CRO - Vol. 27, Number 1, 2016 by MediConcept

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Clinical & Refractive Optometry VOLUME 27, NUMBER 1, 2016

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Vascular Tumors of the Retina and Choroid Treating and Managing Dry Eye Advancing the Diagnostic Use of Tear Osmolarity in Primary Eye Care: Part 1 Advancing the Diagnostic Use of Tear Osmolarity in Primary Eye Care: Part 2

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Clinical &Refractive Optometry

Editorial Board â&#x20AC;˘ Volume 27, Number 1, 2016 Editor-in-Chief

Associate Editor

Richard Maharaj, OD Toronto, Ontario

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

Editors Emeriti Brad Almond, OD Calgary, Alberta

Barbara Caffery, OD Toronto, Ontario

John Jantzi, OD Vancouver, British Columbia

Yvon RhĂŠaume, OD Montreal, Quebec

Contributing Editors Scott D. Brisbin, OD Edmonton, Alberta

Gerald Komarnicky, OD Vancouver, British Columbia

Langis Michaud, OD Montreal, Quebec

Barbara Robinson, OD Waterloo, Ontario

Lorance Bumgarner, OD Pinehurst, North Carolina

Bart McRoberts, OD Vancouver, British Columbia

Rodger Pace, OD Waterloo, Ontario

Jacob Sivak, OD, PhD Waterloo, Ontario

Louis Catania, OD Philadelphia, Pennsylvania

Ron Melton, OD Charlotte, North Carolina

Maynard Pohl, OD Bellevue, Washington

Randall Thomas, OD Concord, North Carolina

Publication Staff Publisher Lawrence Goldstein

Managing Editor Mary Di Lemme

Senior Medical Editor Evra Taylor

Layout Editor Colin MacPherson

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

About This Issue This online issue of CRO (Clinical & Refractive Optometry) is being sent to you at no charge with the compliments of the CSCRO (Canadian Society of Clinical & Refractive Optometry). Each of the scientific articles contained in this issue have been approved by COPE for 1-hour of CE credit and are available at a cost of $25 per course. To take any of the CE credit courses in this issue, please follow the instructions on the test questionnaire pages. Please note that you can always upgrade to a print edition subscription of CRO (Clinical & Refractive Optometry) which will include 4 prepaid CE credit courses in every issue. For more details and to subscribe, please see the Subscription Upgrade Form on page 17.

Clinical&Refractive Optometry

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

Contents • Volume 27, Number 1, 2016

CE CREDIT ARTICLES 3 A Review of Cavernous Hemangioma of the Retina and Other Vascular Tumors of the Retina and Choroid Derek MacDonald, OD ABSTRACT: Vascular tumors of the retina and choroid may be found in isolation or in association with syndromes involving cutaneous and central nervous system lesions. Ophthalmic lesions may be sight-threatening, and may be the presenting sign of systemic disease with life-threatening consequences. The role of the eye care practitioner in establishing a prompt and accurate diagnosis cannot be understated.

Treating and Managing Dry Eye Shachar Tauber, MD ABSTRACT: Much has been learned about the tear film (and its impact on dry eye) over the years, from the discovery of its multilevel properties, increased understanding on the role of mucin, through to the interaction between the surface and the tear film. From an epidemiological standpoint, dry eye prevalence is in the range of between 6% and 14%, although most people have experienced dry eye in one of its many forms.

Advancing the Diagnostic Use of Tear Osmolarity in Primary Eye Care: Part 1 Richard Maharaj, OD ABSTRACT: The intrinsic and extrinsic risk factors associated with ocular surface diseases, as well as tear film osmolarity — and its role in optometric care are — are key elements in the diagnosis and treatment of dry eye disease. The goal of a stable tear film is based on the perfect interaction between the lipid, mucus and aqueous layers delivered by the meibomian glands, the goblet cells, and the lacrimal and accessory glands respectively, as well as the optimal interface between these layers and the lid mechanics. The examination of tear chemistry will play an increasingly major role in the diagnosis and treatment of dry eye disease and in the future of eye care.

Advancing the Diagnostic Use of Tear Osmolarity in Primary Eye Care: Part 2 Richard Maharaj, OD

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 © 2016 Mediconcept. The contents of the publication may not be mechanically or electronically reproduced in whole or in part without the written permission of the publisher. All drug advertisements have been cleared by the Pharmaceutical Advertising Advisory Board.

ABSTRACT: Osmolarity testing is a critical element in expanding optometrists’ diagnostic capability around their contact lens practice. Other metrics can be employed; however, tear osmolarity is an extremely good tool to use so that patients understand their situation very quickly. In addition, clinically, it has already been proven from an evidence-based perspective. Tear osmolarity is the only element that truly adds to the clinical decision. Tear chemistry and dry eye management are areas that will see enormous growth in the next decade.

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ISSN: 1705-4850; Date of Issue: January/February 2016

Cover Image: Patient with longterm contact lens discomfort. Courtesy of: Dr. Richard Maharaj

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Clinical & Refractive Optometry is pleased to present this continuing education (CE) article, originally published in CRO 25:1, by Dr. Derek MacDonald entitled A Review of Cavernous Hemangioma of the Retina and Other Vascular Tumors of the Retina and Choroid. In order to obtain a 1-hour Council of Optometric Practitioner Education (COPE) approved CE credit, please refer to page 10 for complete instructions.

A Review of Cavernous Hemangioma of the Retina and Other Vascular Tumors of the Retina and Choroid Derek MacDonald, OD, FAAO

ABSTRACT Vascular tumors of the retina and choroid may be found in isolation or in association with syndromes involving cutaneous and central nervous system lesions. Ophthalmic lesions may be sight-threatening, and may be the presenting sign of systemic disease with life-threatening consequences. The role of the eye care practitioner in establishing a prompt and accurate diagnosis cannot be understated.

INTRODUCTION Cavernous hemangioma of the retina is a relatively rare benign vascular tumor typically found unilaterally in Caucasian patients. Its ophthalmoscopic appearance is quite unique: multiple intraretinal aneurysms filled with venous blood resembling a cluster of grapes projecting above the retinal surface. Intravenous fluorescein angiography demonstrates a pathognomonic pattern of early hypofluorescence and late hyperfluorescence, but no leakage, as fluorescein layers above stagnant red blood cells in each individual aneurysm. As the lesion tends to be stable, regular observation is the rule, unless its location, vitreous hemorrhage, or retinal traction compromise vision. Differential diagnoses include other vascular tumors or anomalies of the retina or choroid: arteriovenous malformations, Coats’ disease, capillary hemangiomas, vasoproliferative tumors of the retina, and choroidal hemangiomas. Whether sporadic or part of a syndrome, ophthalmic lesions may be sight-threatening. Associated cutaneous and central nervous system lesions may be

D. MacDonald — D. & K. MacDonald & Associates, Waterloo, ON Correspondence to: Dr. Derek MacDonald, D. & K. MacDonald & Associates, 354 King Street North, Waterloo, ON N2J 2Z2; E-mail: derek.macdonald@rogers.com This article has been peer-reviewed.

life-threatening, making prompt and accurate identification critical. Given that presenting signs and symptoms are often visual, this responsibility may fall upon the eye care practitioner.

VASCULAR TUMORS OF THE RETINA AND CHOROID Cavernous Hemangioma of the Retina This is a rare vascular hamartoma, a benign disorganized overgrowth of otherwise normal tissue, typically found unilaterally, primarily in Caucasians.1-4 The average age of onset is the early to mid-twenties, with a slight (60:40) predilection for females.5 These lesions, while most often sporadic, have been classified as part of the phakomatoses, congenital multisystem disorders characterized by the presence of hamartomas in the eye, skin, visceral organs, and central nervous system (CNS).6-13 Defects in the tumor suppression gene resulting in uncontrolled cell growth have been implicated in the formation of these (and other) hamartomas.14 The most common symptoms in patients with CNS lesions include headaches, and seizures and focal neurologic deficits resulting from hemorrhagic stroke and brainstem abnormalities.15-23 Ophthalmic cavernous hemangiomas have been reported, albeit infrequently, in isolated cases of blue rubber bleb nevus syndrome (BRBNS, previously known as Gascoyen’s syndrome). Lesions of the skin and gastrointestinal tract, causing hemorrhage and anemia typically beginning in infancy, characterize this autosomal dominant (AD) condition, which has been reported in the literature fewer than 200 times. CNS involvement is rare. Differential diagnoses include other conditions associated with vascular skin lesions, including Sturge-Weber syndrome and von Hippel-Lindau disease.24-28 The retinal lesions (Fig. 1) are typically sessile clusters of saccular thin-walled aneurysms within the inner retina filled with dark red venous blood.29,30 Their appearance has been likened to that of a bunch of grapes, and they may be found at any location of the retina, including the optic nerve head (ONH).31 Lesions vary in size, from several disc diameters to those involving multiple quadrants of the fundus.32 There are no prominent vessels feeding or draining the lesion. Growth is rare,

Vascular Tumors of the Retina and Choroid — MacDonald

changes in head position. Ultrasonography shows high internal reflectivity (echodense), and intravenous fluorescein angiography (IVFA) demonstrates early hypofluorescence. During the late venous phase, fluorescein slowly trickles into the aneurysms, but does not leak; rather, it pools in the superior plasma, creating a vivid pathognomonic layering appearance that persists long after the dye leaves the rest of the retinal circulation. This unique IVFA appearance aids in the differential diagnosis versus other vascular tumors/anomalies of the retina and choroid, including: • Arteriovenous malformations (sometimes in association with Wyburn-Mason syndrome) • Coats’ disease • Capillary hemangiomas (sometimes in association with von Hippel-Lindau disease) • Vasoproliferative tumor of the retina • Circumscribed or diffuse choroidal hemangiomas (the latter in association with Sturge-Weber syndrome)38-40

Fig. 1 Cavernous hemangioma of the retina.

although enlargement of an overlying epiretinal membrane (ERM) and hemodynamic fluctuations in lesion size are possible. An ERM may be absent in lesions involving the ONH. The aneurysms demonstrate a histologically normal endothelium, maintaining an intact blood/retinal barrier (BRB), and are not typically prone to leakage or intraor sub-retinal exudation. As such, they usually remain visually asymptomatic unless there is vitreous hemorrhage (VH), retinal traction, or macular involvement. VH is uncommon (<15% of reported cases), although there are reports of labor-induced hemorrhage of cavernous hemangioma of the retina.33,34 Optical coherence tomography (OCT) has indicated that, in the absence of trauma and/or Valsalva maneuver, growth and contraction of the ERM is responsible for VH.35 Progressive thrombosis of individual aneurysms may occur over time. Given the stability of the majority of these lesions, treatment of an asymptomatic cavernous hemangioma is contraindicated; indeed, there are reports of laser photocoagulation resulting in reduced post-treatment vision secondary to VH, scarring, and retinal traction. Serial fundus photography is recommended.36 Slow venous perfusion leads to relative stagnation within the hemangioma; gravitational layering of clear plasma atop red blood cells can form a “pseudo-hypopyon” within individual aneurysms.37 This layering effect can shift with

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Arteriovenous Malformations of the Retina Arteriovenous malformations (AVM), previously termed racemose hemangiomatosis, involve anomalous dilated shunt vessels directly connecting the arterial and venous systems (anastomoses).41 They are usually found unilaterally (96%), originating at the ONH, although they may also be found in the mid-periphery.42 The diagnosis may be made at any age. Mild (Group I) cases may remain undiagnosed, whereas moderate (Group II) and severe (Group III) presentations with more extensive arteriovenous anastomoses are usually symptomatic and accompanied by similar malformations in the midbrain and ipsilateral cerebrum as sporadic Wyburn-Mason syndrome. Massively dilated, directly connected arteries and veins demonstrate high-velocity flow of oxygenated blood, and may be indistinguishable from each other in Group III lesions, resembling a “bag of worms” (Fig. 2). While Group I lesions rarely progress, those of Group II and III are prone to exudation, retinal and vitreous hemorrhage, venous occlusion, and secondary neovascular glaucoma; severe vision loss may occur. IVFA demonstrates abnormal arteriovenous communication, high laminar flow and adjacent capillary dropout. Leakage may be noted secondary to vasoocclusion. Ultrasonography shows a solid lesion with high internal reflectivity. Intracranial lesions, causing subarachnoid hemorrhage and/or hydrocephalus, typically become symptomatic by age forty. In the presence of ophthalmic lesions, neurologic work-up and imaging are essential. Neither retinal nor intracranial lesions are amenable to therapy.43 Coats’ Disease First described in 1908, Coats’ disease is not a true neoplasm, but rather a sporadic, unilateral (80 to 95%),

Fig. 2 Group III arteriovenous malformation in Wyburn-Mason syndrome (Asia Pacific Academy of Ophthalmology).

