Dry Eye Disease What Is It, Why Does It Occur and How Can It Be Diagnosed and Treated? J

Home , Meibomian gland, Paraben

Dry Eye Disease What is it, why does it occur and how can it be diagnosed and treated? J. Daniel Nelson, Jennifer P. Craig, Lyndon Jones, Fiona J. Stapleton, Mark D.P. Willcox, James S. Wolffsohn and David A. Sullivan, on behalf of the participants in the TFOS Dry Eye Workshop II (TFOS DEWS II TM )

Introduction Dry eye disease (DED) afflicts hundreds of millions of people throughout the world, is one of the most frequent causes of patient visits to eye care practitioners, and has no cure. Moderate to severe DED is associated with significant pain, limitations in performing daily activities, reduced vitality, poor general health, and often depression.

To increase our understanding of DED, the Tear Film & Ocular Surface Society (TFOS), a non- profit organization, launched the TFOS Dry Eye Workshop II (TFOS DEWS II). This Workshop involved the efforts of 150 clinical and basic science research experts from around the world and required more than 2 years to complete.

The TFOS DEWS II report was published in the July 2017 issue, and the Executive Summary in the October 2017 issue, of The Ocular Surface and downloadable versions are available on the TFOS website: www.TearFilm.org.

Some highlights of the conclusions and recommendations of the TFOS DEWS II are presented in this summary. Figure 1. Classification of DED

What is DED? TFOS DEWS II defined DED as follows: “Dry eye is a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film, and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles.” DED is classified etiologically into two predominant and non-mutually exclusive categories: aqueous deficient (ADDE) and evaporative (EDE) (Figure 1). Most DED is evaporative in nature. The unifying characteristic of DED is the loss of tear film homeostasis. Such imbalance may be detected as an abnormality in any one or more of a myriad of tear film and ocular surface features.

Why does DED occur? The core mechanism of DED is evaporation- induced tear hyperosmolarity, which is the hallmark of the disease (Figure 2). It damages the ocular surface both directly and by initiating inflammation, which can lead to a self-perpetuating, vicious cycle of DED. The major cause of EDE is meibomian Figure 2. Pathophysiology of DED gland dysfunction (MGD).

www.tearfilm.org Consistent risk factors for DED include age, sex, race, MGD, connective tissue disease, Sjögren syndrome, androgen deficiency, computer use, contact lens wear, estrogen replacement therapy, hematopoietic stem cell transplantation, certain environmental conditions (such as pollution, low humidity, and sick building syndrome) and medication use (for example, antihistamines, antidepressants, anxiolytics, and isotretinoin). Iatrogenic DED is also common and can be induced by a number of clinical interventions, including many topical and systemic drugs, and ophthalmic surgical (e.g. refractive, cataract, 1 2 3 4

glaucoma, vitreoretinal) and non-surgical (e.g. P P P P E E E E botulinum toxin application, cosmetic) procedures. T T T T S S S S How is DED diagnosed? TFOS DEWS II recommends a sequence of tests for diagnosis of DED and assessment of its severity (Figure 3). This diagnostic process first utilizes triaging questions to exclude conditions that mimic DED. A DED diagnosis then requires a positive score on one of two specific symptom questionnaires, followed by at least one positive clinical sign indicating reduced non-invasive breakup time, elevated or a large interocular disparity in osmolarity, or ocular surface staining. How is DED treated? TFOS DEWS II also recommends a series of staged management and treatment options with proven efficacy, that aim to restore tear film homeostasis.These are listed in the Table below. Figure 3. Diagnostic approach for DED

STEP TFOS DEWS II recommendations for the staged management and treatment of DED • Education regarding the condition, its management, treatment • Identification and potential modification/elimination of offending and prognosis systemic and topical medications • Modification of local environment • Ocular lubricants of various types (if MGD is present, then 1 • Education regarding potential dietary modifications (including consider lipid-containing supplements) oral essential fatty acid supplementation) • Lid hygiene and warm compresses of various types If above options are inadequate consider: • Non-preserved ocular lubricants to minimize preservative- • In-office intense pulsed light therapy for MGD induced toxicity • Prescription drugs to manage DED • Tea tree oil treatment for Demodex (if present) o Topical antibiotic or antibiotic/steroid combination applied to • Tear conservation the lid margins for anterior blepharitis o Punctal occlusion o Topical corticosteroid (limited-duration) 2 o Moisture chamber spectacles/goggles o Topical secretagogues • Overnight treatments (such as ointment or moisture chamber o Topical non-glucocorticoid immunomodulatory drugs devices) o Topical lymphocyte function-associated antigen-1 antagonist • In-office, physical heating and expression of the meibomian drugs glands (including device-assisted therapies) o Oral macrolide or tetracycline antibiotics

If above options are inadequate consider: • Oral secretagogues • Therapeutic contact lens options 3 • Autologous/allogeneic serum eye drops o Soft bandage lenses o Rigid scleral lenses

If above options are inadequate consider: • Topical corticosteroid for longer duration • Other surgical approaches (eg tarsorrhaphy, salivary gland • Amniotic membrane grafts transplantation) 4 • Surgical punctal occlusion

Acknowledgments: We thank Amy Gallant Sullivan and Sabrina Zappia (www.citynetonline.it) for their professional assistance with this TFOS DEWS II highlight report. A listing of Workshop participants, as well as a direct link to the entire TFOS report, can be found at: www.TearFilm.org.

