A, Johnston S. Neonatal Eye Disorders Requiring Ophthalmology Consultation. NeoReviews 2011:12; e216-e222. 15. Ikeda N, Hayasaka S, Hayasaka S, Watanabe K. Alkali burns of the eye: effect of immediate copious irrigation with tap water on their severity. Ophthalmologica 2006; 220: 225-228. 16. Kuckelkorn R, Schrange N, Keller G, et al. Emergency treatment of chemical and thermal eye burns. Acta Ophthalmol Scand Feb 2002; 80(1): 4-10. 17. Levin A, Forbes B, Alexander R, Jenny C. Information Statement: Abusive Head Trauma, Shaken Baby Syndrome. American Academy of Ophthalmology. June 2010 San Francisco, California. www.aao.org 18. McCabe CF, Donahue SP. Prognostic indicators for vision and mortality in shaken baby syndrome. Arch Ophthalmol 2000; 118: 373-377. 19. San Giovanni JP, Chew EY, Reed GF, et al. Infantile cataract in the collaborative perinatal project: prevalence and risk factors. Arch Ophthalmol 2001; 120: 1559-1565. 20. Inavi GM, Schnall BM, Lehman SS, et al. Visual outcome and success of amblyopia treatment in unilateral small posterior lens opacities and lenticonus initially treated nonsurgically. JAAPOS 2005; 9: 449-454. 21. Cheng KP, Hiles DA, Biglaw AW, et al. Visual results after early surgical treatment of unilateral congenital cataracts. Ophthalmology 1991; 98: 903-910. 22. Gelbart SS, Hoyt CS, Jastrebski G, et al. Long-term visual results in bilateral congenital cataracts. Am J Ophthalmol 1982; 93:615-621. 23. Walton DS, Katsavounidou G. Newborn primary congenital glaucoma 2005 update. J Pediatric Ophthalmol Strabismus 2005; 42: 333-341. 24. Ho CL, Walton DS. Primary megalocornea: clinical features for differentiating from infantile glaucoma. J Pediatr Ophthalmol Strabismus 2004; 41: 11-17. 25. Wayman LC, Larson LI, Maus TL, et al. Additive effective of dorzolamide on aqueous humor flow in patients receiving long-term treatment with timolol. Arch Ophthalmol 1988; 116: 1438-1440. 26. McPherson SD Jr, Berry DP. Goniotomy vs external trabeculotomy for developmental glaucoma. Am J Ophthalmol 1983; 95: 427-431.

Common Ocular Disorders in the Pediatric Population â&#x20AC;&#x201D; Sendrowski, Lingua

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QUESTIONNAIRE Common Ocular Disorders in the Pediatric Population David P. Sendrowski, OD, FAAO; Robert W. Lingua, MD 1. ❑ ❑ ❑ ❑

According to the paper, what percentage of pediatric conjunctivitis is bacterial? 30% 50% 75% 80%

2. ❑ ❑ ❑ ❑

Which of the following is an advantage of fourth generation fluoroquinolones? Shorter duration of use Patients have been shown to be more compliant to these than to previous agents Greater efficacy in the pediatric population than in the adult population Greater safety profile

3. ❑ ❑ ❑ ❑

All of the following are characteristics of phlectenular disease, EXCEPT: Unilaterality Highly responsive to topical corticosteroid therapy Extremely prevalent in children with severe staphylococcus lid infections More prevalent in female population than in male population

Clinical and Refractive Optometry 28:1, 2017

COPE-APPROVED CE CREDIT APPLICATION FORM

Which is the most common type of periocular infections in children? Lid infections Conjunctivitis Orbital cellulitis Nasolacrimal duct obstruction

5. ❑ ❑ ❑ ❑

Blunt trauma accounts for what percentage of emergency room admittances in children? 20% 40% 65% 70%

6. ❑ ❑ ❑ ❑

According to the paper, all of the following are signs and symptoms of blunt injury to the eye or orbit, EXCEPT: Loss of balance Pain Redness Tearing

7. ❑ ❑ ❑ ❑

In cases of suspected child abuse, what is the mortality rate for repeated trauma? 20% 30% 50% 65%

8. ❑ ❑ ❑ ❑

All of the following statements regarding pediatric cataracts are true, EXCEPT: Their severity is determined in part by their location and clinical appearance They occur very rarely They are a treatable disorder They are a common disorder

9. ❑ ❑ ❑ ❑

All of the following statements about strabismus in the pediatric population are true, EXCEPT: Its prevalence is high in children with bilateral cataracts In patients with strabismus from bilateral cataracts, amblyopia occurs in roughly 50% of cases It occurs predominantly in women and men between ages 35 to 50 It is rarely a cause of amblyopia

10. ❑ ❑ ❑ ❑

All of the following are common bacterial pathogens, EXCEPT: Pneumococcus Staphylococcus Moraxella Streptococcus

28.1:17

4. ❑ ❑ ❑ ❑

Common Ocular Disorders in the Pediatric Population — Sendrowski, Lingua

CLICK HERE TO PRINT THIS CE CREDIT ARTICLE AND TEST

Clinical & Refractive Optometry is pleased to present this continuing education (CE) article by Dr. Joyce Hsieh and Dr. Pauline F. Ilsen entitled Ophthalmic Artery Steal. In order to obtain a 1-hour Council of Optometric Practitioner Education (COPE) approved CE credit, please refer to page 42 for complete instructions.

Ophthalmic Artery Steal

CASE REPORT

Joyce Hsieh, OD; Pauline F. Ilsen, OD

A 60-year-old male presented with concerns of a red, painful left eye of one week’s duration. Also of note: he reported that for the past few months, he had been experiencing short-lived episodes of graying vision that would last five to ten seconds and then spontaneously resolve. However, on the morning he presented for his eye examination, he reported persistent profound loss of vision in the left eye with the ability to perceive “just shadows.” The patient denied symptoms of jaw claudication, headache, scalp tenderness, malaise, fever, and night sweats. He noted intentional weight loss during the last few months due to dietary changes in order to maintain better glycemic control. The patient’s past ocular history was largely unremarkable with good visual acuity noted at his last dilated exam, which had been performed two months prior. His systemic health was significant for type 2 diabetes mellitus, hypertension, hyperlipidemia, and benign prostate hypertrophy for which he was taking lovastatin, glyburide, metformin, and terazosin. Additionally, he reported 40 years of tobacco use (approximately 2.5-3 packs/day) and extensive ethanol consumption (6 pack of beer/day). On examination his best-corrected visual acuity was 20/20 in his right eye and hand motion at three feet in the left eye. Extraocular motility testing was normal while pupil evaluation revealed a fixed mid-dilated left pupil. Slit lamp biomicroscopy demonstrated age-appropriate findings in the right eye while the left eye was characterized by microcystic edema with Descemet’s folds temporally, grade 2+ dilated conjunctival vessels, 1+ flare but no cell in the anterior chamber, as well as neovascularization of the iris root inferotemporally and temporally. Goldmann intraocular pressures (IOP) were 12 mm Hg in the right eye and 30 mm Hg in the left eye. Gonioscopic examination confirmed angle neovascularization in the nasal aspect of the left eye as well as engorgement of the arterial circle. By Spaeth classification, both the right and left eyes were open to D40R. Fundus evaluation of the right eye was notable for segmental hypoplasia of the optic nerve and a choroidal nevus in the posterior pole. The detail of the left eye was limited by the edematous cornea, so B-scan ultrasound

ABSTRACT The optometrist needs to be aware of the potential manifestations of ophthalmic artery steal and its appropriate management, both ocular and systemic. Timely diagnosis by an eyecare specialist can play a crucial role in reducing patient mortality.