Fig. 3 Coats’ disease (Asia Pacific Academy of Ophthalmology).

idiopathic, progressive retinal telangiectasia (Fig. 3). It most often affects the inferior and temporal mid-periphery in otherwise healthy young males (4:1 to 10:1 versus females). No ethnic predilection has been identified. In Coats’ disease, the anterior segment remains normal. Some investigators consider it part of a disease continuum including juxtafoveal telangiectasia and Leber’s miliary aneurysms. The latter presents with little if any exudation in the temporal periphery.44 Two pathologic processes are in play: a breakdown of the BRB at the endothelial level and degeneration of the pericytes.45 The former causes lipid infiltration into the vessel walls, while the latter leads to aneurysm formation and vessel closure. Significant vision loss results from massive circumferential intra- and sub-retinal lipid exudation; hemorrhage and neovascularization are rare.46 Exudative macular/retinal detachment (RD), in the absence of appreciable vitreoretinal traction, occurs in over 80% of cases. Presenting visual acuity is 6/60 (20/200) to no light perception in 76% of cases. Strabismus and leukocoria are common.47 A critical differential diagnosis is retinoblastoma; however, the mean age at diagnosis of Coats’ disease is eleven years, while retinoblastoma typically presents in infancy. IVFA shows capillary non-perfusion, characteristic “light bulb” vascular dilatations and extensive leakage of the telangiectasia in all phases. Ultrasonography demonstrates sub-retinal opacities due to exudation and a linear echo typical of RD.

Treatment in mild to moderate disease aims to minimize exudation and prevent RD through laser or cryo-ablation of the abnormal vasculature. Intravitreal triamcinolone acetonide (IVTA) and anti-vascular endothelial growth factor (anti-VEGF) agents show promise as adjunct therapies. In advanced cases, however, vitrectomy or enucleation may be necessary. Capillary Hemangiomas of the Retina Capillary hemangiomas of the retina, also known as angiomatosis retinae, hemangioblastomas and hemangioendotheliomas, are benign tumors of the vascular stromal cells. They may occur sporadically (as von Hippel’s disease) or as phakomatoses, the most frequent and earliest manifestation of von Hippel-Lindau (VHL) disease.48,49 Bilateral orange-red retinal lesions are found in up to 50% of cases associated with VHL disease. They typically present between the ages of ten and forty and are solitary in two-thirds of cases. They may be central or mid-peripheral (the latter is more common, with two-thirds found temporally), and resemble a two- to three-disc diameter coil of capillaries with a single prominent feeding artery and draining vein, even when the tumor is small (Fig. 4). Prominent vessels emanating from the ONH are highly suggestive of a peripheral capillary hemangioma. Juxtapapillary lesions, usually at the temporal ONH margin, may be mistaken for papilledema or peripapillary choroidal neovascularization (CNV), and may lack exaggerated feeding vessels.50 Intraretinal and sub-retinal exudation may remain localized,

Vascular Tumors of the Retina and Choroid — MacDonald

Fig. 4 Capillary hemangioma of the retina (West Coast Retina Medical Group).

Fig. 5 Vasoproliferative tumor of the retina (Open-i U.S. National Library of Medicine).

but can affect the posterior pole as an “exaggerated macular response” or lead to exudative and/or tractional RD.51 IVFA is an informative ancillary investigation showing significant leakage, unlike cavernous hemangioma of the retina. Long-standing highly exudative lesions can be mistaken for Coats’ disease, although capillary hemangiomas tend to be more discrete, and Coats’ disease lacks prominent feeding/draining vessels. Ultrasonography, demonstrating mid- to high-degree internal reflectivity and sub-retinal fluid, is also helpful in differential diagnosis versus cavernous hemangioma.52 In these and other vascular lesions, fundus autofluorescence (FAF) is increased in the presence of early damage to the retinal pigment epithelium (RPE), and decreased in the presence of RPE death.53 Some advocate prophylactic treatment, given that progressive lesion enlargement and leakage are all but inevitable. Multiple-session laser photocoagulation, cryotherapy or radiotherapy may be utilized, particularly when tumors are smaller than 4.5 mm. Post-treatment, new lesions are likely to form. While photodynamic therapy (PDT) has proven promising, anti-VEGF injection outcomes have been variable.54,55 During or post-tumor treatment, vitrectomy may be considered in the presence of persistent ERM or tractional macular detachment.56 VHL disease (or cerebelloretinal hemangioblastomatosis) is a rare multiple-system AD familial cancer affecting, at most, 1:36,000 births. It involves renal carcinoma in 40% of patients by age sixty, pheochromocytoma (adrenal gland tumors), pancreatic cysts, and capillary hemangiomas of the eye and CNS, most commonly the cerebellum. Penetrance is agedependant, and may not be fully realized until the age of sixty-five. It is the only one of the phakomatoses lacking skin lesions and primary involvement of the anterior segment of the eye is uncommon. Retinal lesions are among the most common initial manifestations, found in 95% of patients by age ten.57-59 Given the potential for

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serious systemic involvement and associated mortality, detection of capillary hemangioma of the retina should trigger prompt medical consultation and, given AD inheritance, examination of other family members. Vasoproliferative Tumors of the Retina Vasoproliferative tumors of the retina (VPTR) were first identified in the early 1980s as presumed acquired retinal hemangiomas or localized peripheral adult Coats’ disease. It was thought that they were not true neoplasms, but rare, sporadic, benign peach/yellow elevated proliferations of glial, endothelial, and RPE cells.60 VPTR occur around the age of forty in both healthy men and women as solitary lesions in the far peripheral inferior temporal sensory retina (Fig. 5). In contrast to capillary hemangiomas, feeding vessels are absent or only mildly dilated. As they are very peripheral, some lesions may remain asymptomatic and require only periodic monitoring. Visual acuity, however, is reduced to 6/18 (20/60) or worse 40% of the time. Floaters and photopsia may also be reported. Surrounding intra- and sub-retinal exudation is found in 75% to 80% of cases and results in extensive fibrous metaplasia of the RPE.61 Eventual exudative RD, remote macular edema (ME) and ERM formation are common. Spectral domain and enhanced depth imaging OCT (SD and EDI OCT) may be helpful in delineating macular changes associated with these, indeed all, vascular tumors. Their anterior location makes imaging studies of the mass itself difficult. However, telangiectatic vessels on and within the lesions have been shown to hyperfluoresce on wide-field IVFA; ultrasound indicates a solid mass with variable internal reflectivity. Approximately one-quarter of VPTR are secondary to pre-existing

Fig. 6 Circumscribed choroidal hemangioma (Duane’s Ophthalmology).

inflammatory/degenerative ocular disease of childhood, including intermediate uveitis, retinitis pigmentosa, Coats’ disease, toxocariasis, toxoplasmosis, and retinopathy of prematurity.62 Secondary tumors may be bilateral, multiple, and accompanied by anterior chamber and vitreous cells.63 Some have hypothesized that these lesions are best classified as a proliferative vitreoretinopathy (PVR) variant. Recent histopathologic investigation has suggested less microvascular and more astrocytic (spindle cell) proliferation. Perhaps VPTR have been inappropriately characterized as non-neoplastic, and are better termed ‘retinal reactive astrocytic tumors’.64 When treatment is indicated, triple freeze-thaw cryotherapy and laser photocoagulation (for smaller lesions), radiotherapy (for larger lesions), and PDT may be considered. AntiVEGF agents are being investigated, and while initially promising, no conclusive results are yet available. Circumscribed Choroidal Hemangiomas In contrast to the retinal lesions already discussed, choroidal hemangiomas are vascular tumors of the uvea.65 Circumscribed choroidal hemangiomas (CCH) are relatively rare and benign hamartomas not associated with any systemic disease. They typically occur sporadically before the age of forty and may remain asymptomatic for years before causing reduced visual acuity due to sub-retinal fluid.66 These highly vascular tumors appear as slightly elevated (<6 mm) orange masses posterior to the temporal equator, accompanied by an adjacent exudative or serous RD when symptomatic.67 There are, however, no prominent feeding or draining vessels (Fig. 6). A pigmented margin may be the only feature distinguishing CCH from the normal adjacent choroid.

Ultrasonography shows a smooth, discrete, domeshaped mass with high internal reflectivity. IVFA demonstrates the choroidal origin of the lesion, showing early hyperfluorescence due to a lacy network of intrinsic vessels. Indocyanine green angiography (ICGA), offering increased choroidal visibility, shows late phase “washout” following initial intense hyperfluorescence. CCH is frequently misdiagnosed. Differential diagnoses include amelanotic choroidal melanoma (more yellow/tan in color, overlying drusen, slower IVFA filling, low internal reflectivity on ultrasonography), choroidal metastases (multiple, creamy yellow lesions), and atypical central serous retinopathy. Treatment, only when symptomatic, may be via aggressive plaque or external beam radiotherapy or laser photocoagulation. The latter is followed by recurrence in 40% of cases. PDT, repeated as required, is preferred for subfoveal CCH due to the fact that it spares the retina and effectively eliminates the sub-retinal fluid in 90% of cases.68 Anti-VEGF injections, both stand-alone and in concert with PDT, are being investigated.69 Long-duration infrared laser therapy, transpupillary thermotherapy (TTT), is 90% effective for selective destruction of extrafoveal lesions. Regardless of treatment modality, long-term visual prognosis is guarded. Diffuse Choroidal Hemangiomas Unlike circumscribed lesions, diffuse choroidal hemangiomas (DCH) are part of Sturge-Weber syndrome (SWS, also known as neuro-oculo-cutaneous hemangioma, or encephalotrigeminal or encephalofacial angiomatosis). Unlike other phakomatoses, SWS is not an inherited disorder, but rather a rare, sporadic condition of unknown etiology. It is typified by cutaneous nevus flammeus, or port wine stain, in the dermatome supplied by the ophthalmic (V1) branch of the trigeminal nerve.70 The lesion rarely involves the maxillary (V2) and mandibular (V3) branches. The congenital dark reddish flat DCH found in nearly 75% of cases of SWS are unilateral, poorly-defined, and ipsilateral to the port wine stain.71 Given their occasional similarity in appearance to circumscribed choroidal hemangiomas, the presence of a cutaneous lesion is an important differential diagnostic aid. Although congenital, DCH may not become symptomatic until adolescence through increased hyperopia and/or exudative RD. Ultrasonography demonstrates diffuse, ill-defined choroidal thickening. IVFA shows early and persistent hyperfluorescence; the latter characteristic is unlike circumscribed lesions. Treatment modalities include low-dose radiotherapy, anti-VEGF injection and multifocal PDT.72 Vision loss in SWS is usually a consequence of congenital glaucoma ipsilateral to, and strongly associated with, port wine staining of the eyelid. Glaucoma is found in up to 70% of cases, and is typically treated through

Vascular Tumors of the Retina and Choroid — MacDonald

multiple, often unsuccessful, filtering procedures. Proposed mechanisms for the insidious elevation of intraocular pressure (IOP) include increased episcleral venous pressure and anterior chamber angle abnormalities, including neovascularization. Affected individuals may also suffer from ipsilateral cerebral venous malformation (parietal and occipital leptomeningeal angiomatosis, the third component of the neuro-oculo-cutaneous triad). This is best visualized through magnetic resonance imaging (MRI) with contrast.73 SWS causes developmental delay, headaches, visual field defects, transient neurologic deficits, and in 80% of patients, contralateral, occasionally intractable seizures within the first two years of life. Pharmacologic anti-seizure treatment may need to be prompt and aggressive; early surgical intervention is controversial.