www.tearfilm.org The Ocular Surface xxx (2017) 1e11

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The Ocular Surface

journal homepage: www.theocularsurface.com

TFOS DEWS II Report Executive Summary

Jennifer P. Craig a, 1, J. Daniel Nelson b, c, 1, Dimitri T. Azar d, Carlos Belmonte e, f, Anthony J. Bron g, h, Sunil K. Chauhan i, Cintia S. de Paiva j, Jose A.P. Gomes k, Katherine M. Hammitt l, Lyndon Jones m, Jason J. Nichols n, Kelly K. Nichols n, Gary D. Novack o, p, Fiona J. Stapleton q, Mark D.P. Willcox q, James S. Wolffsohn r, * David A. Sullivan i, a Department of Ophthalmology, New Zealand National Eye Centre, The University of Auckland, Auckland, New Zealand b Department of Ophthalmology, HealthPartners Medical Group and Clinics, St Paul, MN, USA c Department of Ophthalmology, University of Minnesota, Minneapolis, USA d University of Illinois at Chicago College of Medicine, Chicago, IL, USA e Instituto de Neurociencias de Alicante, University Miguel Hernandez-CSIC, Spain f Instituto Fernandez-Vega, Oviedo University, Spain g Nufﬁeld Department of Clinical Neurosciences, University of Oxford, Oxford, UK h Vision and Eye Research Unit, Anglia Ruskin University, Cambridge, UK i Schepens Eye Research Institute, Massachusetts Eye and Ear, and Department of Ophthalmology, Harvard Medical School, Boston, MA, USA j Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA k Department of Ophthalmology and Visual Sciences, Federal University of Sao Paulo/Paulista School of Medicine, Sao Paulo, Brazil l Sjogren's€ Syndrome Foundation, Bethesda, MD, USA m Centre for Contact Lens Research, School of Optometry and Vision Science, University of Waterloo, Waterloo, Ontario, Canada n University of Alabama at Birmingham School of Optometry, Birmingham, AL, USA o Pharma Logic Development, San Rafael, CA, USA p Departments of Pharmacology and Ophthalmology, University of California, Davis, School of Medicine, USA q School of Optometry and Vision Science, University of New South Wales, Sydney, New South Wales, Australia r School of Life and Health Sciences, Aston University, Birmingham, UK article info abstract

Article history: This article presents an Executive Summary of the conclusions and recommendations of the 10-chapter Received 2 August 2017 TFOS DEWS II report. The entire TFOS DEWS II report was published in the July 2017 issue of The Ocular Accepted 4 August 2017 Surface. A downloadable version of the document and additional material, including videos of diagnostic and management techniques, are available on the TFOS website: www.TearFilm.org. © 2017 Elsevier Inc. All rights reserved.

1. Introduction activities, reduced vitality, poor general health, and often depression. Dry eye disease (DED) affects hundreds of millions of people To increase our understanding of DED, the Tear Film & Ocular throughout the world and is one of the most frequent causes of Surface Society (TFOS), a non-profit organization, launched the patient visits to eye care practitioners. It is a symptomatic disease, TFOS Dry Eye Workshop II (TFOS DEWS II) in March 2015 [1]. This characterized by a vicious cycle of tear film instability and hyper- initiative reflected the TFOS mission, which is to advance the osmolarity, which leads to increased ocular surface inflammation, research, literacy, and educational aspects of the scientific field of damage and neurosensory abnormalities. Moderate to severe DED the tear film and ocular surface. The goal of the TFOS DEWS II was to is associated with significant pain, limitations in performing daily achieve a global consensus concerning multiple aspects of DED. More specifically, TFOS DEWS II sought to: 1) Update the definition and classification of DED; 2) Evaluate critically the epidemiology, * Corresponding author. Schepens Eye Research Institute, 20 Staniford Street, pathophysiology, mechanism, and impact of this disorder; 3) Boston, MA 02114, USA. Develop recommendations for the diagnosis, management and E-mail address: [email protected] (D.A. Sullivan). therapy of this disease; and 4) Recommend the design of clinical 1 Co-first author. http://dx.doi.org/10.1016/j.jtos.2017.08.003 1542-0124/© 2017 Elsevier Inc. All rights reserved.