INTRODUCTION Vascular “steal” can be defined as the compensatory siphoning or redirecting of blood flow from one area to another. Fisher first employed the term “subclavian steal” in reference to the phenomenon of reversed blood flow through the vertebral artery as a means of compensating for proximal stenosis of the ipsilateral subclavian artery.1 The distal subclavian artery would “steal” blood from the vertebral circulation, with reverse flow through the vertebral artery, in order to maintain an adequate supply to the upper extremity beyond the point of subclavian occlusion.1 “Ophthalmic artery steal” has been used in the literature in a slightly different fashion, as a means of describing the reversed blood flow through the ophthalmic artery to compensate for inadequate flow in the internal carotid artery, typically when there is an occlusion of the internal carotid just proximal to the origin of the ophthalmic artery. In this situation, the ophthalmic artery is serving as a conduit for blood from branches of the external carotid to the internal carotid; hence, it is actually the internal carotid that is “stealing” blood by means of reverse flow through the ophthalmic.2,3,4 A case of a patient with ocular ischemic syndrome from suspected ophthalmic artery steal phenomenon is presented. J. Hsieh — Chief of Optometry, Kaiser Permanente, Woodland Hills Medical Center, Woodland Hills, CA; 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 The authors have no financial or proprietary interest in any of the material mentioned in this article. This article has been peer reviewed.

Clinical and Refractive Optometry 28:1, 2017

Fig. 1 Fundus photographs taken nine days after initial presentation demonstrate arteriolar attenuation and diffuse retinal edema OS.

Fig. 2 Fluorescein angiography at 45 seconds demonstrates patchy choroidal filling and delayed retinal arteriolar filling, suggesting a partially reperfused central retinal artery occlusion and reduced ophthalmic artery perfusion.

was utilized. Ultrasonography was grossly unremarkable without evidence of mass or retinal detachment. Despite limited views, it was determined that the left fundus demonstrated attenuated retinal vessels and diffuse edema of the posterior pole; however, the presence of a cherry red spot was equivocal. The diagnosis of neovascular glaucoma was made, and several differential diagnoses for the underlying etiology were considered: central retinal artery occlusion (CRAO), ocular ischemic syndrome, retrobulbar mass, and/or giant cell arteritis in the absence of classic systemic symptoms. An urgent carotid duplex was ordered and the following labs were obtained: complete blood count (CBC), Westergren erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), finger-stick glucose, glycosylated hemoglobin (HbA1c), prothrombin time (PT),

international normalized ratio (INR), liver function tests (LFTs), urinalysis, and a lipid panel. A review of recent vital signs in the record revealed that the patientâ&#x20AC;&#x2122;s systolic blood pressure had varied between 140 and 170 mm Hg and his diastolic blood pressure had ranged from 70 mm Hg to 90 mm Hg. In line with the trend, his blood pressure was 161/85 on the day of his urgent visit. The complete blood count was entirely within normal range. The ESR was 1 mm/hr (normal <30), the CRP level was 0.16 mg/dL (normal <0.744), whole blood glucose measured 180 mg/dL, HbA1c was 7.4%, PT was 12.71 seconds (normal 11.8-13.5) and INR was 1.0. While the alanine aminotransferase level was elevated at 80 mg/dL (normal 7.0-45.0mg/dL), all of the other liver enzymes were normal, and urinalysis was negative for glycosuria or proteinuria. The lipid panel was largely within normal limits with the exception of slightly reduced HDL levels of 27.1 mg/dL (>40 desirable); the total cholesterol level was 141 mg/dL (normal <200), the triglyceride level was 115 mg/dL (normal 40-160), and the LDL was 90mg/dL (<130 desirable). To address the elevated intraocular pressure, the patient was immediately started on oral acetazolamide 250mg four times a day as well as topical dorzolamide/ timolol maleate twice a day and brimonidine solution three times a day in the left eye. Additionally, the patient was prescribed prednisolone acetate 1% (Pred ForteÂŽ, Allergan) every hour and atropine 1% twice a day for the left eye. Fundus photography and fluorescein angiography were ordered immediately but ultimately obtained nine days later (Fig. 1) and a consultation with retina clinic was arranged. On that day, 1508 spots of panretinal photocoagulation were applied to the left eye, followed by 301 shots the following day, by which time the IOP had dropped to 10 mm Hg in the right eye and 13 mm Hg in the left eye. On the third day, an intravitreal bevacizumab injection was administered OS. Five days

Ophthalmic Artery Steal â&#x20AC;&#x201D; Hsieh, Ilsen

later the visual acuity in the left eye had stabilized at hand motion vision, there was full regression of the iris neovascularization, and the IOP remained controlled at 10 mm Hg. Nine days later, the fundus examination was unchanged. The fluorescein angiogram of the right eye was unremarkable; however, the left eye demonstrated not only delayed retinal arteriole filling as had been expected, but also patchy choroidal flush (Fig. 2). Therefore, this was not just a partially-reperfused central retinal artery occlusion given the concurrent obstruction of the choroidal circulation; the collective findings suggested reduced blood flow occurring earlier in the orbital pathway, presumably at the level of the ophthalmic artery. While all the labs returned within expected ranges, the carotid ultrasound showed probable occlusion of the left internal carotid artery starting from the carotid bulb, which was the likely culprit in the ocular findings described earlier (Fig. 3). Subsequent magnetic resonance imaging, including diffusion-weighted images and magnetic resonance angiography (MRA) of the head and neck confirmed 100% obstruction of the left internal carotid artery at its origin (Fig. 4) The right and left external carotid arteries were found to be patent, as well as the right internal carotid artery. The left middle cerebral artery (MCA) showed diminished caliber, flow signal, and cortical branches, suggesting hypoperfusion to the left MCA territory. The left MCA appeared to be “diminutive” and supplied predominantly across the anterior portion of the circle of Willis. There was proximal occlusion of the left vertebral artery with distal reconstitution and focal stenoses in the proximal right vertebral artery with focal flow gaps, indicating the possibility of high-grade stenosis. No large posterior communicating artery could be visualized. Additionally, the MRI of the brain showed no signs of acute infarct or heme. Since the patient was asymptomatic by that time, carotid endarterectomy was not indicated and the patient was scheduled for regular follow-up with vascular clinic. As far as eye care, the patient was monitored frequently while on maximally tolerated medical therapy until the neovascularization, initially responsive to pan-retinal photocoagulation and intravitreal bevacizumab, returned approximately one month after his first evaluation. Gonioscopy was repeated, which revealed an angle classification of AQ30 with nearly 360 degree synechial closure in the left eye. He was arranged for Ahmed valve surgery OS to reduce the dependence on topical ocular anti-hypertensive medications and for the anticipated rise in IOP in the future. The patient was maintained on dorzolamide hydrochloride-timolol maleate (Cosopt®, Merck Frosst) b.i.d. and Pred Forte 1% t.i.d. OS postoperatively, but he subsequently passed away of unknown etiology approximately two months after completion of Ahmed valve surgery.