CONCLUSION Cavernous hemangioma of the retina is a relatively rare benign vascular tumor, often asymptomatic, typically requiring nothing more than regular monitoring. Treatment is only indicated in the presence of visual compromise resulting from vitreous hemorrhage or macular traction. When associated with neurologic symptoms or cutaneous lesions, neuroimaging is advised. Differential diagnoses include other vascular tumors or anomalies of the retina and choroid: arteriovenous malformations, Coats’ disease, capillary hemangiomas, vasoproliferative tumors of the retina, and choroidal hemangiomas. In some situations, these ophthalmic lesions are sporadic, while others may be part of the phakomatoses, congenital inherited lesions characterized by the presence of hamartomas in the eye, skin, visceral organs and central nervous system. Given the potential for ocular morbidity and systemic mortality, eye care practitioners play a very important role in early detection and accurate diagnosis. ❏

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Acknowledgement: The author gratefully acknowledges the invaluable assistance of Dr. John Gonder in reviewing this manuscript.

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Niccol W, Moore RF. A case of antiomatosis retinae. Br J Ophthalmol 1934; 18(8): 454-457. Klein M, Goldberg MF, Cotlier E. Cavernous hemangioma of the retina: a report of four cases. Ann Ophthalmol 1975; 7(9): 1213-1221. Vela JI, Garcia-Vilaro M, Buil JA. Haemorrhage of a cavernous haemangioma of the optic disc in pregnancy. BMJ Case Reports 2010; doi:10.1136/bcr.03.2010.2806. http://casereports.bmj.com/content/2010/bcr.03.2010.2806.full?si d=90e7407c-2880-4eb4-8efc-652796e34b4c Smith BT, Joseph DP. Labor-induced hemorrhage of a retinal cavernous hemangioma. Ophthalmic Surg Lasers Imaging 2009; 40(4): 419-420. Pringle E, Chen S, Rubinstein A, et al. Optical coherence tomography in retinal cavernous haemangioma may explain the mechanism of vitreous haemorrhage. Eye 2009; 23(5): 1242-1243. Backhouse O, O’Neill D. Cavernous haemangioma of the retina and skin. Eye 1998; 12: 1027-1028. Dunbar M. Did lesion reduce VA? Rev Optom online 2010; http://www.revoptom.com/content/c/22529/ Spalton DJ, Hitchings RA, Hunter P. Atlas of clinical ophthalmology. London, England: Gower 1984; 15: 16-20. Cavallerano AA, Gutner R, Oshinskie L. Macular disorders: an illustrated diagnostic guide. Newton, Massachusetts: ButterworthHeinemann, 1997: 117. Kanski JJ. Clinical ophthalmology 2nd edition. Rochester, Kent, England: Butterworth-Heinemann, 1989: 39-40, 399-410. Yannuzzi LA. Tumors of the retina, choroid, and vitreous. In: The retina atlas. St. Louis, Missouri: Mosby, 1995: 69-109. Turell ME, Singh AD. Vascular tumors of the retina and choroid: diagnosis and treatment. Middle East Afr J Ophthalmol 2010; 17(3): 191-200. Singh AD, Rundle PA, Rennie I. Retinal vascular tumors. Ophthalmol Clin N Am 2005; 18(1): 167-176. Reichstein DA, Recchia FM. Coats’ disease and exudative retinopathy. Int Ophthalmol Clin 2011; 51: 93-112. Ghorbanian S, Jaulim A, Chatziralli IP. Diagnosis and treatment of Coats’ disease: a review of the literature. Ophthalmologica 2012; 227: 175-182. Rubin MP, Mukai S. Coats’ disease. Int Ophthalmol Clin 2008; 48: 149-158. Shields JA, Shields CL, Honavar SG, Demirci H. Clinical variations and complications of Coats’ disease in 150 cases: the Sanford Gifford Memorial Lecture. Am J Ophthalmol 2001; 131(5): 561-571. Rho TM. von Hippel-Lindau’s disease: a report of five cases. Can Med Assoc J 1969; 101(3): 135-142. Shields CL, Shields JA, Barrett J, De Potter P. Vasoproliferative tumors of the ocular fundus. Arch Ophthalmol 1995; 11(5)3: 615-623. Kritzinger EE, Wright BE. Color atlas of the eye and systemic disease. Weert, Netherlands: Wolfe Medical Publications, 1984: 60-67. Pierro L, Guarisco L, Zaganelli E, et al. Capillary and cavernous hemangioma of the optic disc. Echographic and histological findings. Acta Ophthalmol Suppl 1992; 204: 102-106. Heimann H, Jmor F, Damato B. Imaging of retinal and choroidal vascular tumours. Eye 2013; 27(2): 208-216. (epub ahead of print: 2012 Nov 30. doi:10.1038/eye. 2012.251:1-9).

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Madreperla SA. Choroidal hemangioma treated with photodynamic therapy using verteporfin. Arch Ophthalmol 2001; 119(11): 1606-1610. McDonald HR, Schatz H, Johnson RN, et al. Vitrectomy in eyes with peripheral retinal angioma associated with traction macular detachment. Ophthalmology 1996; 103: 329-335. Papastefanou VP, Pilli S, Stinghe A, et al. Photodynamic therapy for retinal capillary hemangioma. Eye 2013 27(3): 438-442. (epub ahead of print 2013 Jan 4. doi:10.1038/eye. 2012.259:1-5). Singh AD, Shields CL, Shields JA. von Hippel-Lindau disease. Surv Ophthalmol 2001; 46(2): 117-142. Moore AT, Maher ER, Rosen P, et al. Ophthalmological screening for von Hippel-Lindau disease. Eye 1991; 5: 723-728. Kuo MT, Kou HK, Kao ML, et al. Retinal capillary hemangiomas: clinical manifestations and visual prognosis. Chang Gung Med J 2002; 25(10): 672-682. Chew EY. Ocular manifestations of von Hippel-Lindau disease: clinical and genetic investigations. Trans Am Ophthalmol Soc 2005; 103: 495-511. Rennie IG. Retinal vasoproliferative tumours. Eye 2010; 24: 468-471. Heimann H, Bornfeld N, Vij O, et al. Vasoproliferative tumours of the retina. Br J Ophthalmol 2000; 84(10): 1162-1169. Shields JA, Reichstein D, Mashayekhi A, Shields CL. Retinal vasoproliferative tumors in ocular conditions of childhood. J AAPOS 2012; 16(1) 6-9. Shields CL, et al. Retinal vasoproliferative tumors. Arch Ophthalmol; (epub ahead of print 2012 Nov 9. doi:10.1001/2013. jamaophthalmol.524:1-7). Poole Perry LJ, Jakobiec FA, Zakka FR, et al. Reactive retinal astrocytic tumors (so-called vasoproliferative tumors): histopathologic, immunohistochemical, and genetic studies of four cases. Am J Ophthalmol 2013; 155(3): 593-608. (epub ahead of print 2012 Dec 12. doi:10.1016/j.ajo.2012.09.002:1-17). Shields CL, Honavar SG, Shields JA, et al. Circumscribed choroidal hemangioma. Ophthalmology 2001; 108(12): 2237-2248. Mashayekhi A, Shields CL. Circumscribed choroidal hemangioma. Curr Opin Ophthalmol 2003; 14: 142-149. Singh AD, Kaiser PK, Sears JE. Choroidal hemangioma. Ophthalmol Clin North Am 2005; 18(1): 151-161. Elizalde J, Vasquez L, Iyo F, Abengoechea S. Photodynamic therapy in the management of circumscribed choroidal hemangioma. Can J Ophthalmol 2012; 47(1): 16-20. Hsu CC, Yang CS, Peng CH, et al. Combination photo-dynamic therapy and intravitreal bevacizumab used to treat circumscribed choroidal hemangioma. J Chin Med Assoc 2011; 74(10): 473-477. Baselga E. Sturge-Weber syndrome. Semin Cutan Med Surg 2004; 23(2): 87-98. Scott IU, Alexandrakis G, Cordahi GJ, Murray TG. Diffuse and circumscribed choroidal hemangiomas in a patient with Sturge-Weber syndrome. Arch Ophthalmol 1999; 117(3): 406-407. Ang M, Lee SY. Multifocal photodynamic therapy for diffuse choroidal hemangioma. Clin Ophthalmol 2012; 6: 1467-1469. Lo W, Marchuk DA, Ball KL, et al. Updates and future horizons on the understanding, diagnosis, and treatment of Sturge-Weber syndrome brain involvement. Dev Med Child Neurol 2012; 54(3): 214-223

Vascular Tumors of the Retina and Choroid — MacDonald

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QUESTIONNAIRE A Review of Cavernous Hemangioma of the Retina and Other Vascular Tumors of the Retina and Choroid Derek MacDonald, OD, FAAO 1. ❑ ❑ ❑ ❑ 2.

Which of the following patient profiles most accurately describes a patient with cavernous hemangioma of the retina? East Indian male, age 45 Caucasian female, age 22 Caucasian male, age 15 African-American female, age 60

❑ ❑ ❑ ❑

All of the following represent the most common symptoms in patients with central nervous system (CNS) lesions, EXCEPT: Headaches Seizures Dizziness Focal neurologic deficits

3. ❑ ❑ ❑ ❑

Which statement about arteriovenous malformations of the retina (AVM) is FALSE? Mild cases may exhibit some intermittent symptoms Severe vision loss may occur Patients with Group II lesions are typically symptomatic In more advanced cases, vitreous hemorrhage may occur

Clinical and Refractive Optometry 27:1, 2016

All of the following statements describe Coats’ disease, EXCEPT: It is unilateral It occurs on a sporadic basis It is more prevalent in females It is progressive

5. ❑ ❑ ❑ ❑

What is the presenting visual acuity in most patients with Coats’ disease? 6/30 (20/100) 6/60 (20/200) 6/90 (20/300) 6/120 (20/400)

6. ❑ ❑ ❑ ❑

All of the following statements about von Hippel-Lindau (VHL) disease are true, EXCEPT: Systemic involvement is extremely rare, occurring in roughly 5% of patients Retinal lesions are found in 95% of patients by age ten It is a hereditary cancer Penetrance is age-dependent

All of the following may manifest as characteristics of vasoproliferative tumors of the retina (VPTR), EXCEPT: Loss of visual acuity Floaters Diplopia Photopsia

❑ ❑ ❑ ❑ 8. ❑ ❑ ❑ ❑

Laser photocoagulation for circumscribed choroidal hemangiomas (CCH) is followed by recurrence in what percentage of cases? 25% 30% 35% 40%

9. ❑ ❑ ❑ ❑

Congenital diffuse choroidal hemangiomas (DCH) is characterized by all of the following, EXCEPT: Choroidal thickening It occurs predominantly in men Port wine stain They are part of Sturge-Weber syndrome (SWS)

10. ❑ ❑ ❑ ❑

In cases of SWS, glaucoma occurs in what percentage of cases? 40% 50% 70% 80%

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Vascular Tumors of the Retina and Choroid — MacDonald

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Clinical & Refractive Optometry is pleased to present this continuing education (CE) article, originally published in CRO 25:1, by Dr. Shachar Tauber entitled Treating and Managing Dry Eye. In order to obtain a 1-hour Council of Optometric Practitioner Education (COPE) approved CE credit, please refer to page 18 for complete instructions.

Treating and Managing Dry Eye Shachar Tauber, MD

ABSTRACT Much has been learned about the tear film (and its impact on dry eye) over the years, from the discovery of its multi-level properties,1 increased understanding on the role of mucin,2 through to the interaction between the surface and the tear film.3 From an epidemiological standpoint, dry eye prevalence is in the range of between 6% and 14%, although most people have experienced dry eye in one of its many forms.

INTRODUCTION This article reviews dry eye, its epidemiology, etiology, prevalence, and therapeutic options.