Please cite this article in press as: Craig JP, et al., TFOS DEWS II Report Executive Summary, The Ocular Surface (2017), http://dx.doi.org/10.1016/ j.jtos.2017.08.003 2 J.P. Craig et al. / The Ocular Surface xxx (2017) 1e11 trials to assess future interventions for DED treatment. and future research. The TFOS DEWS II involved the efforts of 150 clinical and basic The Subcommittee's recommended classification of DED is science research experts from around the world, who utilized an shown in Fig. 1. The upper portion of the figure represents a clinical evidence-based approach and a process of open communication, decision algorithm, beginning with the assessment of symptoms, dialogue and transparency to increase our understanding of DED. and followed by review for signs of ocular surface disease. DED This process required more than 2 years to complete. exhibits both symptoms and signs, and can be differentiated from The entire TFOS DEWS II report was published in the July 2017 other ocular surface disease with the use of triaging questions and issue of The Ocular Surface. A downloadable version of the docu- ancillary testing. It is to this DED group that diagnostic subtyping, ment and additional material, including videos of diagnostic and conventional DED management strategies, apply. Symptomatic and management techniques, are available on the TFOS website: patients without demonstrable clinical signs do not fall into the www.TearFilm.org. It is anticipated that translations of the report DED group, but are differentiated into pre-clinical ocular surface will be offered in many languages, including, but not limited to, disease or neuropathic pain (non-ocular surface disease). Chinese, French, German, Italian, Japanese, Korean, Polish, Portu- Conversely, asymptomatic patients exhibiting signs are differenti- guese, Romanian, Spanish, Turkish and Vietnamese. These trans- ated into patients with poor corneal sensitivity, or those with lations, when completed, will be available on the TFOS website. prodromal signs, who may be at risk of developing manifest DED An Executive Summary of the conclusions and recommenda- with time or provocation, for example following ophthalmic sur- tions of the TFOS DEWS II report is presented in this article. The gery or contact lens fitting. Finally, the option exists for patients material is abstracted from the reports of ten TFOS DEWS II Sub- without either signs or symptoms to be classified, according to the committees, which were Definition and Classification; Epidemi- flow chart, as ‘normal’. ology; Sex, Gender, and Hormones; Pathophysiology; Tear Film; The lower portion of Fig. 1 represents the etiological classifica- Iatrogenic Dry Eye; Pain and Sensation; Diagnostic Methodology; tion of DED, and highlights the two predominant and non-mutually Management and Therapy; and Clinical Trial Design. Additional exclusive categories; ADDE and EDE. Epidemiological and clinical details and all references can be obtained in the open access, online evidence suggest that the preponderance of DED is evaporative in version. nature, which is reflected by devotion of a greater proportion of Fig. 1 to EDE than to ADDE. While it is possible that ADDE can occur 2. Definition and classification [2] without obvious signs of EDE and vice versa, as DED progresses, it is increasingly likely that characteristics of both ADDE and EDE will The goals of the TFOS DEWS II Definition and Classification become evident. Further subclassification of ADDE and EDE is not Subcommittee were to create an evidence-based definition and a detailed in Fig. 1, but is acknowledged to relate to a vast range of contemporary classification system for DED. The new definition is conditions, as described in the TFOS DEWS II Pathophysiology as follows: report. ADDE describes conditions affecting lacrimal gland function. EDE is recognized to include both lid-related (for example, “Dry eye is a multifactorial disease of the ocular surface char- meibomian gland dysfunction [MGD] and blink-related) and ocular acterized by a loss of homeostasis of the tear film, and accom- surface-related (such as mucin and contact lens-related) causes. panied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and 3. Epidemiology [3] neurosensory abnormalities play etiological roles.” The TFOS DEWS II Epidemiology report examines literature on The terminology in this definition, including diction, word order, the prevalence, incidence, risk factors, natural history, and emphasis, and accepted meaning, was critical in creating an inter- morbidity and reviewed questionnaires used in epidemiological nationally accepted definition. The term “multifactorial disease” studies of DED. The report focuses on epidemiological studies recognizes DED as a significant and complex, functional disorder published since the previous TFOS DEWS report in 2007. A meta- that cannot be characterized by a single process, sign or symptom. analysis of all published prevalence data was undertaken to esti- The term “ocular surface” is defined as comprising the structures of mate the impact of age (Table 1) and sex on symptoms and signs of the ocular surface and adnexa, including the tear film, lacrimal and DED. Global mapping of DED prevalence was undertaken using meibomian glands, cornea, conjunctiva and eyelids. “Homeostasis” geospatial analysis. The report summarizes the available evidence describes a state of dynamic equilibrium in the body with respect to on the epidemiology of DED and provides recommendations for its various functions, and to the chemical composition of the fluids future needs and opportunities. and tissues. Disruption of homeostasis is considered to be the DED epidemiology continues to be challenged by the failure for unifying characteristic that encompasses the myriad of signs of tear a standardized definition and diagnostic criteria to be used. film and ocular surface imbalance that might be observed in DED. Consequently, the report describes prevalence based on commonly The term “symptoms” embraces a broad range of possible patient- used diagnostic criteria, including those based on symptoms, on reported experiences associated with DED including, but not self-report of a practitioner diagnosis, and on DED signs. limited to, discomfort and visual disturbance. The key elements While much new information has been published in the last contributing to the pathophysiological process, including tear film 10 years, no population studies have reported on prevalence of instability, hyperosmolarity, inflammation and damage, recognized DED for populations south of the equator. Much of the attention as etiological triggers of the vicious circle, were deemed important, has focused on Asia and Europe. The prevalence of DED, with and along with neurosensory abnormalities, which have featured without symptoms, ranged in prevalence from 5 to 50%. DED increasingly in the recent literature, for inclusion in the definition. prevalence based on signs alone was generally higher and more In the classification of DED, the latest evidence supports a variable, reaching up to 75% in some populations. Criteria for scheme based on its pathophysiology in which aqueous deficient positive DED signs varied between studies and it was acknowl- dry eye (ADDE) and evaporative dry eye (EDE) exist as a continuum, edged that some signs may reflect secondary outcomes or may be such that elements of each need to be considered in diagnosis and related to normal aging. Very few studies were conducted in management. This approach is not intended to override clinical younger populations (less than 40 years of age) but indications assessment and judgment but to help guide clinical management are that DED is also prevalent in these populations. The evidence

Fig. 1. DED classification scheme. Please see the original report for a complete description of this figure [2]. for Asian race as a risk factor for DED now appears mostly The economic burden on society and impact of DED on the in- consistent. dividual, through its detrimental effect on vision, quality of life, and The meta-analysis confirmed that symptomatic disease and work productivity, as well as the psychological and physical impact signs of DED increase with age, however prevalence of signs of pain, are considerable. The most significant costs are indirect showed a greater increase per decade than symptomatic disease. costs due to reduced work productivity. Questionnaires used to Higher rates of DED are reported in women than men, although evaluate DED vary in their utility for epidemiological studies and the differences generally become significant only with increasing further evidence for normative ranges and clinically significant age. changes are required. Risk factors were categorised as consistent, probable, and Future research needs include better evaluation of the preva- inconclusive, in line with the previous TFOS DEWS report [4]. Age, lence of DED of varying severity and in youth, the incidence of sex, race, MGD, connective tissue disease, Sjogren€ syndrome, disease in different populations, and the impact of modifiable risk androgen deficiency, computer use, contact lens wear, estrogen factors such as mobile device usage. Geographical mapping ap- replacement therapy, hematopoietic stem cell transplantation, proaches will further allow the impact of climate, environment and certain environmental conditions (such as pollution, low humid- socioeconomic factors on DED to be elucidated. There has been ity, and sick building syndrome) and medication use (for example, limited study of the natural history of both treated and untreated antihistamines, antidepressants, anxiolytics, and isotretinoin) DED and this remains an important area for future research. were identified as consistent risk factors. Probable risk factors included diabetes, rosacea, viral infection, thyroid disease, psy- 4. Sex, gender, and hormones [5] chiatric conditions, pterygium, low fatty acid intake, refractive surgery, allergic conjunctivitis, and additional medications (e.g. One of the most compelling features of DED is that it occurs anti-cholinergic, diuretics, b-blockers). Inconclusive DED risks are more frequently in women than in men. In fact, the female sex is a Hispanic ethnicity, menopause, acne, sarcoidosis, smoking, significant risk factor for the development of DED. That such a sex- alcohol, pregnancy, demodex infestation, botulinum toxin injec- related variation exists in the prevalence of an eye disease, or any tion, multivitamins and oral contraceptives. other ocular function, should not be a surprise, as sex-related