Clinical and Refractive Optometry 28:1, 2017

While certain tests were not utilized during the time of the patient’s exam that would confirm the exact mechanism of his clinical outcome, it was concluded, based on the extent and severity of cerebrovascular stenosis, that the patient had experienced ocular ischemic syndrome caused by a phenomenon known as ophthalmic artery steal. The MRA suggested poor perfusion globally throughout his intracranial system, overwhelming the compensatory collateral flow via the circle of Willis to overcome the carotid occlusion. This likely prompted the additional enlistment of secondary collaterals such as the external carotid artery with the ophthalmic artery serving as the conduit for blood transport. The ischemia sustained by the left eye suggests ophthalmic artery steal occurred, in which blood was directed in the retrograde direction, away from the globe and toward the brain, leaving the eye vulnerable to the sequelae of hypoperfusion. Several interesting points regarding the cerebrovascular system and the intertwined role of the ocular blood supply can be learned from this case. Additionally, the mechanism by which an internal carotid artery occlusion results in ocular ischemia is explained in detail.

DISCUSSION Pathophysiology of Ophthalmic Artery Steal It must be noted that while most frequently associated with obstruction of the internal carotid arteries, the primary source of the brain’s blood supply, ophthalmic artery steal is also occasionally a sequelae of blockage at the level of the aortic arch and can also feasibly occur when there is vascular obstruction anywhere along the pathway from the left ventricle to the brain.5 Indeed ophthalmic artery steal is a rare clinical entity since the human body can typically compensate for impeded blood flow to the brain through the development of alternative intracranial collateral vessels not derived from the ocular blood supply.3,6,7,8 However, the system can fail in a patient with very severe vascular disease, when the intracranial mechanisms alone are insufficient in compensating for cerebrovascular hypoperfusion; in this infrequent scenario, ocular blood flow is enlisted and diverted toward the brain to the detriment of the eye and as such, its presence is often an indicator of severely impaired cerebral blood flow.3,8 In order to understand the hemodynamic interplay between the eye and the brain, it is imperative to review the basics of the cerebral and orbital vasculature systems, namely how they function in healthy individuals and also how they are altered when vascular health becomes compromised. Under normal conditions, the cerebrum receives the majority of its blood supply from the internal carotid artery and its branches, while the remaining 20%

Fig. 3 Color doppler ultrasonography revealed 90% to 100% stenosis of the left internal carotid artery Fig. 4 Complete occlusion of the left internal carotid artery, complete occlusion of the left vertebral artery, and “flow gaps” in the right vertebral artery are demonstrated on magnetic resonance angiography.

is supplied by the vertebral artery system.9 After yielding its first branch to the eye as the ophthalmic artery, the internal carotid artery subsequently divides into the anterior and middle cerebral arteries, which collectively supply the parietal lobe, the medial aspect of the frontal lobe, and the lateral portion of the temporal lobes.9 The vertebral arteries, in contrast, carry the burden of the posterior cerebral vascular supply. The left and right vertebral arteries join to form the solitary basilar artery, which supplies the brainstem and cerebellum; the basilar artery then splits into two posterior cerebral arteries that then nourish the occipital lobes and the medial portions of the temporal lobes.9 The internal carotids and the vertebral branches in turn join together via communicating arteries to form the circle of Willis,9 thereby unifying the anterior and posterior networks as well as the right and left hemispheric systems.3 This Willisian network of vessels typically compensates for any stenotic or occlusive event by redirecting blood flow from patent pathways to areas of diminished cerebral perfusion3,6,7,9 (Fig. 5). Ordinarily the orbital blood supply exists relatively independently of the cerebral system. The eye is largely supplied by the ophthalmic artery with minor contributions from the external carotid artery (ECA) via the infraorbital artery and the middle meningeal artery branches.10,11 Distally, the ophthalmic artery typically divides into three branches, the first of which is the central retinal artery (CRA), which supplies the inner retina from the nerve fiber layer at the most anterior aspect to the inner portion of the inner nuclear layer at the most posterior aspect. The other two branches from the ophthalmic artery are the medial and lateral posterior ciliary arteries.12 These give rise to long posterior ciliary arteries, which supply the anterior aspect of the globe, and

between seven to ten short posterior ciliary arteries, which compose the bulk of the choroidal/choriocapillaris system.12 While the central retinal artery feeds the inner portion of the retina, the choroidal system supplies the outer layers, which traditionally includes the outer portion of the inner nuclear layer through to the retinal pigment epithelium.12 These two systems, the orbital and cerebral, tend to run parallel and independently of one another unless poor cerebral perfusion necessitates cooperation. In the event of carotid stenosis or occlusive disease, the human body can elicit several compensatory mechanisms to overcome focal blockage, the success of which can determine a myriad of systemic manifestations ranging from clinically “normal” when effective collaterization takes hold to the unfortunate other end — debilitating cerebral infarct — presumably when adequate ancillary blood supply cannot be established.4,13 In most patients with severe ipsilateral carotid disease, the circle of Willis is the primary collateral system;3,7,8,14,15,16 this network can be recruited almost instantaneously,14 and when functional, can re-perfuse ischemic areas very effectively since blood supplied by the patent contralateral internal carotid can travel in any necessary direction either via the anterior communicating arteries or by the vertebral system via the posterior communicating arteries.3,15,16 In this situation there is no intervention of the ophthalmic artery and hence no disruption of ocular blood flow. The ophthalmic artery ipsilateral to the occlusion continues to maintain blood flow in the normal and undisturbed anterograde direction

Ophthalmic Artery Steal — Hsieh, Ilsen

B. Ophthalmic artery steal

Fig. 6 (A) Diagram of normal circulation. (B) Reverse flow through the ophthalmic artery (ophthalmic artery â&#x20AC;&#x153;stealâ&#x20AC;?) from the external carotid.