TEAR FILM STRUCTURE For many years, ophthalmology taught that the tear film was comprised of three distinct layers. What has been found is that it is actually an indistinct transition where the mucins are dissolved within the aqueous in a gradient (Fig. 1). The lipid layer is the thinnest of the layers and acts to prevent the evaporation produced by the meibomian glands. The aqueous layer is the thickest layer, and its role is to transport oxygen, enzymes, proteins, and other matter. The mucin layer is the innermost layer closest to the cornea, and it serves as a coating for the hydrophobic cornea regulating surface tension; it is produced by goblet cells and is composed of 21 different mucins.

ETIOLOGY Dry eye worsens with age and can be due to numerous causes. Therefore, it is important to regard dry eye not as a disease but as a multi-factorial disorder; and because of this, treatment has been extremely difficult to develop and S. Tauber — Section Chair Ophthalmology, Director of Ophthalmic Research and Telemedicine, Cornea and Refractive Surgeon, Mercy Eye Specialists, Springfield, MO Correspondence to: Dr. Shachar Tauber, Mercy Clinic Eye Specialists Ophthalmology - Surgery Center, 1229 E. Seminole, Suite 420, Springfield, MO 65804; E-mail: Shachar.Tauber@Mercy.Net This article has been peer-reviewed.

Clinical and Refractive Optometry 27:1, 2016

be proven as effective. Other than such environmental factors as air-conditioning and cold or dry weather, there are many other factors including different surgeries and disease entities that can cause dry eye. Medication-Induced Dry Eye Many patients present to us on multiple medications including beta-blockers, antihistamines, diuretics, chemotherapy, and anti-depressants. In fact, more patients on anti-depressants seek refractive surgery, which is an interesting relationship worthy of further investigation. Glycocalyx The glycocalyx is where the mucin attaches to the corneal epithelium and this interdigitation is quite important: when it fails, clinical dry eye develops (Fig. 2). The glycocalyx is a cotton-candy-like substance that grabs the mucin layer of the tear and allows it to adhere to the microvilli or the surface epithelium. Thus the ocular surface is made up of stroma matrix and fibroblasts, the epithelial cell membrane, the aqueous, the glycocalyx, and the mucin. Innervations Innervations are important as they are the sensory component going from the cornea to the lacrimal nucleus (Fig. 3). If those nerves are interfered with, outgoing messages to different parts of the lacrimal system will be affected. This is a problem often encountered in laser in-situ keratomileusis (LASIK), where it interferes with the corneal nerves.

DRY EYE CLASSIFICATION The National Eye Institute has classified dry eye into two general categories: tear deficient and evaporative; and within each main category are subcategories. Under “tear deficient” we find such conditions as Sjögren’s and auto-antibodies, and non-Sjögren’s and lacrimal deficiency, lacrimal obstruction, and reflex. Under “evaporative” we find the subcategories oil deficient lid-related, contact lenses, and surface changes.

TEAR FILM DEFICIENCIES Various dry eye disorders can be placed under one of three areas of tear film insufficiency: lipid, aqueous, and mucin.

Fig. 1 The traditional tear film model compared to the updated tear film model

Fig. 2 Glycocalyx helps mucin adhere to corneal epithelial cells; any damage to the glycocalyx means mucin deficiency, causing tear film destabilization and break up

eye symptoms, and begins a downward spiral. If we operate on these people, there is a risk of wound healing issues, infection, and chronic inflammation, whether performing LASIK, cataract surgery, transplant surgery, or glaucoma surgery. Therefore, treating the dry eye prior to surgery is indicated.

Fig. 3 Nerve distribution in a normal eye

Lipid Layer Deficiency Under this category we find a diverse group of disorders that lead to changes in meibomian gland secretions, including blepharitis. Aqueous Layer Deficiency As with lipid layer deficiency, there are many disorders that can lead to aqueous layer insufficiency and dry eye. These include: inflammation, trauma, neurological defects, and congenital absence, among others. Mucins Again, there are many potential causes of disruption to this tear film layer, including: Stevens-Johnson syndrome, pemphigoid, vitamin A deficiency, trachoma, and radiationinduced issues.

DRY EYE CYCLE Typically, a patient will present complaining of discomfort, which is actually environmental or contact lens intolerance. This creates surface changes that further worsen the dry

Tear Film Instability The tear film instability cycle (Fig. 4) begins with surface desiccation and leads to a hydrophobic cornea to which the mucin is unable to attach. This exposes the epithelial cells to evaporation, resulting in an inflamed cornea. Regardless of the original causal factor(s), the cycle remains the same: tear production decreases or tear evaporation increases; there is an increase in tear osmolarity and toxin concentrations; and goblet cell density decreases and epithelial desquamation increases. This leads to a breakdown of the cornea-tear interface and leads to an increase in such inflammatory mediators as cytokines and leukotrienes. The last step of this cycle is permanent surface stem cell, stromal matrix, and neurotrophic damage. Patients are then very susceptible to infection, inflammation, and ulceration of the cornea. When metaplasia is encountered in the lid margin, it becomes difficult for the ophthalmologist to separate the concomitant blepharitis and dry eye. Due to the advanced progression of the disease at this point, there are now overlapping issues with oil release, tear film evaporation, and dry eye exacerbation. Unprotected Surface What are the consequences of an unprotected surface? At time zero, when the blink occurs, the tear protects the ocular surface until that tear breaks up. If the tear breaks up prior to the subsequent blink, it results in ocular staining of the now unprotected surface. When repeated

Treating and Managing Dry Eye â&#x20AC;&#x201D; Tauber

Fig. 4 The process of tear film destabilization and the resulting corneal cell damage

Fig. 5 The OPI measures TFBUT as related to blink interval to determine whether the ocular surface has adequate tear film protection

PREVALENCE The prevalence of diagnostic dry eye must not be underestimated; because it is so common, it tends to be ignored. The symptoms can be extremely confusing; patients may present with decreased vision, and it is difficult to determine whether one is dealing with an early cataract, early Fuchs, or indeed an ocular surface issue.

TESTING TOOLS

Fig. 6 An evaluation (in seconds) of tear film break up elapsed time

over the course of a day, this can result in 4,000 to 8,000 seconds where the surface is unprotected and causes epithelial desiccation.

OCULAR PROTECTION INDEX (OPI) The OPI (Fig. 5) measures the tear film break up time (TFBUT). We then divide that time by the interval between blinks (IBI). Simply, if the patient blinks prior to TFBUT, then the ratio is >1 and the ocular surface is protected. Conversely, if the TFBUT occurs prior to the blink the ratio is <1, and the ocular surface is unprotected. There is a host of conditions that affect an individual’s blink rate. For example: hormonal changes, mental disorders, menstrual phase, muscular fatigue, drug interactions, computer use, and talking. It is recommended that clinicians watch their patients while taking their history to determine their blink rate.

Clinical and Refractive Optometry 27:1, 2016

In addition to observation of TFBUT, there are many diagnostic tools at our disposal for dry eye evaluation. Multiple dyes will stain the cornea and tear including Rose Bengal (which stings significantly), Lissamine Green, and fluorescein staining (frequently used). Fluorophotometry and osmolarity testing are quite complex and have not yet been sufficiently standardized to be used clinically.

TFBUT TFBUT is diagnostically helpful, but must also be standardized. Improved tear-film evaluation techniques include using ≤ 5µl of sodium fluorescein and Wratten filters for optimal imaging. Figure 6 shows one such tear-film evaluation in action. Another method to evaluate TFBUT is to ask patients to blink twice and look straight ahead. Using a stopwatch, time the seconds until they say they have ocular awareness. One second following ocular awareness equals the symptomatic tear break up time.

THERAPEUTIC OPTIONS Patient education is tantamount in helping them take a proactive role in the treatment process. Patients must be taught awareness of TFBUT, drying medications (i.e., oral antihistamines and antidepressants), adverse environments (i.e., dry, windy places), and visual tasking (i.e., computer usage, reading).

Artificial Tears There is a lengthy list of tear substitutes. The optimal artificial tear characteristics have increased dwell time and long-lasting protection. It must have minimal blurring and lid-caking, offer improved comfort, and it should contain non-irritating preservatives. However, rather than simply managing dry eye by flooding it, future therapy is going to involve treating dry eye via targeting the different tear film layers. Secretagogues Secretagogues will soon treat production of essential tear components at all three levels: there is the 15(S)-HETE that stimulates mucin production, as well as the INS-365 that stimulates all three tear-film layers. Anti-Evaporatives This upcoming therapeutic category stimulates lipid secretion to enhance and optimize the barrier function of the lipid layer. Anti-evaporatives include topical androgens that regulate the quality and quantity of lipid secretions, as well as lipid component replacements such as lipocalin, phosphatidylcholine, and castor oil. Anti-Inflammatories Anti-inflammatories target the inflammation component of dry eye at the lacrimal gland. It has been demonstrated that reducing the inflammatory response of the dry eye

WITH

is an effective treatment option; Restasis® is one such anti-inflammatory that has received FDA approval and is used widely in the United States. Other anti-inflammatories include low-dose steroids and tetracyclines. Mucomimetics The mucomimetics, as the name implies, mimic the functions of naturally occurring mucins; by stabilizing the tear film, they actually result in a healthier ocular surface. MILCIN™ is one mucomimetic that is on the horizon as a treatment option.

CONCLUSION To reach our collective goal of ocular surface protection, we must heal the damage and reduce inflammation and irritation. This will likely be accomplished by a line of products rather than one “cure-all”. With the many causes of dry eye and nearly as many therapeutic approaches, we will certainly be looking at combination therapy, with different treatments for different ideologies. ❏

REFERENCES 1. 2. 3.

Wolf. Normal Physiology of the Ocular Surface. Section 8 Basic and Clinical Sciences Course, American Academy of Ophthalmology 2002-2003, page 49. Holly FJ. Formation and stability of the tear film. Int Ophthalmol Clin 1973; 13(1): 73-96. Tseng SC, Tsubota K. Important concepts for treating ocular surface and tear disorders. Am J Ophthalmol 1997; 124: 825-835.

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QUESTIONNAIRE Treating and Managing Dry Eye Shachar Tauber, MD 1. ❑ ❑ ❑ ❑

According to the paper, what is the prevalence of dry eye? 6%-14% 10% 20% 25%

2. ❑ ❑ ❑ ❑

Which of the following is the thinnest tear film layer? Mucin Aqueous Lipid They all are of equal thickness

3. ❑ ❑ ❑ ❑

Aqueous layer deficiency can be caused by all of the following, EXCEPT: Trauma Inflammation Neurological defects Heredity

Clinical and Refractive Optometry 27:1, 2016

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Mucin layer deficiency can be caused by all of the following, EXCEPT: Pemphigoid Vitamin A deficiency Scleroderma Trachoma

5. ❑ ❑ ❑ ❑

All of the following can affect an individual’s blink rate, EXCEPT: Computer use Age Talking Drug interactions

6. ❑ ❑ ❑ ❑

All of the following are important characteristics of artificial tears, EXCEPT: Comfort Minimal blurring Long-lasting protection Rapid runoff

7. ❑ ❑ ❑ ❑

All of the following elements can cause dry eye, EXCEPT: Eye strain due to prolonged computer use Cold weather Air conditioning Certain types of surgery

8. ❑ ❑ ❑ ❑

In the last step of the tear film instability cycle, patients are vulnerable to all of the following, EXCEPT: Ulceration of the cornea Sjögren’s syndrome Inflammation Infection

9. ❑ ❑ ❑ ❑

Which of the following is the optimal treatment approach for dry eye? Anti-inflammatories Anti-evaporatives Combination therapy Mucomimetics

10. ❑ ❑ ❑ ❑

Which of the following is the thickest tear film layer? Aqueous layer Mucin layer Lipid layer They are all of equal thickness

27:1, 16

4. ❑ ❑ ❑ ❑

Treating and Managing Dry Eye — Tauber

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Clinical & Refractive Optometry is pleased to present this continuing education (CE) article, originally published in CRO 26:3, based on the first part of a presentation given by Dr. Richard Maharaj at the CRO 2015 Meeting in Toronto, Ontario in which he discussed the increasingly important role of tear osmolarity in optometric practice. We are presenting this paper for a second time so that it can be read in association with Part 2 of Dr. Maharaj’s presentation (on page 29) given in Vancouver. In order to obtain a 1-hour Council of Optometric Practitioner Education (COPE) approved CE credit, please refer to the page 27 for complete instructions.