Please cite this article in press as: Craig JP, et al., TFOS DEWS II Report Executive Summary, The Ocular Surface (2017), http://dx.doi.org/10.1016/ j.jtos.2017.08.003 4 J.P. Craig et al. / The Ocular Surface xxx (2017) 1e11

Table 1 Regression analysis of prevalence data by age for each diagnostic subgroup.

2 Diagnostic subgroup N of studies Slope estimate (per decade of age) Std error of slope estimate p-value (H0: slope ¼ 0) R 1. Symptoms or OSDI 23 8 3.43 0.57 0.001 0.858 2. Self-report of a clinician diagnosis of dry eye 8 2.01 0.73 0.034 0.556 3. WHS Criteria 8 0.44 0.57 0.475a 0.088 b4. Schirmer 5 10.55 1.78 0.010 0.921 b5. Tear break up time 5 9.71 1.20 0.004 0.956 b6. Corneal staining 5 7.63 1.67 0.020 0.875 b7. MGD 5 5.23 1.44 0.036 0.815

OSDI - Ocular Surface Disease Index; WHS - Women's Health Study; MGD - meibomian gland dysfunction. Please see the original report for a complete description of this figure [3]. a Indicates that there is no change in prevalence by age for the WHS criteria. b Regression analyses are based on estimates of prevalence from age 40e49 and beyond (i.e., missing values for prevalence for ages 15e18, 19e29, and 30e39). differences are present in almost every cell, tissue and organ system Overall, sex, gender and hormones play a major role in the of the body. Indeed, since 1945, more than 575,000 scientific re- regulation of ocular surface and adnexal tissues, and in the differ- ports have been published which address the basic and/or clinical ence in DED prevalence between women and men. impact of sex on human physiology and pathophysiology. The TFOS DEWS II Sex, Gender, and Hormones report details 5. Pathophysiology [7] numerous sex-related differences that have been identified in the eye. Many of these differences have been attributed to the effects of On the basis of peer-reviewed literature, the TFOS DEWS II sex steroids (e.g. androgens and estrogens), hypothalamic-pituitary Pathophysiology Subcommittee concluded that the core mecha- hormones, glucocorticoids, insulin, insulin-like growth factor 1 and nism of DED is evaporation-induced tear hyperosmolarity, which is thyroid hormones. For example, androgens are extremely impor- the hallmark of the disease. It damages the ocular surface both tant in the regulation of the ocular surface and adnexa. They appear directly and by initiating inflammation. The cycle of events, to mediate many of the sex-related differences in these tissues. described as the Vicious Circle of DED, is shown at the center of Androgen deficiency, in turn, predisposes to lacrimal gland Fig. 2. dysfunction, serves as a risk factor for MGD, and is associated with Two forms of DED are recognized, ADDE and EDE. In ADDE, tear the development of both ADDE and EDE. In contrast to androgens, hyperosmolarity results when lacrimal secretion is reduced, in the role of estrogens at the ocular surface is less well defined, with conditions of normal evaporation from the eye. In EDE, tear effects that appear to be sex-, tissue-, and dose-specific. hyperosmolarity is caused by excessive evaporation from the In addition, sex-related differences may arise from the sex exposed tear film in the presence of a normally functioning lacrimal chromosome complement, including differences in parent-of- gland. Since tear osmolarity is a function of tear evaporation in origin effects, X chromosome gene dosage (e.g. X-inactivation) either ADDE or EDE, tear hyperosmolarity arises due to evaporation and genes in the non-recombining region of the Y chromosome, as from the ocular surface and, in that sense, all forms of DED are well as from sex-specific autosomal factors and epigenetics (e.g. evaporative. In other words, EDE is more accurately considered a microRNAs, DNA methylation and acetylation, histone hyper-evaporative state. modifications). In DED, tear hyperosmolarity is considered to be the trigger for a It is important to note that the word “sex” is used for a reason. cascade of signaling events within surface epithelial cells, which Although “sex” and “gender” are often used interchangeably, they leads to the release of inflammatory mediators and proteases. Such have distinct meanings. As stated in a 2001 report by the Institute mediators, together with the tear hyperosmolarity itself, are un- of Medicine [6], “sex” refers to the classification of living things, derstood to cause goblet cell and epithelial cell loss and damage to generally as male or female, according to their reproductive organs the epithelial glycocalyx. Inflammatory mediators from activated T- and functions assigned by chromosomal complement. “Gender” cells, recruited to the ocular surface, reinforce damage. The net refers to a person's self-representation as a man or woman, or how result is the characteristic punctate epitheliopathy of DED and a social institutions respond to that person based on the individual's tear film instability which leads at some point to early tear film gender presentation. Gender is rooted in biology, but is shaped by breakup. This breakup exacerbates and amplifies tear hyper- environment and experience. In other words, sex distinguishes osmolarity and completes the vicious circle events that lead to males and females based on their biological characteristics. Gender, ocular surface damage. Ultimately this is thought to lead to self- in turn, reflects socially constructed characteristics such as behav- perpetuation of the disease. iors and expectations related to being a man, masculine, or being a Tear film instability can be initiated without the prior occur- woman, feminine. Furthermore, gender is dynamic, context-related rence of tear hyperosmolarity, by conditions that affect the ocular and operates on a spectrum. surface, including xerophthalmia, ocular allergy, topical preserva- In effect, both sex and gender affect health and disease, as well tive use and contact lens wear. In this case, early tear film breakup is as patients' perceptions about their health. Gender also affects in- hypothesized to be the primary basis for tear film hyperosmolarity dividuals' access to and interactions with the health care system. initially experienced locally at the site of breakup, and with Many health disparities are associated with gender. Disparities increasing severity, at some point becoming detectable in tear arise from a range of influences that are biological, behavioral/ meniscus samples. This represents an ocular surfaceerelated form perceptual, cultural, and societal. Therefore, both sex and gender- of EDE. In MGD-related EDE tear hyperosmolarity results from a dterms that are distinguishable, but intertwined, should be tear film lipid layer deficiency. In ADDE the onset of early breakup considered, as they both have pronounced effects on health and on during the evolution of the disease, may add a secondary evapo- health disparities. Gender and biological sex affect DED risk, pre- rative element to the DED. sentation of the disease, immune responses, pain, care-seeking There are various causes of ADDE. It may result from blocking behaviors, service utilization, and a myriad of other facets of eye the sensory drive to the lacrimal gland that is essential to maintain health. tear film homeostasis. Bilateral topical anesthesia can cause both a