Fig. 5 Illustration of cerebral circulation and circle of Willis.

(Created by:

Mr. Terrence M. Washington, Medical Illustrator)

as it is perfused by the external carotid artery rather than the now occluded internal carotid artery.7 The demand for collateralization can exceed the capacity of the circle of Willis in cases of system-wide stenosis, bilateral internal carotid artery disease, or anatomical limitations such as congenitally hypoplastic or absent vessels.2,3,7,14,15,17 In such scenarios, secondary collaterals such as the leptomeningeal anastomoses3,4,14,17 or collaterals with the ipsilateral external carotid 2,3,6,7,14,17,18 become necessary, which then use the ophthalmic artery as a conduit to supply the occluded ipsilateral internal carotid artery.7,8,19 Kluytmans et al reported that patients with a normal volume of anterograde flow through the ophthalmic artery essentially had patent collaterization via the circle of Willis in that secondary collaterals such as the ophthalmic artery were not recruited.15 In their study, the presence of the ophthalmic artery collateral, usually a mechanism of second resort, was indicative of more severely impaired hemodynamic perfusion to the brain15 (Fig. 6). It is believed that much like primary collaterals, secondary collaterals develop in the prenatal period but the maximum functionality of such pathways takes time to develop.3 Some studies regard the ophthalmic artery to be a less than ideal collateral pathway given the relative limits to its blood volume capacity in supplying the brain,4,8,14 while van Laar et al indicate collateralization with the ECA via the ophthalmic artery is substantial enough to maintain sufficient cerebral perfusion to preserve patient life.18 In either scenario, recruitment of

Clinical and Refractive Optometry 28:1, 2017

the ophthalmic artery as a collateral is suggestive of more severe and/or extensive occlusive disease8,15 since this indicates inadequate perfusion though the primary collateral system alone. In secondary collateral development, blood derived from the branches of the ECA, the superficial temporal, facial, supraorbital, maxillary, and middle meningeal arteries,3,10,11 travel through the ophthalmic artery, reversing the direction of flow away from the eye toward the brain.2,3,4,7,19,20,21 (Fig. 6). In this process, the ophthalmic artery is the conduit that diverts blood from the patent extracranial circulation to the impaired intracranial system.7 Given the small caliber of the ocular blood vessels prohibiting adequate visualization through traditional angiography, a non-invasive technology referred to as color Doppler imaging (CDI) is often utilized to image the retrobulbar vessels and their internal patterns of flow.2,7,16,19,20,22 CDI yields color schemes depicting the pattern of blood flow superimposed upon a B-scan ultrasound of the vascular anatomy.19 By using this technology, Yamamoto et al were able to shed light on the role of the retrobulbar vascular system and to explain the variable clinical presentation in the eye when internal carotid artery (ICA) occlusion occurs. They identified various groups of patients with an ICA occlusion based on four different patterns of orbital blood flow.2 In situations where the occluded ICA received collateral support only from the circle of Willis, the ophthalmic artery (OA) and likewise as expected, downstream at the level of the central retinal artery (CRA) and the choroidal system, demonstrated undisturbed blood flow.2 The second category involved collateralization via a branch of the ECA by way of the OA with continued but limited perfusion to the ophthalmic arteryâ&#x20AC;&#x2122;s branches, the central retinal artery and the short posterior ciliary arteries.2 Under this model, given perfusion to the ICA as well as the ocular end arteries (the CRA and the choroidal circulation), it was assumed that some of the blood flow from the OA was not directed exclusively to the cerebral

Table I Ocular manifestations of ophthalmic artery steal Spectrum of Clinical Findings Normal Asymptomatic, clinically “normal”

Acute

Chronic

Moderate retinal opacification

Rubeosis irides

Variable cherry red spot

Retinal arterial attenuation

Vascular box-carring

Dilated, non-tortuous veins

Retinal artery attenuation

Mid-peripheral intraretinal hemorrhages

No retinal hemes/exudates

Optic disc collaterals

Intraretinal gray lesions (choroid)

Optic nerve edema

Late optic atrophy

Retinal arteriolar pulsation

Delayed RPE hyperplasia

Neovascularization NVG

Primary sx: profound vision loss

Primary sx: amaurosis fugax

tissues in the retrograde direction but also a portion managed to reach the eye in the normal anterograde fashion.2 In the third group, secondary collaterals from the ECA were recruited but none of the retrograde flow within the OA was directed toward the eye, fully exemplifying the phenomenon of ophthalmic artery steal.2,7 This form of collateralization shunts blood to the lower resistance vessels of the intracranial system with the outcome of terminated retrobulbar flow.7 The final category Yamamoto et al identified was one in which no effective collateralization developed, leaving the eye and the cerebral tissues devoid of any measurable vascular flow, causing cerebral infarct and ocular ischemia.2 Such differences in blood flow patterns presumably explains why some eyes become ischemic after an ICA occlusion (when retrobulbar flow is diminished or absent) and why other eyes appear to have undisturbed ocular blood flow after a carotid occlusive event. It is believed that any reverse flow through the OA occurs in approximately 38.5% to 76% of patients with internal carotid artery occlusion4,7,8 and with lower frequency in patients with significant stenosis.19 Reverse flow through the OA is indicative of secondary collateralization via the ECA, usually as a result of an ICA occlusion in the setting of overall poor intracranial arterial status.3,7,19 This agrees with Costa et al’s finding that reverse flow through the OA is much more common in patients with severe bilateral disease as the intracranial collaterals (i.e., the circle of Willis) are generally the first and only line of collaterization if patent and sufficient.3,6,16 One critical finding of Yamamoto et al’s study was that ocular ischemia is caused by reverse OA flow, but retrograde ocular blood flow did not always result in ocular ischemia.2 Only those with high velocity reverse OA flow seemed to be susceptible to the ravages of ocular ischemia as the rapid retrograde redirection of blood resulted in severely diminished or absent perfusion through the ocular end arteries2 as measured by reduced

peak systolic velocities in both the central retinal and short posterior ciliary arteries.16,19,20,22 Specifically, it was found that further downstream, reduced perfusion at the level of the posterior ciliary artery moreso than at the central retinal artery was particularly devastating as far as patient susceptibility to ocular ischemic syndrome with vision loss.19 This is presumably due to the numerous ocular structures dependent on perfusion by the posterior ciliary arteries, namely the optic nerve, choroid, RPE, and the outer retinal layers.19 The variety of collateral pathways and flow patterns of the retrobulbar vasculature in ICA occlusion seems to explain why the clinical outcome can be so variable — ranging from a complete absence of clinical signs to devastating ocular ischemia with profound vision loss and deterioration.19 Clinical Manifestations of Ophthalmic Artery Steal In internal carotid occlusion, the clinical manifestations within the eye can be quite variable.7,16,19,20,23 Depending on the mode of collaterization (primary vs. secondary), the direction of blood flow through the OA (anterograde vs. retrograde), as well as the magnitude of the flow (high velocity vs. low velocity), the eye can be potentially spared of ischemic changes, as in the case of a patient with 100% effective intracranial collaterization through the circle of Willis.2 However, it is possible that collaterization with the extracranial blood supply, which requires retrograde flow through the OA to supply the brain, leaves the eyes potentially vulnerable to ocular ischemia.2,7,8,19,20,22 According to Fogelholm and Vuolio whose study depended on archaic x-ray technology only, there is no time required for the OA to develop into a collateral; rather, they believed the OA to be fully patent and functional at the moment of ICA occlusion.4 A more current researcher, Liebeskind, suggested that while anatomically capable of collateral formation at birth, the OA it is not necessarily at peak capacity as a collateral circuit until cerebral hypoperfusion necessitates it.3