Advancing the Diagnostic Use of Tear Osmolarity in Primary Eye Care: Part 1 Richard Maharaj, OD, FAAO

ABSTRACT The intrinsic and extrinsic risk factors associated with ocular surface diseases, as well as tear film osmolarity — and its role in optometric care are — are key elements in the diagnosis and treatment of dry eye disease. The goal of a stable tear film is based on the perfect interaction between the lipid, mucus and aqueous layers delivered by the meibomian glands, the goblet cells, and the lacrimal and accessory glands respectively, as well as the optimal interface between these layers and the lid mechanics. The examination of tear chemistry will play an increasingly major role in the diagnosis and treatment of dry eye disease and in the future of eye care.

INTRODUCTION Dr. Maharaj began his presentation by stating that during his longstanding practice he has seen a large number of dry eye patients, specifically dry eye patients with ocular surface diseases. His point of view is that when an optometrist sees a particular disease day in and day out, it alters their perspective. One of the focuses of Dr. Maharaj’s work is how osmolarity fits into the primary eye care arena. His primary interests are the intrinsic and extrinsic risk factors associated with ocular surface diseases and his presentation concentrated on the history and relevance of tear film osmolarity — and its role in optometric care.

SUGGESTING AN ALTERNATIVE TEAR FILM MODEL Dr. Maharaj described the various layers of the tear film: the lipid, mucus and aqueous layers delivered by the meibomian glands, the goblet cells, and the lacrimal and Maharaj — Clinic Director, eyeLABS, Brampton, Ontario; Staff Optometrist, Humber River Regional Hospital - York/Finch Eye Associates, Toronto, Ontario Correspondence to: Dr. Richard Maharaj, 7900 Hurontario, Suite 406, Brampton, ON L6Y 0P6; E-mail: rmaharaj@eyelabs.ca This article has been peer-reviewed.

Clinical and Refractive Optometry 27:1, 2016

accessory glands respectively. The goal of a stable tear film is based on the perfect interaction between these layers, as well as the optimal interface between these layers and the lid mechanics (Fig. 1). A large part of this is the sensory motor component of the ocular surfaces. In cases of dry eye or other surface diseases, typically the patient presents by saying, “I'm uncomfortable. I feel gritty, I feel sandy.” They often describe some form of discomfort, prompting the question of the underlying cause. Dr. Maharaj stated that he examines this query in terms of three major categories. Pathology is first and foremost. Both pathological and age-related changes conspire to break down the ocular surface. The second element is environmental or external factors and the third being anatomical considerations, involving an examination of the blink mechanism. It’s not a perfect vertical movement; in fact, there are torsional, tangential and vertical movements of both the upper and lower eyelid. It’s a very complex series of mechanisms that add up to a perfect blink; and in fact, the majority of dry eye sufferers, more than 60% of them, have some form of lid dysfunction or blink closure; rather, the lack thereof. What may be defined as lagophthalmos in some cases may not, in fact, be so obvious. What’s more, these microanatomical changes at the level of the blink have a huge impact. Depending on the ethnicity of the patient and their age, and with various activities, these movements can change. Dr. Maharaj underscored the fact that optometrists tell their patients about the 20/20/20 rule, trying to drive home the message that the anatomy of the blink matters.

ENVIRONMENTAL FACTORS In terms of external environmental factors, seasonal allergens in the air definitely have an impact on dry eye disease. For a dry eye patient who has a less than perfect tear film, allergens may be the tipping point: they may represent the element that shifts a patient from being asymptomatic to symptomatic, as a large part of the disease exists in the asymptomatic stage. Another important aspect is the effect of the office environment on the blinking process. In a large room, patients can undertake preventive measures such as artificial

Stable Tear Film Maintenance Lacrimal Gland Anatomical

Meibomian Gland

Aqueous Lipid Mucin

Goblet Cells Stable Tear Film Lid Blinking Sensory Motor Lid Closure

Chemical Composition of Human Tear & Plasma

Tear Clearance & Spread

↓ Evaporation

Water Solids (total) NA+ K+ CLHCO3Ca2+ Glucose Total protein Amino Acids Urea

TEARS

PLASMA

98.2% 1.8% 142meq/l 15-29meq/l 120-135meq/l 26meq/l 2.29mg/100ml 3-10mg/100ml 0.6-2g/100ml 8g/100ml 0.04mg/100ml

94% 6% 137-142meq/l 5meq/l 102meq/l 24.3meq/l 80-90mg/100ml 6.78g/100ml 20-40mg/100ml Dr. Vijay Joshi, MS, MBBS Ophthalmology

Fig. 1 Proper interaction between tear film layers is vital to a stable tear film.

Fig. 2 Human tear and plasma share similar chemistry.

tears as they know in advance that their eyes are going to get irritated. Foreign bodies such as microparticulates including make-up, dust, epidermis and devitalized epithelium, are evident in patients’ tear film all the time. The following question arise: Should we address this? Is it normal? In a healthy eye with a healthy tear film, that may not be necessary; however, said Dr. Maharaj, how does an optometrist know if a patient has a healthy tear film? Here, diagnostics play a significant role. Contact lenses are an obvious additional environmental factor, and represent an etiology for which practitioners are, in fact, responsible. Currently, optometrists are using single use and reusable lenses, and are adding different solutions and playing with various materials. However, as Dr. Maharaj pointed out, a contact lens is still a foreign body being introduced into patients’ eyes. They’re being used for good reason and with good intent, with a body of science behind them, but the fact remains that a foreign body will be recognized by one’s body as foreign, contributing to inflammation and therefore an immunological response will be triggered. All of the above are extrinsic factors that contribute to patient discomfort.

Currently, practitioners are seeing a departure from the model of three discrete tear film layers: the mucin, the lipid and the aqueous, with the aqueous making up the bulk of the layers. The literature is reflecting a shift away from the classical type of “sandwich,” with the aqueous in the middle, the lipid on top and the mucin on the bottom. In an alternate tear film model, a glycocalyx transmembrane emanates through the layers and is anchored to the epithelium. The question arises, “Does the chemical composition of tears affect dry eye progression and is this important?” Dr. Maharaj pointed out that there are several components that the industry is examining very closely. Physicians have relied heavily on lab work, including blood testing, and a shift in direction when it comes to tear chemistry is occurring in much the same way. This is relevant considering that eyes are constantly bathed in this solution that's being produced by the body, so any changes in it make a difference. Inorganic salts in particular — microproteins — contribute heavily to the measurement of tear osmolarity. Tears contain hormones, which is why, in female patients in their fifties who are going through menopause, start to see the onset in their dry eye symptomology. It may in fact be related, and the endorphins that contribute to the sense of pain are also present. The lipid layer is the interface between tears and the air, but the mucin layer is the scaffolding that gives tears their structure. Secretory mucins at the ocular surface interact with epithelial receptors that, so if there is dysfunction in the corneal epithelium or in those receptors, this may indicate a dysfunction in the scaffolding. Figure 2 illustrates a parallel between blood plasma and tears, showing very similar values. Regarding blood chemistry testing and how relevant it is in overall systemic

PATHOLOGICAL AND CHRONOLOGICAL CHANGES Dr. Maharaj highlighted the challenge of lid wiper epitheliopathy. He feels that it is an interesting concept and pathology as, like dry eye, it can start in an asymptomatic phase; indeed, in most cases, it does. Staining is one of the best methods of early testing to help identify the condition; he suggested it for at-risk patients (contact lens wearers, tight lids, obvious and non-obvious MGD patients, etc.). Friction at the lid wiper and ocular surfaces is the key to the dry eye symptomology— and the driving force behind the inflammatory cascade at the ocular surface.

Advancing the Diagnostic Use of Tear Osmolarity in Primary Eye Care: Part 1 — Maharaj

health, Dr. Maharaj proposed the question, is the same level of scrutiny helpful for ocular surface diseases? His response answer is that it is indeed.

DRY EYE DISEASE AND OCULAR WELLNESS The prevalence of dry eye disease has been stated in a number of different ways, depending on how it is defined in the various clinical studies. However, Dr. Maharaj postulated about a unified way of defining dry eye disease such as is done with glaucoma or macular degeneration. Is there a reliable metric that can be used in the primary care arena that helps to define it — because if so, he pointed out, these numbers might actually fall into slightly more agreement. Knowing that in optometric practice dry eye disease is second only to cataracts in terms of prevalence, it's a huge cohort. Dr. Maharaj posed the following questions for consideration: how is it being managed? Are practitioners doing anything different than they were five or ten years ago? Even with the growing number of options in contact lenses and care solutions, the dropout rates by contact lens wearers due to discomfort hasn't changed when considering all of these advances, a decline in dry eye disease should be evident. Dr. Maharaj suggested that a key piece of the puzzle might be missing.

TEAR OSMOLARITY PAST AND PRESENT The history of tear osmolarity began with the late Jeff Gilbard who was, in Dr. Maharaj’s opinion, well ahead of his time. As early as 1978, he proposed that hyperosmolarity is the driving force behind ocular surface disease. He published papers on the correlation between high incidences of eye osmolarity and decreased corneal epithelial glycogen, and conjunctival goblet cell density. In an inverse relationship, the higher the tear osmolarity, the more change in the goblet cell morphology was seen. In 1989, he determined that hyperosmolarity was, in fact, coincident in patients that had good lacrimal gland function but meibomian gland orifices closure. This was the first time anybody had the suggested that hyperosmolarity was actually a major culprit in dye eye disease. Gilbard's work was finally recognized and catapulted to its current status.

DEFINITION AND MEASUREMENT OF OSMOLARITY Osmolarity is the measure of solute concentration. Its unit of measure is osmoles per liter, or in the case of the tear film milliosmoles per liter because the value is so very low. Surprisingly, there are three methods of measuring osmolarity. The first, which does not seems to suit the primary eye care setting, is the freezing point depression.

Clinical and Refractive Optometry 27:1, 2016

When a particular material is frozen — for instance, water — it freezes at 0 degrees. If the solute level or the osmolarity of that solution is higher, the freezing point drops and that point of depression, that delta between 0 and the freezing temperature, can be extrapolated to osmolarity. The sample requires 0.2 uL so it's still rather large but it can be done, and it is used in lab testing, stated Dr. Maharaj. The converse is also true. The second method — vapor pressure — can also be tested to correlate to osmolarity. Again, the mechanism is extremely complex and it doesn't lend itself very well to primary care; however, there are several institutions that use vapor pressure to measure osmolarity — not tear osmolarity, as it uses quite a large sample size. The third method is commonly recognized and used: electrical impedance. The conductivity of the fluid is changed and it is proportional to the osmolarity or concentration of the solution. It actually requires a very small sample of approximately 50 nL, which is perfect because only a small amount of tears is available, about 17 uL. It has been available through TearLabTM testing for some time.