Fig. 2. Pathophysiology of DED. Please see the original report for a complete description of this figure [7]. reduction in tear secretion and blink rate. DED due to a block in many mechanistic aspects are not yet understood, the figure at- reflex tearing can be caused by chronic abuse of topical anesthetics, tempts to summarize the current view. The upper part of the figure trigeminal nerve damage and refractive surgery including LASIK illustrates the etiology of the two forms of MGD that result in low surgery. The delivery of aqueous tears to the tear sac can also be delivery of meibum, cicatricial and non-cicatricial MGD. reduced by obstruction to the lacrimal ducts, which might occur in With age, there is an increase in meibomian gland dropout, any form of cicatricial conjunctival disease, such as trachoma, particularly after the age of 50 years, which correlates with the ocular cicatricial pemphigoid, erythema multiforme, graft-versus- appearance of primary MGD. A fall in bioavailable androgens may host-disease and chemical burns. A number of drugs in systemic contribute to these events. In youth, treatment of acne vulgaris use, such as antihistamines, b-blockers, antispasmodics, diuretics with cis-retinoic acid may induce gland atrophy and MGD, while in and some psychotropic drugs, can cause a reduction in lacrimal an older age group, androgen receptor insensitivity or blockade secretion and are risk factors for DED [3,8]. Also, tear secretion rate may induce signs of MGD. The anti-glaucoma drugs pilocarpine and falls in later life. timolol also have direct effects on human meibomian gland In the Western world the most common cause of ADDE is in- epithelial cells that may influence their morphology, survival and/ flammatory infiltration of the lacrimal gland, encountered most or proliferative capacity, and possibly promote MGD. Poly- severely in the DED associated with autoimmune disorders such as chlorinated biphenyls may cause a systemic disorder that includes Sjogren€ syndrome (SSDE) and, with lesser severity, in non-Sjogren€ MGD-like features. Certain skin disorders, such as acne rosacea, syndrome (NSDE). Inflammation causes both acinar and ductal atopic dermatitis, seborrheic dermatitis and psoriasis are associ- epithelial cell dysfunction and/or destruction and a potentially ated with non-cicatricial MGD, while cicatricial conjunctival dis- reversible neurosecretory block. Circulating antibodies to the eases such as trachoma, erythema multiforme and pemphigoid, muscarinic (M3) receptor may also cause a receptor block. Low lead to cicatricial MGD. tissue androgen levels may predispose to lacrimal gland A key event in non-cicatricial MGD is hyperkeratinization of inflammation. the terminal ducts, leading to duct obstruction, duct dilatation Epithelial injury and defective glycocalyx, loss of tear volume and disuse atrophy of the glands. Later, obliteration of the gland and of goblet cell mucin, lead to increased frictional damage and orifices may occur. Obstruction may be exacerbated by changes in friction-related symptoms. The tear hyperosmolarity and epithelial oil composition that increase meibum viscosity. The degree to injury caused by DED stimulates corneal nerve endings, leading to which inflammatory changes are found around affected glands symptoms of discomfort, increased blink rate and potentially, to a varies in different reports, but signs of inflammation are common compensatory, reflex increase in lacrimal tear secretion. This at the lid margin. Inflammatory mediators and lipids may be compensatory secretion is more likely in EDE, where lacrimal gland released into tears and onto the ocular surface to cause epithelial function is potentially normal. damage. In cicatricial MGD, submucosal conjunctival scarring A schematic diagram to show the etiology and mechanism of drags the meibomian orifices, terminal ducts and mucocutaneous MGD, which is the major cause of EDE, is shown in Fig. 3. Although junction posteriorly, across the posterior lid border and onto the

Please cite this article in press as: Craig JP, et al., TFOS DEWS II Report Executive Summary, The Ocular Surface (2017), http://dx.doi.org/10.1016/ j.jtos.2017.08.003 6 J.P. Craig et al. / The Ocular Surface xxx (2017) 1e11