Ophthalmic Artery Steal — Hsieh, Ilsen

Table II Clinical features of acute ophthalmic artery hypoperfusion vs. central retinal artery occlusion OAH

CRAO

VA: HM to NLP Cherry red spot: variable (+) to (-) Retinal whitening: moderate to severe Pigment disturbance: (+) FA: delayed retinal and choroidal flows; late choroidal stain ERG: reduced/absent a- and b-waves Decreased IOP (early?)

VA: CF to HM (better if (+) cilioretinal artery) Cherry red spot: (+) Retinal whitening: mild to moderate Pigment disturbance: (-) FA: delayed retinal flow only ERG: reduced b-wave

Therefore, the exact onset of ophthalmic artery steal after an ICA occlusion is debatable though more likely to be of delayed onset.3 A spectrum of clinical presentations (Table I) in the eye can occur in the setting of internal carotid artery occlusion.19,22 On the most benign end and under the most ideal conditions, this may result in a clinically normal appearing eye and a systemically asymptomatic patient.19,22 This would occur under circumstances in which, despite the presence of reverse OA flow due to a diversion of blood from the ECA to the brain, a portion of the extracranial blood supply is still sent to the eye, providing it with enough blood to sustain function.7 Should ophthalmic artery hypoperfusion from the steal phenomenon occur, it can manifest differently in the eye depending on the rapidity with which blood flow is re-directed away from ocular structures.2,20 If done rapidly, this may present itself similar to a direct and acute occlusion of the ophthalmic artery, which would basically appear as a concomitant central retinal artery occlusion superimposed on an acute choroidal infarct.21 One would find moderate retinal opacification that extends into most layers of the retina, possibly as deep as the outer retinal layers and even the retinal pigment epithelium.21,24 A less likely finding would be the faint hint of a cherry red spot depending on the contrast between the retinal opacification and the underlying level of choroidal perfusion – this is much less likely than in a CRAO where choroidal perfusion is intact and a cherry-red spot is prominent.25,26 Box-carring of the vessels, retinal arterial attenuation, and a likely absence of hemorrhages or exudates are also possible findings of acute ophthalmic artery hypoperfusion,25 which can occur either via direct occlusion as in the case of a retinal embolus or indirectly by the ophthalmic artery steal phenomenon.21,24 In acute ophthalmic artery hypoperfusion, occasionally gray intraretinal lesions can also appear as focal manifestations of retinal ischemia deep to the retinal vessels,21,24 postulated to be in the vicinity of the outer nuclear and outer plexiform layers.24 In late stages, the posterior segment can be characterized by optic atrophy and prominent retinal pigment epithelium hyperplasia within weeks to months of the event given the extensive retinal

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involvement.25 It is believed that the poor choroidal perfusion results in ischemia and permanent damage to the RPE that results in changes including hyperplasia, dropout, and metaplasia, localized mostly in the macula.25 This is a distinction from the fundus appearance of a pure central retinal artery occlusion, which is typically not marked by late pigmentary changes, as the ischemia is limited to the inner retinal layers.27 A key diagnostic tool to distinguish between acute ophthalmic artery hypoperfusion and a CRAO would be fluorescein angiography: in early phases, ophthalmic artery hypoperfusion produces delayed central retinal artery filling as well as delayed choroidal flush.21,24,25,26 In a “classic” central retinal artery occlusion, only the retinal system is delayed and choroidal filling occurs within the normal time frame. Later frames of the angiogram may show several areas of leakage at the level of the retinal pigment epithelium in ophthalmic artery hypoperfusion due to compromised outer retinal blood flow and subsequent breakdown of the blood-retina barrier;21,25,28 such late angiographic findings are not seen in CRAO. Additionally, while unlikely to be used in diagnosis, electroretinography (ERG) would show extinguished a- and b-wave responses due to the loss of functionality of both the inner and outer retina due to simultaneous inner and outer retinal ischemia in ophthalmic artery hypoperfusion.25 In contrast, in central retinal artery occlusion, typically, only the b-wave would be extinguished while the a-wave, which represents the outer retina, is preserved given the uncompromised choroidal blood supply.25 Furthermore, the vision loss in CRAO tends to dwell on the order of count fingers to hand motion whereas vision loss with ophthalmic artery hypoperfusion is usually more profound since the ischemia is more extensive.25 Acute painless vision loss is the most common symptom of patients presenting with acute ophthalmic artery hypoperfusion.25,29 More concerning and more widely known on the spectrum of ocular manifestations of the ophthalmic artery steal phenomenon is ocular ischemic syndrome, which occurs when the ocular bloodflow is reduced on a more delayed and chronic scale.23 This seems more in line with the studies of Liebeskind et al as ophthalmic artery steal occurs secondary to extracranial collateralization,

Table III Suggested laboratory and imaging studies in suspected ophthalmic artery steal Ancillary Ophthalmic Tests

Labs and Vitals

Imaging Studies

Fluorescein angiography (FA) Electroretinography (ERG) B-scan ultrasonography

Blood pressure Lipid panel Erythrocyte sedimentation rate (ESR)

Carotid duplex ultrasound Brain magnetic resonance imaging (MRI) Magnetic resonance angiography (MRA)/ Computed tomography angiography (CTA) Orbital Color Doppler Imaging (CDI)