OSMOLARITY VERSUS OSMOLALITY As a differentiation between osmolality, and osmolarity, osmolality refers to the solute concentration per kilogram; it's the solvent measured as a solid as opposed to a liquid. Tear film never solidifies therefore in this discussion, stated Dr. Maharaj, osmolality and osmolarity are synonymous. These two words can be used interchangeably; however, in the literature it is referred to as osmolarity. In the DEWS (International Dry Eye Workshop) report in 2007, tear osmolarity was actually incorporated as part of the definition of dry eye disease. The IOP at or above which practitioners should be concerned in glaucoma patients is 21, an extremely important recognized benchmark; it has helped to identify glaucoma patients far earlier — and, in Dr. Maharaj’s view, the specificity and sensitivity in optometry practices have increased as a result of that. Knowing that the prevalence of dry eye disease is significantly greater than that of glaucoma, and that there is a metric that has been included in the definition, it does make sense that practitioners can delve into this disease through their patient base and see if there is preventative action they can take. Patients who test above 308 milliosmoles per liter do, in fact, have the disease. Tear osmolarity is the global marker agreed upon by both ODs and MDs alike, which is a rarity, but in the presence of a measure that is so strong, it begs further exploration. It is elevated in the diabetic population and in patients on chronic glaucoma medication who are exposed to BAK on a regular basis. The dry eye disease population is paralleled only by that

Defining the Disease At 308 mOSm/L cutoff • Specificity = 88% and Sensitivity = 75% At 315 mOSm/L cutoff • Specificity = 92% and Sensitivity = 73% • PPV 85% - i.e. “The % of time a metric > 308 mOsm/L will actually be DED Recall • Sensitivity % of persons who actually have the disease. • Specificity % of persons who do not have the disease. • Positive Predictive Value is the percent of people with a positive test who have the disease. • Negative Predictive Value is the percent of people with a negative test who do not have the disease.

Observed Differences in Hyperosmolarity & Normal Participants =< 308 mOsm/L

> 308 mOsm/L

Avg osmolarity

297 +/- 7

323 +/- 17

Inter-eye difference

6 +/- 6

17 +/- 16

McDonald ASCRS 2013- Osmolartiy Prevalence Study (from Donnenfeld)

Fig. 3 Using sensitivity and specificity to define dry eye disease.

Differences in Hyperosmolar & Normal Participants =< 308 mOsm/L > 308 mOsm/L Overall population

52%

48%

Pts reporting 3 or more DED symptoms

49%

51%

Reporting less than 3 DED 54% symtpoms (Asymptomatic)

46%

McDonald ASCRS 2013- Osmolartiy Prevalence Study (from Donnenfeld)

Fig. 5 Dry eye symptoms in hyperosmolar and normal patients.

of diabetes in the United States, with some 25 million people affected.

ROLE OF OSMOLARITY IN DRY EYE DISEASE The 308 mOsms/L figure was derived from a 2010 study by Michael Lemp, published in 2011 (Fig. 3). It postulated and confirmed that above 308 mOsms/L, one sees an increase in inflammation and apoptosis, as well as a breakdown in useful homeostasis. However, the question remains, what causes dry eye disease hyperosmolarity? Compared to other markers such as tear break-up time, Schirmer's and the ocular surface increase index, osmolarity has much greater sensitivity and specificity. In Dr. Lemp’s paper, above the cutoff of 308, sensitivity was at 70% and specificity was at 88%. Specificity indicates that the number of patients who test negative is high; therefore, if it's good at determining who doesn't have it, it's good at

Fig. 4 Comparing hyperosmolar and normal participants.

determining who does have it. As osmolarity increases, so does specificity. Furthermore, in the second best measure, ocular surface disease index, in Dr. Lemp’s research the agreement still wasn't as high as with osmolarity.

PREVALENCE OF DRY EYE DISEASE Dr. Eric Donnenfeld began a prevalence study in 2012, which was taken over by Dr. Marguerite McDonald in 2013. It comprised approximately 9,000 patients sequentially, excluding those who had been artificial teared within two hours of testing. Their demographics and history were taken followed by a series of yes or no questions. The patients were then classified as either having dry eye disease or having normal or low osmolarity. Of particular interest, Dr. Maharaj stated, was that for patients who had normal osmolarity, below 308, the inter-eye difference was actually quite low at ±6. For patients above 308, the inter-eye difference is actually fairly significant, at 17±16 (Fig. 4). A similar trend was that the inter-eye difference above the 308 threshold increases. At the same time, osmolarity tended to be higher in the more painful eye. Dr. Maharaj noted that these are now regarded as trends to look for. In patients with dry eye disease, often one eye feels worse than the other. Furthermore, it's quite possible that after measuring their osmolarity, the delta is actually in favour of the eye that is more uncomfortable. Figure 5 presents rates of symptomatology in hyperosmolar and normal patients. Fifty percent of those with normal osmolarity reported three or more dry eye-like symptoms; therefore, 50% were experiencing some other disease causing their symptomology. Close to half of these 9,000 dry eye patients were silently suffering and were only uncovered by the osmolarity testing, stated Dr. Maharaj.

Advancing the Diagnostic Use of Tear Osmolarity in Primary Eye Care: Part 1 — Maharaj

The salient point is that patients who are symptomatic and have abnormal tear film still need to get run through for diagnosis. In addition, they need to be examined for corneal health, staining and other standard testing for other possible contributing factors.

RELATIONSHIP BETWEEN OSMOLARITY AND MEIBOMIAN GLAND DYSFUNCTION Dr. Anthony Bron et al in the UK have put forth the concept of a solute gradient of the tear film, using a tear prism model: it has a thick base and a thin apex, with solute concentration in osmolarity highest at the apex and lower at the base. As a result, there is a driving force from tear film to the lid margin and therefore the meibomian gland orifice (MGO) forcing solutes towards the lid margin and into the MGO. This may in fact be a key mechanism in the genesis of MGD demonstrating its origin in hyperosmolar environments.

patients developed dry disease, who were normal preoperatively. The literature cites postoperative dry eye prevalence anywhere from 8% to 52%. In light of these negative surgical effects, Dr. Maharaj posed the question, is there room for optometrists to do more to these patients pre-surgically in order to identify them properly?

PREVENTIVE MEASURES FOR DRY EYE DISEASE

Dr. Maharaj mentioned that the average dry eye patient is female, over age 30, is a contact lens wearer, and uses a computer. This demographic also fits the profile of the decision-makers in families. These are patients who, if they’re well taken care of and identified in the asymptomatic phase, can be steered clear of a disease that will induce anxiety, depression, and a whole cascade of events that can be life altering — and his first-hand experience bears witness to this. Regarding contact lens dropouts, the number in recent years is 30% in the first year of wear alone, despite advances in contact lens materials and solutions.

The TearLab™ detection test for dry eye disease has been on the market for a while. It comprises a detection system, with a simple applicator and disposal test cards that produce the result number. In July 2015, i-Pen® was launched by I-MED Pharma as another point of detection test, again using a simple single, disposable chip. Rather than being housed in a charger, it is a hand-held battery operated device which is very simple to operate. It gives the reading in less than 5 seconds and patients are very comfortable during the test procedure. Dr. Maharaj stated that the modern focus of medical endeavours is prevention. This raises the issue of when to initiate preventative measures in dry eye disease management like diagnostic testing which may impact early intervention and treatment, as has already happened in diseases like glaucoma and macular degeneration, for example. Dr. Maharaj remarked that surgical patient remains under the optometrist’s care, and always will be, the optometrist’s patient. His view is that ODs are “lending” the person to ophthalmology to perform a surgical medical procedure — and that patient will return to the OD. The chances are, he stated, that if there are any complications, it will flow through the optometrist’s office, and it is incumbent upon ODs to manage the situation.

DRY EYE DISEASE IN SURGICAL PATIENTS

CONCLUSION

IMPACT OF DRY EYE ON OPTOMETRIC PRACTICE

William Trattler MD did a retrospective study called the PHACO study which examined 272 eyes of 136 patients for incidence of DED in a surgical population. Using the ITF, the International Task Force classification on dry eye, almost 63% of patients had abnormal break-up times; 21% had an abnormal Schirmer's score; and almost 77% were positive for corneal staining, 50% of which had central staining. 87% of the dry eye patients identified were asymptomatic. This potentially represents a high number of patients emerging post-surgery with postoperative dryness. In many cases DED is present preoperatively and not adequately managed. In a small internal study at his clinic in Brampton of approximately 100 patients, looking at their ocular surface disease index, and fluorescein staining, 23% of post-cataract

Clinical and Refractive Optometry 27:1, 2016

Dr. Maharaj concluded his presentation by commenting that the contact lens landscape is rapidly evolving. Google, for instance, is now hoping to develop a contact lens that measures blood glucose. Additionally, he asserted that the modulus of that lens will be slightly higher than current options, and the coefficient of friction will probably be higher. The ways in which this and other contact lens advances will impact optometric practice should impact the overall management of the ocular surface as a consequence. He feels strongly that tear chemistry will play an increasingly major role in the future of eye care, and that what worked five or ten years ago should not, in fact, work in the upcoming five or ten years. If it does, he opined, the chances are that doctors of optometry and ophthalmologists alike are doing something wrong. ❏

27:1, 16

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QUESTIONNAIRE Advancing the Diagnostic Use of Tear Osmolarity in Primary Eye Care: Part 1 Richard Maharaj, OD, FAAO 1. ❑ ❑ ❑ ❑

What percentage of dry eye sufferers have some form of lid dysfunction? More than 40% More than 50% More than 60% More than 80%

2. ❑ ❑ ❑ ❑

All of the following statements about dry eye disease are true, EXCEPT: It can start in the asymptomatic phase Contact lenses are an environmental factor in dry eye etiology Make-up is one of several foreign bodies that are evident in patients’ tear film all the time Most patients present for the first time with advanced dry eye disease

3. ❑ ❑ ❑ ❑

All of the following statements about tear osmolarity and dry eye disease are true, EXCEPT: Andropause may trigger the onset of dry eye symptomatology Menopause may trigger the onset of dry eye symptomatology Microproteins contribute to the measurement of tear osmolarity Dropout rates by contact lens wearers due to discomfort haven’t changed

Advancing the Diagnostic Use of Tear Osmolarity in Primary Eye Care: Part 1 — Maharaj

COPE-APPROVED CE CREDIT APPLICATION FORM

Which osmolarity indicates dry eye disease? 150 milliosmoles per liter 270 milliosmoles per liter 308 milliosmoles per liter 400 milliosmoles per liter

5. ❑ ❑ ❑ ❑

Which of the following ocular conditions is most prevalent? Dry eye disease Glaucoma Blepharitis Keratitis

6. ❑ ❑ ❑ ❑

In glaucoma patients, an IOP at or above which level is concerning to practitioners? 15 21 25 30

7. ❑ ❑ ❑ ❑

In Dr. Lemp’s research, osmolarity above the cut-off of 308 milliosmoles per liter, specificity was at what percentage? 55% 60% 78% 88%

8. ❑ ❑ ❑ ❑

All of the following characteristics describe the typical dry eye patient, EXCEPT: Female Over age 30 Contact lens wearer Extended contact lens wearer

9. ❑ ❑ ❑ ❑

Which of the following is the rate of contact lens dropout in the first year of wear? 20% 25% 30% 35%

10. ❑ ❑ ❑ ❑

In Dr. Trattler’s research, what percentage of dry eye patients were identified as asymptomatic? 42% 55% 72% 87%

27:1, 16

4. ❑ ❑ ❑ ❑

Clinical and Refractive Optometry 27:1, 2016

CLICK HERE TO PRINT THIS CE CREDIT ARTICLE AND TEST

Clinical & Refractive Optometry is pleased to present this continuing education (CE) article based on the second half of a presentation given by Dr. Richard Maharaj at the CRO 2015 Meeting in Vancouver, BC in which he discussed the application of tear osmolarity metrics in general optometricpractice. In order to obtain a 1-hour Council of Optometric Practitioner Education (COPE) approved CE credit, please refer to page 34 for complete instructions.

Advancing the Diagnostic Use of Tear Osmolarity in Primary Eye Care: Part 2 Richard Maharaj, OD, FAAO

ABSTRACT Osmolarity testing is a critical element in expanding optometrists’ diagnostic capability around their contact lens practice. Other metrics can be employed; however, tear osmolarity is an extremely good tool to use so that patients understand their situation very quickly. In addition, clinically, it has already been proven from an evidence-based perspective. Tear osmolarity is the only element that truly adds to the clinical decision. Tear chemistry and dry eye management are areas that will see enormous growth in the next decade.

Fig. 1 Patient with long-term contact lens discomfort (OS).