Fig. 3. Pathophysiology of MGD. Please see the original report for a complete description of this figure [7]. tarsal plate, where the narrowed and displaced ducts can no proteins and peptides. Tear proteins have been reported to differ in longer deliver meibum effectively to the tear film lipid layer. Low tears from DED subjects, but no definitive set of proteins or their meibum delivery and changes in oil composition can lead to tear degrees of change are yet validated to aid diagnosis. This is an area film instability, increased tear evaporation and ultimately to EDE. that should receive increased attention. In low delivery MGD, symptoms may arise from the local lid dis- Changes to the tear film clearly occur in DED. However, the lack ease itself, from lid disease with ocular surface damage and from of unified clinical parameters in tear film studies and the relatively EDE. limited understanding of the structure of the tear film has hampered comprehension of how these changes occur and their significance in the pathophysiology of DED. Improvements in the fi 6. Tear lm [8] ability to characterize the biochemistry of the tear film may lead to the identification of new markers that can be used to diagnose, The TFOS DEWS II Tear Film Subcommittee recommended a potentially predict, and even treat DED. A holistic approach to fi two-phase model of the tear lm, which has a lipid layer overlying a understanding tear film structure and function will undoubtedly muco-aqueous phase. Wax and cholesteryl esters (non-polar lipids) lead to better treatments for patients with this disease. make up the majority of the tear lipid layer and these are spread onto the muco-aqueous layer by an underlying layer of polar lipids, including (O-acyl)-u-hydroxy fatty acids and possibly phospho- 7. Pain and sensation [9] lipids. The role of the tear film lipid layer alone in preventing evaporation and breakup of tears on the eye is controversial. It is As noted by the TFOS DEWS II Pain & Sensation Subcommittee, likely that interactions of the whole tear film, including lipids, pain can be differentiated into nociceptive and neuropathic types. mucins, proteins and salts, prevent evaporation and collapse, but Nociceptive pain occurs in response to actual or threatened damage further work is needed to confirm this together with the relative to tissues. However, neuropathic pain occurs due to a lesion within roles of the various components. the somatosensory nervous system and is commonly referred to as Several studies have attempted to correlate changes in tear lipid pathologic pain or pain without biological value. biochemistry with DED, but no definitive linkage has yet been Pain associated with DED is transmitted via the peripheral axons made. In contrast, tear osmolarity received considerable attention of trigeminal ganglion (TG) neurons innervating the cornea and as the hallmark of DED, increasing with the severity of DED. conjunctiva. Within the corneal stroma, they form a subepithelial The muco-aqueous layer overlies the apical epithelial cells and nerve plexus whose ascending branches ramify extensively to their carbohydrate-rich glycocalyx. Changes in the amount of terminate within the surface epithelial layers. Functionally, sensory mucin or the glycosylation of different components have been re- nerves belong to polymodal nociceptor neurons, pure mechano- ported in tears collected from DED patients. The muco-aqueous nociceptor neurons and cold thermoreceptor neurons. Polymodal layer contains at least four major mucins, and over 1500 different nociceptors are normally silent and respond to chemical,

Fig. 4. Diagram summarizing how ocular inflammation of various etiologies or ocular surface drying in DED, provoke variable increases (þ) or decreases () of nerve impulse activity in polymodal- and mechano-nociceptors and in cold thermoreceptors of the high background, low threshold (HB-LT) and low background, high threshold (LB-HT) types. Together these changes elicit conscious sensations of different quality, as well as changes in tear flow and in spontaneous and reflex blinking. mechanical, and thermal stimuli. The inflammatory mediators to date no regulatory role for nerves or neurotransmitters has released during injury sensitize them. The transient receptor po- been identified. tential cation channel subfamily V member 1 (TRPV1) is important In addition to regulation of tear production, ocular surface for sensory transduction and sensitization of polymodal noci- nerves mediating sensations contribute to blinking behavior ceptors. Pure mechano-nociceptors are also silent at rest and (Fig. 4). It has been suggested that spontaneous blinking is main- respond only to mechanical forces perhaps through piezo2 and tained, at least in part by the continuous nerve impulse firing of eye other non-identified transducing channels. Cold thermoreceptors surface cold thermoreceptors, an effect likely mediated by the continuously discharge nerve impulses at the normal eye surface connections of TG neurons with brainstem Vi/Vc neurons which in temperature, respectively augmenting or decreasing the basal turn project to the motor neurons of the facial nerve (Cranial nerve firing frequency with cooling or warming. TRPM8 is their main cold VII). Nociceptor sensory input, projecting to neurons at the VcC1 transducing channel and is also sensitive to osmolarity increases. region, initiates reflex blinking through their projections to ViVc Inter-blink tear evaporation causes discrete cooling of the ocular transition neurons, and sets blink amplitude and peak velocity of surface and tear osmolarity rises, thereby augmenting basal activity corneal reflex blinks. of cold thermoreceptors. This is consistent with the hypothesis that In DED, reduced tear secretion leaves the corneal epithelium cold-sensitive fibers contribute to the reflex control of basal tear exposed to adverse environmental conditions and often leads to production and blinking. variable levels of inflammation and to peripheral nerve terminal The TG neurons from the ocular surface project primarily into damage. Inflammation causes sensitization of polymodal noci- two spatially discrete regions within the trigeminal brain stem ceptors and mechano-nociceptors, while it depresses cold ther- nuclear complex: the transition region between caudal Vi and Vc moreceptor activity. However, in experimental DED the (ViVc transition) and at the Vc/upper cervical cord junction (VcC1 sensitization of nociceptor fibers is discrete and the most promi- region). Evidence suggests that the VcC1 region plays a dominant nent nerve disturbance is the sustained, abnormal increase in cold role in sensory-discriminative aspects of ocular pain. ViVc transi- thermoreceptor nerve activity that occurs in parallel with tion neurons are excited by bright light and are activated by morphological changes in corneal innervation. This suggests that changes in the moisture status of the ocular surface. Ocular neurons dryness-induced nerve damage dominates over inflammation, at the ViVc transition project to brain regions that control lacri- causing abnormal activity primarily in cold terminals. In parallel mation (superior salivatory nucleus) and blinking (facial motor with these changes in peripheral nerve activity, brainstem ocular nucleus) as well as to the sensory thalamus. Thus, it is suggested neurons at both ViVc and VcC1 regions display enhanced that ocular neurons at the ViVc transition play a significant role in responsiveness. maintaining ocular surface homeostasis. The secretory activity of the main lacrimal gland is regulated 8. Iatrogenic dry eye [10] by autonomic sympathetic and parasympathetic nerves whose activity is regulated by reflex influences from sensory neurons As reported by the TFOS DEWS II Iatrogenic Dry Eye Subcom- supplying the ocular surface. Parasympathetic innervation is more mittee, DED can be caused by a variety of iatrogenic interventions, extensive. Very little is known about the neural control of acces- including topical and systemic drugs, the use of contact lenses, and sory lacrimal glands, but it appears to be similar to the main ophthalmic surgical and non-surgical procedures. lacrimal gland. While nerves are present around the meibomian Topical medications that cause DED (Table 2) interact with the glands, there are no studies examining the role of sensory or ocular surface by exerting allergic, toxic and immuno-inflammatory autonomic nerves and their neurotransmitters in regulating the effects. Preservatives, such as benzalkonium chloride, may cause or holocrine secretion of the meibomian gland. Activation of sensory aggravate DED through their toxic and proinflammatory effects, as nerves supplying the rat cornea evokes goblet cell mucous well as detergent tensioactive properties. Moreover, a great variety secretion; however efferent nerve type(s) involved in this reflex of systemic drugs, such as vasodilators, sulfonylureas, anxiolytics, response remain to be established. Several non-neural processes antidepressants, antihistamines, and those listed in Table 3, may regulate the release of mucins from stratified squamous cells, but also induce DED secondary to decreased tear production, altered