C-reactive protein (CRP) Fasting plasma glucose (FPG) Hemoglobin A1c (HbA1C) Prothrombin time (PT) Partial thromboplastin time (PTT) International normalized ratio (INR)

which is typically recruited later than at the time of ICA occlusion when the intracranial mechanisms have been exhausted.3 In some studies, it has been found that 4% to 18% of patients with ocular ischemic syndrome have underlying carotid occlusion.19,23 In its earliest stages, ocular ischemic syndrome is often referred to as venous stasis retinopathy, when the funduscopic changes are consistent with chronic low perfusion pressure to the eye.30 It is believed to occur with higher frequency in patients with compromised cerebral perfusion, given the necessity to recruit the ophthalmic artery as a collateral rather than the usually more effective intracranial Willisian system.16,30 Clinically, this can manifest with rubeosis irides, arterial attenuation, dilated, non-tortuous veins, mid-peripheral intraretinal hemorrhages, optic disc collaterals, optic nerve edema,21 and retinal arteriolar pulsation.19,25,30 Classically, the patient experiences amaurosis fugax,21 presumably due to fluctuating perfusion to the eye that can result in permanent loss of vision.19 Other patients may be completely asymptomatic.19 Left untreated, anterior neovascularization caused by belatedly detected ocular ischemic syndrome can result in neovascular glaucoma.30 Initially, reduced blood flow to the ciliary body can cause a reduction in intraocular pressure secondary to reduced production of aqueous humor from an ischemic ciliary body.5,23 However, as the new vessel growth progresses, obstruction of the trabecular meshwork can cause a steady imbalance between the outflow and the production of aqueous, resulting in elevated IOP.23 Symptoms in such a patient will not only include preceding episodes of amaurosis fugax, but also blur, photophobia, and pain from the corneal edema that can result from an acute rise in IOP.5,30 Cataract and uveitis can also occur in such instances.16,23 Ophthalmic Differential Diagnoses There is a wide range of potential conditions that must be considered when faced with what appears to be ophthalmic artery hypoperfusion. In the acute presentation,

higher on the list of differentials would be central retinal artery occlusion from embolic disease,32 vasculitis including giant cell arteritis, hypercoagulability disorders,33,34 compression, laceration, and vasospasm. Concurrent central retinal artery occlusion and choroidal infarct, commotio retinae with a history of recent trauma, or an inheritied metabolic lysosomal storage disease such as Tay-Sachs are also possibilities for the clinical picture involving diffuse retinal opacification with a variable cherry-red spot.31,32 In contrast, advanced diabetic retinopathy and central retinal vein occlusion would be more consistent with a chronic presentation of ocular ischemia as demonstrated by the presence of neovascularization. While ocular ischemic syndrome usually is a result of an ICA occlusion, this entity can feasibly occur as a result of any mechanism that drives retrobulbar blood flow rapidly away from the eye such as in the case of high-flow carotid-cavernous fistula.24 Systemic Considerations Systemically, the patient may be completely asymptomatic after an ICA occlusion provided that collateral systems are recruited quickly and effectively to overcome cerebral hypoperfusion. However, if the collateralization is poor on a systemic level, the patient may experience transient ischemic attacks, with symptoms such as unilateral weakness, speech disturbances, confusion, and temporary monocular vision loss.35,36,37,38,39 Typically, the patient with ophthalmic artery hypoperfusion secondary to the steal phenomenon has stenosis or occlusion of the ipsilateral internal carotid artery along with extensive stenosis throughout the cerebrovascular system.3,7,16 This is a rare clinical entity, and the signs and symptoms can be quite variable, because intracranial collateralization is generally a very effective compensatory mechanism.3 Generally patients with this clinical picture of ophthalmic artery hypoperfusion, however, have ipsilateral carotid disease with several comorbidities, including hypertension, diabetes mellitus, and atherosclerosis.19

Ophthalmic Artery Steal â&#x20AC;&#x201D; Hsieh, Ilsen

Ophthalmic and Systemic Diagnostic Testing As far as ocular testing is concerned, clinical historytaking is critical first and foremost. Inquiring about patient ocular and systemic symptoms suggestive of transient ischemia, laterality of the symptoms, rapidity of onset, and quality of vascular health are examples of questions to be posed. Visual acuity measurements, pupil testing, IOP readings, gonioscopy, funduscopic exam, and fluorescein angiography are critical elements of ocular testing. ERG could be of interest as well, though not necessarily practical, accessible, or essential to diagnosis.25,40 Systemic diagnostic investigation is imperative as is cooperation with other disciplines, potentially including the patient’s primary care provider, as well as specialists in neurology, cardiology, and vascular surgery. Carotid duplex ultrasound is the initial means for determining if carotid stenosis is present.3 Further investigation of the cerebral vasculature typically would involve magnetic resonance or computed tomography angiography.3 Color Doppler imaging (CDI) of the orbit would be helpful to determine the type of flow through the ophthalmic artery and its branches, which are all considerably smaller caliber vessels not readily imaged by traditional ultrasound techniques alone.19,20,22 How carotid occlusive disease will impact the patient’s ocular circulation is best understood with the evaluation of blood flow in the ocular end arteries with regard to direction of flow, systolic velocity, as well as the amount of vessel resistance (as measured by the pulsatility index).19,20,22 In addition to these imaging techniques, certain laboratory tests are critical in ruling out other systemic etiologies for the patient’s ocular condition, and these include Westergren erythrocyte sedimentation rate (ESR), C-reactive protein, lipid panel, blood glucose, and complete blood count (CBC). Blood pressure should also be measured.21,24,31 Management As far as the ocular management of patients manifesting clinical signs and symptoms of ophthalmic artery steal phenomenon, there is no accepted or proven means for attempting to restore vision loss from ischemia.23,25,41,42 The treatment strategies are largely aimed at preventing progression to more serious ocular sequelae. Frequent follow-up with dilated fundus exams and gonioscopy to monitor for neovascularization is critical.31 In the event that new vessel growth occurs in the angle or on the iris, pan-retinal photocoagulation should be performed to reduce vascular demand and hence the release of vaso-proliferative factors.31 However, if the neovascularization progresses to glaucoma, topical intraocular pressure lowering medications should be implemented and surgical referral is indicated if maximally tolerated medical therapy cannot achieve adequate pressure control.

Clinical and Refractive Optometry 28:1, 2017

One study has shown that systemic intervention for occlusive disease may arrest the progression of neovascularization as the internal carotid artery and subsequently the ophthalmic artery regain perfusion.2,21 It has also been found that following carotid endarterectomy, return of blood flow may cause some reversal of vision loss in some patients.21 Such decisions regarding carotid endarterectomy should be left in the hands of the patient and their vascular specialist as the decision is usually based principally on the risks of cerebral infarction.19,41 While some researchers suggest carotid endarterectomy may be indicated in patients with ocular manifestations of ophthalmic artery steal as a means to improve visual status, other authors believe that insufficient evidence exists to conclude that this procedure is indicated for patients with these clinical findings.19,41 As an alternative, Yamamoto et al found that patients suffering from ophthalmic artery steal may benefit from STA-MCA bypass (anastomosis of the superficial temporal and middle cerebral arteries) by creating an alternate collateral with the ECA and in the process, reducing the impact on the ophthalmic circulation.2,23 The idea is to restore cerebral perfusion surgically, but there is no widespread consensus on the utility of this method with regard to the preservation of the ocular circulation.2 It should be noted that while possible retention of vision can occur with rapid anterograde reperfusion of the ophthalmic artery,24,43 usually the visual prognosis is relatively grim once ischemia to the ocular structures is so vast.42 However, patient management should not be delayed given the underlying risks to patient mortality. With timely examination and diagnosis, the patient may be spared further systemic and visual loss despite already sustained ocular damage.