INTRODUCTION Dr. Maharaj explained that he would be presenting several cases he has encountered in his clinic, followed by some of the diagnostic capabilities that influence optometrists’ treatment choices, and how they apply to osmolarity. He stated that in the past four years since osmolarity testing has become widely available, there has been little in terms of guidance regarding how to use it, which may have resulted in practitioners not actually using it to the extent that it is valued. Dr. Maharaj summarized three key factors that induce dryness, namely, pathological/ chronological, external, and anatomical influences. Case #1 A 27-year-old male presented to the clinic. He had been a contact lens wearer for roughly six years and had never been happy with his contact lens comfort. He used Air Optix® (Alcon, Mississauga, ON), a monthly lens modality, along with OPTI-FREE® Replenish® multipurpose solution (Alcon, Mississauga, ON). He noted seasonal allergies in his medical history. He had had a two-week onset of red, R. Maharaj — Clinic Director, eyeLABS, Brampton, Ontario; Staff Optometrist, Humber River Regional Hospital - York/Finch Eye Associates, Toronto, Ontario Correspondence to: Dr. Richard Maharaj, 7900 Hurontario, Suite 406, Brampton, ON L6Y 0P6; E-mail: rmaharaj@eyelabs.ca This article has been peer-reviewed.

itchy eyes, with the left eye worse than the right. Figure 1 depicts the left eye. The patient had vernal keratoconjunctivitis (VKC) with trantas dots along his limbus, an infiltrative response, and severe discomfort. Treating the histamine response that was inducing the VKC was certainly integral to managing this patient’s condition. He was started on Lotemax® (loteprednol etabonate ophthalmic suspension 5%, Bausch & Lomb, Vaughan, ON) QID for two weeks – an aggressive regimen to optimize response – along with no contact lens wear for those two weeks. This was done for two reasons: first, because he was highly reactive; he was in a reusable lens, and was also non-compliant with his cleaning; and second, Dr. Maharaj stated, he wanted him to be without his contact lenses for that time in order to be a bit punitive. However, Dr. Maharaj did it with the intention of giving the patient a quick result because he was anticipating transitioning him into a healthier contact lens modality. The healthiest lens is no lens; the second healthiest lens really is a one-day lens. Fewer than 20% of contact lens patients are wearing one-day contact lenses according to Canadian statistics, yet it’s a known fact that they are accompanied by fewer adverse reactions than reusable lenses.

Advancing the Diagnostic Use of Tear Osmolarity in Primary Eye Care: Part 2 — Maharaj

The question was whether or not to change the patient’s contact lens modality. The patient had stated that his problem was long-standing and was actually reporting symptoms of contact lens induced dry eye (CLIDE). After the VKC resolved, Dr. Maharaj took some clinical measurements, specifically, tear breakup, corneal and lid wiper staining, none of which were normal; his tear osmolarity was high at 317 mOsm/L OD and 334 mOsm/L OS. Dr. Maharaj highlighted that he spends extensive time counselling his dry eye patients. He explained to this patient that his tears were very salty (hyperosmolar) and that this was a major contributor of his discomfort. He told the patient that he would send a letter to his referring optometrist, with some recommendations, including discontinuing the contact lens solution as solution toxicity may have been adding to his hyperosmolarity in addition to denatured protein on his monthly contact lens surface. The patient’s optometrist subsequently switched him to a one-day high water content hydrogel material. At onemonth follow-up the patient reported that he was doing very well and wasn’t experiencing nearly the same amount of discomfort as previously. At this point he also wasn't using any additional artificial tears. A follow-up tear osmolarity test revealed that he was down to 304 mOsm/L OD / 296 mOsm/L OS. His readings were not completely in the normal range OD, but he was just subthreshold; however, compared to his 317/334 measurements, he was now in a much better range. In Dr. Maharaj’s view, what was more important here was that the patient understood his situation, which would almost certainly guarantee that compliance would be improved.

PROMOTING PATIENT COMPLIANCE Dr. Maharaj raised the question of what is required to get a patient to be compliant. He suggested that practitioners employ certain clinical practices and integrate them into their contact lens practice to eliminate the commoditization of contact lenses. There is a health aspect to contact lens care which has not been employed to a great enough extent, the result of which is that patients feel as though they can go out and order contact lens online without knowing anything about them. To address this situation, Dr. Maharaj encourages practitioners to build a diagnostic strategy around their contact lens practice in order to insulate the practice. He posed the following questions: What is the osmolarity of their patient? Are practitioners setting their patients up for success or failure? And if so, what are they doing to mitigate it? Furthermore, if they are mitigating it, how are they measuring whether or not clinical choices are in fact successful? Optometrists may be telling patients that they are going to get better by putting them on a one-day lens, but how are they measuring that? Other metrics can be employed; however, tear osmolarity is an extremely good

Clinical and Refractive Optometry 27:1, 2016

tool to use so that patients understand their situation very quickly. What’s more, clinically it's already been proven from an evidence-based perspective. Practitioners use it to engage their patients clinically without becoming too technical. Case #2 Dr. Maharaj introduced his second case, that of a 53-yearold Caucasian female who had been referred to him by an ophthalmologist who had performed LASIK on her in 2007 and had put her on Restasis® (cyclosporine ophthalmic solution 5%, Allergan, Markham, ON) nine months prior to this consultation. She reported using Alrex® (loteprednol), BID or as needed. Dr. Maharaj employs a symptom questionnaire called the SPEED (Standardized Patient Evaluation of Eye Dryness) score, comprising a series of questions that produce a score out of 28, where 28 is the worst a patient can possibly feel. Dr. Maharaj uses the SPEED score method when the patient comes in because it provides him a validated symptom score within just 5 minutes. The SPEED score is very useful and it has been validated by the University of Waterloo. This patient’s score was 23 out of a possible 28, so she was feeling quite miserable. Her tear breakup time was 5s OD and 4s OS, which wasn’t alarming clinically. Although she was on some form of therapy for her dry eye, she still had severe keratopathy. Dr. Maharaj pointed out that Schirmer testing (no anesthetic), tear osmolarity, lid seal and aperture closure were all likely to be abnormal in such a case. He tells his interns that after they've spoken to the patient the first time, they should already have a working diagnosis, and have narrowed the diagnosis down to at least three, if not two differentials. In his view, the test with the greatest diagnostic value is osmolarity. If it were Schirmer, with low tear volume, what would be the optimal treatment? If it's an aqueous deficient patient and they're on Restasis, their aqueous deficiency is being addressed so it would not change your treatment approach. Measuring lid seal and aperture closure is a very quick test that does not cause pain or take more time, but it does not, again, add to the clinical decision. In Dr. Maharaj’s opinion, osmolarity is the only element that truly adds to the clinical decision. He uses an Oculus keratograph 5M to measure meibography in his practice. Meibography is infrared imaging of the anatomy and architecture of the meibomian ductules and acini and it can be done on both top and bottom lids. This patient had significantly atrophied and truncated meibomian gland architecture which was diagnostic of her meibomian gland dysfunction (MGD). She had been on Restasis for nine months and had evaporative dry eye that was not being managed. Dr. Maharaj pointed out that osmolarity actually helps practitioners to discern this because in a

Light Test

No Light between lids

Light between lids

Fig. 2 Use of transilluminator to measure lid aperture seal.

Fig. 3 Before and after treatment for MGD.

patient with an evaporative condition, their osmolarity increases. In terms of lid aperture seal, there's a very quick way to measure this in the office, using a transilluminator on the upper eyelid to retroilluminate the inner eyelid. As shown in Figure 2, on the right-hand side, there is slight leakage of light coming through the upper and lower eyelids, whereas the other eye is perfectly sealed. This is not the same as lagophthalmus. If the lid aperture is not closing, you can assume that there is not good expression of the meibomian glands on lid closure. These patients will progress and develop meibomian gland stagnation and further obstruction. Unfortunately, this patient had progressed to this point. Her osmolarity at this stage was 352/326 mOsm/L OD and OS, respectively; therefore, her symptoms made a lot of sense. In tear chemistry, MMP-9 is an inflammatory marker. InflammaDry® is a point of detection test that can be used to measure the amount of inflammation at the ocular surface as a positive or negative outcome. In this case, the patient measured negative. With glaucoma patients, we measure OCT, visual fields, pachymetry and IOP. With dry eye patients, we examine tear panel testing or tear chemistry. Dr. Maharaj proceeded to describe three patient scenarios regarding osmolarity in chemistry testing. The first is a patient with high osmolarity and normal MMP-9. These are typically early dry eye patients who haven't yet begun to develop up-regulation of their MMP-9 expression. In that scenario, they may also have a normal MMP-9 if they are already on anti-inflammatory treatment. In the case of the 53-yearold woman, she had already been on Restasis for the previous nine months and her MMP-9 was negative, which stands to reason. Osmolarity had not been addressed, though, because she was still an evaporative patient. A second scenario is a patient with high osmolarity and a positive MMP-9, indicating ocular surface inflammation. These are patients who typically have had dry eye

for some time and it has been untreated or poorly managed, essentially producing two positives. A third scenario is a patient with normal osmolarity and abnormal MMP-9. These are cases of less typical dry eye disease which are more likely to be a function of some other ocular surface dysfunction such as EBMD or conjunctival chalasis. Osmolarity provides perspective on MMP-9, and MMP-9 provides perspective on osmolarity. How one uses them together can strengthen one’s diagnosis significantly. Dr. Maharaj was able to determine that this patient had evaporative dry eye because her inflammatory mediators were already being addressed with Restasis. Figure 3 depicts before and after treatment for MGD. Case #3 The next case is of a 39-year-old female who had undergone LASIK seven years prior. She presented with repeated intermittent foreign body sensation in her left eye. She had exposure due to a limited lid seal and had used various types of drops, but nothing gave her sustained relief. She did have a maternal family history of Sjögren's and her current medical history was positive for Raynaud’s disease. Her tear breakup time was certainly reduced in her left eye, and her osmolarity was 273 mOsm/L in her right and 296 mOsm/L in her left eye. The difference of 23 mOsm/L between her two eyes was clinically significant despite each eye’s osmolarity still in the subclinical range, under 308 mOsm/L. Her MMP-9 was negative in her right eye, ironically, and was positive in her left eye. In summary, this patient had a suspect tear osmolarity and a positive MMP-9, so she was clinically defined as having dry eye. Her tear breakup time was almost instant; this patient wasn't even closing her eyes. She had high evaporation, along with lid wiper epitheliopathy. Dr. Maharaj explained that lid wiper epitheliopathy occurs when there is increased friction between the lid wiper and the ocular surface. When hydrodynamic lubrication between the two surfaces is lost,

Advancing the Diagnostic Use of Tear Osmolarity in Primary Eye Care: Part 2 — Maharaj

Before

1 Day After

Fig. 4 Before and after results of surgical triad: scaling, expression, neutralization.

increased friction results in increased inflammation which then leads to epitheliopathy. That area is very close to the meibomian gland tissue, causing further propagation of the lid and gland inflammation. Dr. Maharaj stated that he decided to focus his therapy on her lid margin and lid wiper with a procedure called periocular scaling, expression and neutralization. He has been performing this procedure for the past few years and it has been presented in the literature. It is a non-surgical process done in primary care. Dr. Maharaj also used a non-preserved hyaluronic-based drop instead of Systane® BALANCE (Alcon, Mississauga, ON) which she had been using. Dr. Maharaj began by staining the lid and the line of marks on the lid wiper with lissamine green. He then used a golf spud to debride and scale the surface, passing over the meibomian gland orifice, as well as the lid wiper and mucocutaneous junction. The process involved removing devitalized epithelium, squamous epithelium that was devitalized and, if left long enough, would actually keratinize. He then expressed, using a Mastrota paddle and a cotton-tip applicator. Dr. Maharaj pointed out that effective meibomian gland expression requires a hard back surface: if one is expressing with one’s thumb against the globe, it's insufficient and a hard back surface is needed to push against. The neutralization aspect involves neutralizing the acidic component of the meibum, which is comprised of a fatty acid; otherwise, it retains on the ocular surface and can accelerate devitalization. In patients who have MGD, frothy tears accumulate and develop into acidic keratoconjunctival changes. Neutralizing with a basic solution, such as mineral oil, helps in addition to certain artificial tears with a slightly basic pH. Dr. Maharaj advised to neutralize whatever is being expressed, which also helps to soothe the debrided surface.