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Table 2 Examples of topical treatments that may induce or worsen DED.

Compounds Examples

Adrenergic agonists Apraclonidine, Brimonidine, Dipivefrin Anti-allergics Emedastine, Olopatadine Anti-virals Aciclovir, Idoxuridine, Triﬂuridine bblockers Betaxolol, Carteolol, Levobunolol, Metipranolol, Timolol Carbonic anhydrase inhibitors Brinzolamide, Dorzolamide Cholinergic agonists Pilocarpine, Ecothiopate Decongestants Naphazoline, Tetryzoline Miotics Dapiprazole Mydriatics & cyclopegics Cyclopentolate, Tropicamide, Hydroxyamfetamine Prostaglandins Bimatoprost, Latanoprost, Travoprost, Unoprostone Topical and local anesthetics Cocaine, Proxymetacaine, Tetracaine Topical ocular non-steroidal anti-inﬂammatory drugs Bromfenac, Diclofenac, Ketorolac, Nepafenac

Table 3 prophylactic treatment, as well as efforts to establish appropriate Known or suspected systemic medications causing, contributing to, or aggravating therapeutics, and improving attempts to regulate and oversee DED. medications, preservatives and procedures should be considered. Category Subcategory Analgesic Antirheumatic 9. Diagnostic methodology [11] Cannabinoid Opioid The TFOS DEWS II Diagnostic Methodology Subcommittee Anesthesia Anticholinergic (antimuscarinic) Antiarrythmic/Bronchodilating examined the research evidence for tests to quantify patient Antihistamine symptoms, visual disturbance, tear film stability, osmolarity, tear Antidepressant volume, ocular surface damage, inflammation of the ocular surface Anti-Parkinson's and eyelid signs (such as MGD), and recommended the key diag- Antipsychotic Antispasmodic nostic tests and techniques. While many tests have been suggested Decongestant to be diagnostic of DED, their sensitivity and specificity is highly Antihypertensive Adrenergic blocking dependent on the inclusion criteria and severity of the DED group þ - Na Cl Co-transporter (diuretic) and the population examined. The Subcommittee made the Antileprosy following recommendations to represent the best available evi- Antimalarial Antineoplastic dence to diagnose and subtype DED in a clinical setting. The se- Anxiolytic/hypnotic lection principles were: diagnostic ability; minimal-invasiveness; Chelator/Calcium Regulator objectivity; and clinical applicability. Depressant The recommended tests for the diagnosis of DED and assess- Herbal and Vitamins Hormonal Antiandrogen/Estrogen replacement ment of its severity are presented in Fig. 5 Prior to diagnosis, it is Neurotoxin important to exclude conditions that can mimic DED with a num- Sedative ber of triaging questions (Fig. 5). Such conditions and their differ- entiating features are outlined in the report. Following this, the Dry Eye Questionnaire-5 (DEQ-5) or Ocular Surface Disease Index (OSDI) should be completed to indicate whether a patient might nerve input and reflex secretion, inflammatory effects on secretory have DED, and a positive symptom score on either of these ques- glands, or direct irritation effect through secretion into the tears. tionnaires should then trigger a more detailed examination for DED in contact lens wearers has been identified as an ongoing clinical signs of DED. The presence of any one of three specified issue for many patients. The use of contact lenses can either induce signs; reduced non-invasive break-up time; elevated or a large or be associated with DED. Biophysical changes to the tear film in interocular disparity in osmolarity; or ocular surface staining (of contact lens wearers with DED include a thinner, patchy lipid layer; the cornea, conjunctiva or lid margin) in either eye, is considered tear film instability; lower basal tear turnover rate; and decreased representative of disrupted homeostasis, confirming the diagnosis tear meniscus volume. of DED. If a patient has DED symptoms and their practitioner does Surgical procedures such as corneal refractive surgery and ker- not have access to all these tests, a diagnosis is still possible, based atoplasty may cause or aggravate DED through mechanisms on a positive result for any one of the markers, but may require intrinsic to the procedure (i.e. corneal nerve transection) or even by referral for confirmation if the available homeostasis markers are the use of postoperative topical drugs. Cataract surgery, lid sur- negative. Guidance on how, and in which order, to conduct these geries, botulinum toxin application and cosmetic procedures are tests are provided within the report and videos are available on the also considered risk factors for iatrogenic DED, which can be the TFOS website (www.tearfilm.org). cause of patient dissatisfaction, visual disturbance and poor surgi- Having confirmed that the condition is DED on the basis of a cal outcomes. positive symptom score and one or more positive homeostatic Future directions to address iatrogenic DED include more in marker results, further subtype classification tests such as mei- depth epidemiological studies about the risk factors, development bography, lipid interferometry and tear volume measurement of less toxic medications and preservatives, as well as new tech- should be conducted to determine: 1) where the DED falls on the niques for less invasive eye surgeries. Novel research into detecting spectrum between ADDE and EDE, and 2) the severity of DED, in early DED prior to ocular surgery, determining the benefits of order to guide treatment.