CONCLUSION Ophthalmic artery steal is an infrequently discussed phenomenon, which may have potentially devastating effects on the eye. Optometrists should have an understanding of the role that the ophthalmic artery can play in patients with severe carotid occlusive disease and be aware that this can present itself clinically in a myriad of manifestations. Timely recognition and intervention may help to prevent or mitigate sight- and life-threatening ischemic vascular consequences. ❏

REFERENCES 1. 2.

Fisher CM. A new vascular syndrome “subclavian steal.” N Engl J Med 1961; 265: 912. Yamamoto T, Mori K, Yasuhara T, Tei M, et al. Ophthalmic artery blood flow in patients with internal carotid artery occlusion. Br J Ophthalmol 2004; 88(4): 505-508. Liebeskind DS. Collateral circulation. Stroke 2003; 34: 2279-2284.

9. 10. 11. 12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

Fogelholm R, Vuolio M. The collateral circulation via the ophthalmic artery in internal carotid artery thrombosis. Acta Neurol Scandinav 1969; 24: 78-86. Bullock JD, Falter RT, Downing JE, Snyder HE. Ischemic ophthalmia secondary to an ophthalmic artery occlusion. Am J Ophthalmol 1972; 74: 486-493. Rutgers DR, Klijn CJM, Kappelle LJ, et al. A longitudinal study of collateral flow patterns in the Circle of Willis and the ophthalmic artery in patients with a symptomatic internal carotid artery occlusion. Stroke 2000; 31(8): 1913-1920. Costa VP, Kuzniec S, Molnar LJ, et al. Collateral blood supply through the ophthalmic artery: A steal phenomenon analyzed by color Doppler imaging. Ophthalmology 1998; 105: 689-693. Tatemichi TK, Chamorro A, Petty GW, et al. Hemodynamic role of ophthalmic artery collateral in internal carotid artery occlusion. Neurology 1990; 40: 461-464. Marieb EN, Mallatt J. Human Anatomy. Benjamin Cummings: San Francisco, 2003. Hayreh SS. Orbital vascular anatomy. Eye 2006; 20: 11301144. Hayreh SS. The ophthalmic artery III: Branches. Br J Ophthalmol 1962; 46: 212-247. Harris A, Jonescu-cyupers CP, Kagemann L. Atlas of Ocular Blood Flow. Butterworth Heinemann: Boston, 2003. Mead GE, Wardlaw JM, Lewis SC, and Dennis MS. No evidence that severity of stroke in internal carotid occlusion is related to collateral arteries. J Neurol Neurosurg Psychiatry 2006; 77: 729-733. Yamauchi H, Kudoh T, Sugimoto K, Takahashi M, et al. Pattern of collaterals, type of infarcts, and haemodynamic impairment in carotid artery occlusion. J Neurol Neurosurg Psychiatry 2004; 75: 1697-1701. Kluytmans M, van der Grond J, Klijn CJM, et al. Cerebral hemodynamics in relation to patterns of collateral flow. Stroke 1999; 30: 1432-1439. Costa VP, Kuzniec S, Molnar LJ, et al. Clinical findings and hemodynamic changes associated with severe occlusive carotid artery disease. Ophthalmology 1997; 104: 1994-2002. Rutgers DR, Klijn CJM, Kappelle LJ, van der Grond J. Recurrent stroke in patients with symptomatic carotid artery occlusion is associated with high-volume flow to the brain and increased collateral circulation. Stroke 2004; 35: 1345-1349. Van Laar PJ, van der Grond J, Bremmer JP, et al. Assessment of the contribution of the external carotid artery to brain perfusion in patients with internal carotid artery occlusion. Stroke 2008; 39(11): 3003-3008. Ho AC, Lieb WE, Flaharty PM, et al. Color Doppler imaging of the ocular ischemic syndrome. Ophthalmology 1992; 99: 1453-1462. Fujioka S, Karashima K, Nakagawa H, et al. Classification of ophthalmic artery flow in patients with occlusive carotid artery disease. Jpn J Ophthalmol 2006; 50: 224-228. Ong TJ, Paine M, O’Day J. Retinal manifestations of ophthalmic artery hypoperfusion. Clin Exp Ophthalmol 2002; 30: 284-291. Mawn L, Hedges T, Rand W, et al. Orbital color doppler imaging in carotid occlusive disease. Arch Ophthalmol 1997; 115(4): 492-496.

23. Sturrock GD, Mueller HR. Chronic ocular ischaemia. Br J Ophthalmol 1984; 68: 716-723. 24. Cherny M, O’Day J, Currie J. Intraretinal gray lesions as a sign of reversible visual loss following prolonged ophthalmic artery hypoperfusion. J Clin Neuroophthalmol 1991; 11(4): 228-232. 25. Brown GC, Magargal LE, Sergott R. Acute obstruction of the retinal and choroidal circulations. Ophthalmology 1986; 93: 1373-1382. 26. Fujiwara T, Iida T, Kanda N. Lobular structure of the choriocapillaris in a patient with ophthalmic artery occlusion. Jpn J Ophthalmol 2007; 51(6): 478-480. 27. Hayreh SS, Zimmerman MB. Fundus changes in central retinal artery occlusion. Retina 2007; 27: 276-289. 28. Ko MK, Kim DS. Posterior segment neovascularization associated with acute ophthalmic artery obstruction. Retina 2000; 20(4): 384-388. 29. Soomro H, Armstrong,M, Graham EM, Stanford MR. Sudden loss of vision caused by a vasculitic ophthalmic artery occlusion in a patient with ankylosing spondylitis and Crohn’s disease. Br J Ophthalmol 2006; 90(11): 1438. 30. Klijn CJM, Kappelle LJ, van Schooneveld MJ, et al. Venous stasis retinopathy in symptomatic carotid artery occlusion: prevalence, cause, and outcome. Stroke 2002; 33(3): 695-701. 31. Ehlers JP and Shah CP, editors. 2008. Wills Eye Manual. 5th ed. Philadelphia: Lippincott Williams and Wilkins. 455p. 32. Saatci AO, Saylam GS, Yasti ZO, et al. Neurofibromatosis type I and unilateral ophthalmic artery occlusion. Ophthalmic Genet 1998; 19(2): 87-91. 33. Ang LP, Lim AT, Yap EY. Central retinal vein and ophthalmic artery occlusion. Eye 2004; 18: 439-440. 34. Bachman DM, Green WR, Holman R. Bilateral ophthalmic artery occlusion in a patient with acquired immunodeficiency syndrome and central nervous system lymphoma. Ophthalmology 2002; 109: 1142-1147. 35. Weinberger J, Bender AN, Yang WC. Amaurosis fugax associated with ophthalmic artery stenosis: clinical simulation of carotid artery disease. Stroke 1980; 11(3): 290-293. 36. Rothwell PM, Giles MF, Lovelock CE, Redgrave JNE, et al. A simple score (ABCD) to identify individuals at high early risk of stroke after transient ischaemic attack. Lancet 2005; 366: 29-36. 37. Braat AE, Hoogland PH, de Vries AC, et al. Amaurosis fugax and stenosis of the ophthalmic artery: A case report. Vasc Surg 2001; 35: 141-143. 38. Donders, RCJM. Clinical features of transient monocular blindness and the likelihood of atherosclerotic lesions of the internal carotid artery. J Neurol Neurosurg Psychiatry 2001; 71(2): 247-249. 39. Caplan L, Hertzer N. The management of transient monocular visual loss. J Neuroophthalmol 2005; 25(4): 304-312. 40. Yoshida T, Nakamura M, Miyake Y. Electrophysiological recovery after an ophthalmic artery occlusion during neurosurgery. Retina 2006; 26(1): 112. 41. Wolintz RJ. Carotid endarterectomy for ophthalmic manifestations: Is it ever indicated? J Neuroophthalmol 2005; 25(4): 299-302. 42. Rumelt S, Brown GC. Update on treatment of retinal artery occlusions. Curr Opin Ophthalmol 2003; 14(3): 139-141. 43. Duker JS, Brown GC. Recovery following acute obstruction of the retinal and choroidal circulations: A case history. Retina 1988; 8(4): 257-260.