Clinical and Refractive Optometry 27:1, 2016

Using this technique, Dr. Maharaj’s retrospective analysis of 53 patients revealed that symptomology was improved by approximately 62%, on average. Meibomian gland function, therefore secretion levels, increased by 30% by doing this one procedure. Figure 4 illustrates before and after results in the previously-mentioned 53-year-old patient. A recent study out of the University of Waterloo, by Ngo W, Caffery B, et al in 2015 have demonstrated components of this procedure on a Sjögren’s cohort of patients demonstrated equally positive results. Heated expression such as Lipiflow and alike also work extremely well on MGD. There are various new modalities of care that are targeted toward the lid surface, the lid wiper, and the meibomian gland orifice and structure that greatly help to accent a missing component of the current treatment options. In Dr. Maharaj’s view, practitioners are accustomed to de facto using drops for dry eye disease, without doing anything to actually restore meibomian gland function. The pathway to the meibomian gland orifice can be broken by medicine by decreasing the inflammation which, in turn, decreases devitalization of the epithelium. However, current techniques allow practitioners to physically debride the epithelium which will break this cycle and reduce the osmotic gradient. Traditionally, in patients who are at risk or who already have the condition, he repeats the procedure once every six months. In patients whose secretions are good just by gentle expression, or if he stains and sees nothing there, he won’t perform the procedure. Naturally, if there is no tissue to debride or scale, there's nothing to do; however, by and large, this has not been Dr. Maharaj’s experience. There are other tools that clinicians use for a similar purpose, for instance, BlephEx®, or microblepharoexfoliation. BlephEx is great at dealing with anterior blepharitis specifically. It also helps to remove some of the squamous cells. However, when there is extensive keratinization and a blunter instrument is needed to get under the skin to lift it, often times BlephEx won't achieve this in his experience. Case #4 A 77-year-old female from Winnipeg was very specific about her discomfort which was on her lids and the bottom part of her eye. She had had cataract surgery about 10 years prior, and had been on Restasis for a very long time, along with Lotemax. In addition, she had been put on doxycycline to treat her MGD and she was using copious non-preserved and preserved lubricants as well as lid hygiene procedures, with which she was very vigilant. Conjunctival staining with lissamine green showed some conjunctival rolls indicating a ‘fat conjunctiva’ indicating loss of Tenon’s fascia; this is known as conjunctival chalasis (Fig. 5). In addition, she had floppy eyelid syndrome with one very large roll juxtaposed to her

Fig. 5 Conjunctival chalasis in a 77-year-old female.

inferior eyelid such that whenever she blinked, it rolled up and down, abrading her cornea. Clinical testing revealed positive MMP-9 test, tear breakup was instant as one would expect, and her meibomian gland score was zero because her conjunctiva was actually covering the orifice. While all of this was negative, her tear osmolarity was normal. Technically, said Dr. Maharaj, while this wasn’t consistent with dry eye, if one were to look only at the staining, one would conclude that it was. However, clinically, it was conjunctival chalasis with a desiccated cornea due to mechanical abrasion. The patient was on the maximal therapy. The surgical options were conjunctival resection or amniotic membrane transfer. Dr. Maharaj indicated that there are not a lot of surgeons in his area who surgically treat these cases, although it has been increasingly requested, therefore the interest in it may be rising. On the pharmacologic side, there weren’t many other options apart from Restasis. After consultation with the patient’s family physician, she was put on human autologous serum (HAS), with an aliquot of 20% solution in 5 mL bottles, BID for three months. Dr. Maharaj suggested that it is useful to have a compounding pharmacist on hand in the event that this process is needed. In Ontario, compliance of the family physician is needed to order the appropriate blood work. Autologous serum is plasma which contains growth factors, and normalizes the proliferation and migration of epithelial cells, increases healing rates. There are some adverse reactions that can be associated with HAS, but in this particular case, the risks were acknowledged and the patient did very well. In terms of quality of life alone, she was excessively happy in spite of her loose conjunctiva. She was on a non-preserved hyaluronic-based drop, as well as highdose Omega-3s, and she was closer in line to having her conjunctival resection done. Cyclosporine is extremely effective at controlling inflammation but in some cases, where there is a dense amount of SPK and mechanical trauma, it is not sufficient. The objective in these cases is to minimize friction while controlling inflammation.

As noted in Cornea in a 2011 paper by Dr. Michael Lemp, osmolarity is the single most defining metric for dry eye. If you are looking at a sub-specialty clinic or a subspecialty environment in which to invest, an oculus keratograph 5M which has a comprehensive dry eye module, and a tear osmolarity meter are essential. Additionally, stated Dr. Maharaj, it is critical to identify the general population coming into your office. The role of optometrists in managing disease continues to expand to maximize patient outcomes. Optometrists are, in fact, in charge of prevention as well as treatment; however, if prevention is maximized, there are better chances of successfully treating a condition that has not yet been controlled. Dr. Maharaj opined that tear chemistry – tear panel testing – is an area that will see enormous growth in the next decade. He advocated adding advanced dry eye management to optometrists’ practice. He endorses tear osmolarity testing, whose devices are currently manufactured by two companies. One of these is I-Med Pharma (Montreal, QC) which produces the I-Pen®, a product that will most likely be coming to market in the next few months. It is extremely easy to use, and the cost prohibition that used to be a factor has now been eliminated.

CONCLUSION Dr. Maharaj concluded his presentation with a discussion of Omega-3s, raising the issue of the ethyl ester form versus triglycerides. A poster by Dr. Eric Donnenfeld and his group published at the ASCRS meeting in June 2015 contained a very compelling argument for re-esterified triglyceride (rTG) Omega-3 in a three month course at 2.48 g. Another study examined the Omega-3 index – a red blood cell saturated Omega-3 measurement after dosing with a triglyceride versus an ethyl ester. The triglyceride achieved an 8% blood saturation within 1 month of the above dosing, which ethyl ester never achieved up to 3 months later. This level of saturation also decreases cardiac risk in addition to improving meibomian gland secretion. As a result, Dr. Maharaj is a proponent of rTG Omega-3s, for example, NutraSea HP and Physician Recommended Nutraceuticals. On the subject of differences between the liquid and gel capsulated forms, Dr. Maharaj noted that he prefers liquid where it is available; however, the vast majority of products are produced in gelcap form. He stated that he performs Omega index testing in his office and has not found a difference between liquid and gel caps. In his experience, patients are able to tolerate the liquid better; therefore, if the objective is patient compliance, it is the preferred form of the product. ❏

Advancing the Diagnostic Use of Tear Osmolarity in Primary Eye Care: Part 2 — Maharaj

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QUESTIONNAIRE Advancing the Diagnostic Use of Tear Osmolarity in Primary Eye Care: Part 2 Richard Maharaj, OD, FAAO 1. ❑ ❑ ❑ ❑

All of the following are factors that induce dryness, EXCEPT: Anatomical influences External influences Pathological/chronological influences Hereditary influences

2. ❑ ❑ ❑ ❑

The patient in Case #1 presented with all of the following, EXCEPT: Red, itchy eyes Foreign body sensation in left eye Seasonal allergies Vernal keratoconjunctivitis (VKC)

3. ❑ ❑ ❑ ❑

According to Canadian statistics, what percentage of contact lens patients are wearing a one-day lens? Fewer than 15% Fewer than 20% 20% Fewer than 25%

Clinical and Refractive Optometry 27:1, 2016

COPE-APPROVED CE CREDIT APPLICATION FORM

In Case #1, all of the following describe the patient’s clinical measurements, EXCEPT: Abnormal tear breakup Abnormal lid wiper staining High tear osmolarity Normal corneal staining

5. ❑ ❑ ❑ ❑

At one-month follow-up, all of the following statements describe the patient in Case #1, EXCEPT: Less discomfort Less use of additional artificial tears Lower tear osmolarity Sub-threshold tear osmolarity

6. ❑ ❑ ❑ ❑

All of the following describe the patient in Case #2, EXCEPT: Previous LASIK Low SPEED (Standardized Patient Evaluation of Eye Dryness) score Administration of Restasis Administration of Alrex

7. ❑ ❑ ❑ ❑

All of the following describe the patient in Case #3, EXCEPT: Normal tear breakup time in both eyes Positive for Raynaud’s disease Reduced tear breakup time in left eye Low tear osmolarity

8. ❑ ❑ ❑ ❑

In a retrospective analysis, Dr. Maharaj’s procedure of periocular scaling, expression and neutralization resulted in what percentage of improvement in patient symptomatology? 45% on average 50% on average 55% on average 62% on average

9. ❑ ❑ ❑ ❑

How often does Dr. Maharaj repeat epithelial debridement? Once every 3 months Once every 4 months Once every six months Once every twelve months

10. ❑ ❑ ❑ ❑

All of the following describe the patient in Case #4, EXCEPT: She had had cataract surgery She had been on Restasis for a very long time She was on Lotemax She was diagnosed with dry eye disease

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4. ❑ ❑ ❑ ❑

Advancing the Diagnostic Use of Tear Osmolarity in Primary Eye Care: Part 2 — Maharaj

News and Notes Bausch + Lomb Donates $50,000 to Optometry Giving Sight Bausch + Lomb, recently announced that it has made a $50,000 donation to Optometry Giving Sight, a global fundraising organization that specifically targets the prevention of blindness and impaired vision due to Uncorrected Refractive Error (URE) by providing access to eye examinations and glasses. The donation will support a broad range of sustainable training and education programs that improve eye health for people in developing and under-served communities. “We are committed to helping organizations, such as Optometry Giving Sight, offer eye health services and resources to countries worldwide, particularly those that lack the appropriate resources to support them,” said Mark McKenna, senior vice president & general manager, U.S. Contact Lenses, Bausch + Lomb. “We are proud of the work they do and look forward to our ongoing support for their cause to help bring an end to preventable blindness and vision impairment.” Optometry Giving Sight funds the development of sustainable eye and vision care projects in communities where these do not currently exist. These projects focus on local training and capacity building; infrastructure development and the delivery of eye and vision care services. In addition, Optometry Giving Sight is a member of VISION 2020: The Right to Sight, a joint program of the World Health Organization (WHO) and the International Agency for the Prevention of Blindness (IAPB).

Indications and clinical use: LOTEMAX® Gel (loteprednol etabonate ophthalmic gel 0.5% w/w) is indicated for the treatment of postoperative inflammation and pain following cataract surgery. • The safety and efficacy of LOTEMAX® have not been studied in pediatric patients (<18 years of age) and the product should not be used in these populations. Contraindications: • Suspected or confirmed infection of the eye: viral diseases of the cornea and conjunctiva including epithelial herpes, simplex keratitis (dendritic keratitis), vaccinia, and varicella; untreated ocular infection of the eye; mycobacterial infection of the eye and fungal diseases of ocular structures. • Hypersensitivity to LOTEMAX® or any ingredient in the formulation or container, or to other corticosteroids. Relevant warnings and precautions: • LOTEMAX® Gel is indicated for short-term treatment only (up to 14 days). If LOTEMAX® Gel is used for 10 days or longer, intraocular pressure (IOP) should be closely monitored. • The use of steroids after cataract surgery may delay wound healing. • Prolonged use of corticosteroids may result in cataract and/or glaucoma formation. Should not be used in the presence of glaucoma or elevated IOP, unless absolutely necessary and close ophthalmologic monitoring is undertaken. • LOTEMAX® Gel includes benzalkonium chloride. • Should not be used in pregnant or lactating women unless the benefit to the mother clearly outweighs the risk to the infant/child. For more information: Please consult the Product Monograph at http://www.bausch.ca/en-ca/our-products/ rx-pharmaceuticals/lotemax-gel-loteprednoletabonate-ophthalmic-gel-05-w-w for complete dosing instructions, warnings, precautions, adverse events and patient selection criteria. The Product Monograph is also available by calling 1-888-459-5000.

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