Ophthalmic Artery Steal — Hsieh, Ilsen

28:1, 17

COPE-APPROVED CE CREDIT APPLICATION FORM

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QUESTIONNAIRE Ophthalmic Artery Steal Joyce Hsieh, OD; Pauline F. Ilsen, OD 1. ❏ ❏ ❏ ❏

In the Case Report presented, what was the patient’s visual acuity OD? 6/6 (20/20) 6/12 (20/40) 6/24 (20/80) 6/30 (20/80)

2. ❏ ❏ ❏ ❏

In what percentage of patients with internal carotid artery occlusion does reverse flow through the ophthalmic artery (OA) occur? Under 15% Approximately 25% 36.5%-75% 38.5%-76%

3. ❏ ❏ ❏ ❏

All of the following are relevant tests for suspected ophthalmic artery steal, EXCEPT: Electroencephalogram (EEG) Prothrombin time (PT) C-reactive protein (CRP) Liver function tests (LFTs)

Clinical and Refractive Optometry 28:1, 2017

COPE-APPROVED CE CREDIT APPLICATION FORM

All of the following describe the patient in this Case Report at initial presentation, EXCEPT: Painful left eye Graying vision Significant loss of vision in the left eye Hyperlacrimation upon awakening

5. ❏ ❏ ❏ ❏

Which of the following clinical features occurs in acute ophthalmic artery hypoperfusion, but not in central retinal artery occlusion? Retinal whitening ERG: reduced a-wave Cherry red spot FA: delayed retinal flow

6. ❏ ❏ ❏ ❏

In what percentage of patients with ocular ischemic syndrome is underlying carotid occlusion found? 5% 4%-18% 10%-25% 20%

7. ❏ ❏ ❏ ❏

Patients with ophthalmic artery hypoperfusion typically have all of the following comorbidities, EXCEPT: Diabetes mellitus Sensory peripheral neuropathy Atherosclerosis Hypertension

8. ❏ ❏ ❏ ❏

What percentage of the cerebrum’s blood supply is supplied by the vertebral artery system? 5% 10% 20% 30%

9. ❏ ❏ ❏ ❏

Which of the following statements describes the patient’s condition nine days following initial examination? Hypoplasia of the optic nerve had resolved Lipid panel showed high triglyceride levels Brain MRI revealed evidence of infarction approximately 1 year prior Head and neck magnetic resonance angiography (MRA) revealed 100% obstruction of the left internal carotid artery at its origin

10. ❏ ❏ ❏ ❏

What is the most common symptom in acute ophthalmic artery hypoperfusion? Ocular redness Ocular pain Acute painless vision loss Sudden-onset vertigo

28.1:17

4. ❏ ❏ ❏ ❏

Ophthalmic Artery Steal — Hsieh, Ilsen

News and Notes Essilor Canada Improves Lives by Improving Sight in the Laurentians Dedicated to improving lives by improving sight, a group of 104 employees from Essilor Canada and their partners: the Eye Disease Foundation, the Essilor Vision Foundation, the École d’optométrie de l’Université de Montréal and 6 volunteer optometrists have given back to the community in St. Jerome, Quebec, last January 12. Students from four primary schools were provided with a vision screening and free eyeglasses when needed. This mission, organized in the framework of Essilor’s National Sales Meeting, allowed 253 St. Jerome students to benefit from a vision screening. Of these, 162 had good vision, 70 were referred to an optometrist for a more thorough examination and 21 had to make an urgent appointment with an optometrist. “We have now integrated this type of Giving Back in the structure of our National Sales Meetings. Regardless of where the meeting takes place, we look to help people see the world better by partnering with the local Eyecare Professionals and their Associations,” says Essilor Canada President Pierre Bertrand. New Drugs Added to Prescribing List in Ontario The Ministry of Health and Long-Term Care (MOHLTC) has announced it has expanded the list of drugs that optometrists may prescribe for the treatment of eye and vision conditions. As of February 6, 2017, an additional 11 drugs have been included in the list of drugs controlled by Ontario’s Designated Drugs Regulation. Optometrists should familiarize themselves with the new drugs and prescribe them only in line with the standards of practice set out in the regulation and in OPR 4.4 (updated version coming soon). Optometrists are expected to understand the benefits and risks, including contraindications, of any drug prior to prescribing. For additional information on the amended regulation, including the listing of new drugs, visit the College of Optometrists of Ontario’s website at www.collegeoptom.on.ca. Expanded Parameters for Bausch + Lomb ULTRA® for Presbyopia Contact Lenses Bausch + Lomb recently announced the expanded parameter range for Bausch + Lomb ULTRA® for Presbyopia contact lenses. Since the contact lenses first launched in February 2016, Bausch + Lomb ULTRA® for Presbyopia contact lenses have been available in parameters between -7 D to +2 D. The expansion now extends the power range available to eye care professionals and patients to +4.50 D to -10.00 D (in 0.25 D steps) in both low add and high add. For more information, visit www.bausch.com.

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