Fig. 5. Recommended diagnostic approach for DED. Please see the original report for a complete description of this ﬁgure [11].

10. Management and therapy [12] sequential approach to be followed linearly. Instead, it should be viewed as an organizational tool to help guide initiation of treat- The management of DED is complicated, due to its multifactorial ment with those interventions most likely to benefit most patients etiology. Expanding upon the simple belief that “diagnosis pre- with DED, and progressing to more advanced and specific treat- cedes therapy” means that clinicians must make their best efforts to ments aimed at particular aspects of the DED pathophysiology. On- identify the degree to which EDE, ADDE and/or other ocular surface going scientific evidence, as well as risk versus benefit and cost conditions are contributing to the patient's presentation. This considerations, will also contribute to decisions made in choosing aspect of determining the major causative factors behind the DED is between multiple treatment options. critical to appropriate management. Management algorithms are often constructed to recommend a The ultimate aim of DED management is to restore the ho- sequence of treatments according to the stage of disease, but this meostasis of the ocular surface and tear film, through breaking the construction is complicated in DED, as the disease often varies from vicious cycle of the disease. While certain treatments may be spe- patient to patient, both in severity and in character. Table 4 lists a cifically indicated for one particular aspect of an individual patient's series of management and treatment options that have all been condition, a number of therapies might be appropriately recom- shown to result in alleviation of presenting DED [12]. Should pa- mended in order to treat the multiple aspects of a patient's pre- tients not respond to a given level of management, or should they sentation with DED. While aiming to identify and treat the primary present with more severe DED, the next level of management is source of the disease, the management of DED typically involves recommended and in some cases the previous therapy may be ongoing management to address chronic sequelae, rather than continued in addition to any new therapies. In general, manage- short-term treatment. ment approaches begin with conventional, low-risk and easily The presented management algorithm is not proposed as a rigid accessible patient-applied therapies such as over-the-counter

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Table 4 Recommendations for the staged management and treatment of DED.a,b,c

Step 1: Education regarding the condition, its management, treatment and prognosis Modification of local environment Education regarding potential dietary modifications (including oral essential fatty acid supplementation) Identification and potential modification/elimination of offending systemic and topical medications Ocular lubricants of various types (if MGD is present, then consider lipid-containing supplements) Lid hygiene and warm compresses of various types Step 2: If above options are inadequate consider: Non-preserved ocular lubricants to minimize preservative-induced toxicity Tea tree oil treatment for Demodex (if present) Tear conservation Punctal occlusion Moisture chamber spectacles/goggles Overnight treatments (such as ointment or moisture chamber devices) In-office, physical heating and expression of the meibomian glands (including device-assisted therapies, such as LipiFlow) In-office intense pulsed light therapy for MGD Prescription drugs to manage DEDd Topical antibiotic or antibiotic/steroid combination applied to the lid margins for anterior blepharitis (if present) Topical corticosteroid (limited-duration) Topical secretagogues Topical non-glucocorticoid immunomodulatory drugs (such as cyclosporine) Topical LFA-1 antagonist drugs (such as lifitegrast) Oral macrolide or tetracycline antibiotics Step 3: If above options are inadequate consider: Oral secretagogues Autologous/allogeneic serum eye drops Therapeutic contact lens options Soft bandage lenses Rigid scleral lenses Step 4: If above options are inadequate consider: Topical corticosteroid for longer duration Amniotic membrane grafts Surgical punctal occlusion Other surgical approaches (eg tarsorrhaphy, salivary gland transplantation)

MGD e meibomian gland dysfunction; DED e dry eye disease. a Potential variations within the disease spectrum are acknowledged to exist between patients and the management options listed above are not intended to be exclusive. The severity and etiology of the DED state will dictate the range and number of management options selected from one or more steps. b One or more options concurrently within each category can be considered within that step of the dry eye disease state. Options within a category are not ranked according to importance and may be equally valid. c It should be noted that the evidence available to support the various management options differs and will inevitably be lower for newer management options. Thus, each treatment option should be considered in accordance with the level of evidence available at the time management is instigated. d The use of prescription drugs needs to be considered in the context of the individual patient presentation, and the relative level of evidence supporting their use for that speciﬁc indication, as this group of agents differs widely in mechanism of action.

lubricants for early stage disease, and progress to more advanced 11. Clinical trial design [13] therapies for more severe forms of DED. However, it must be understood that there is significant heterogeneity in the DED patient In order to improve the quality of clinical trials, to optimize population. The approach cannot be overly formulaic and these resources, and to increase the opportunity for novel therapeutics to recommendations may be modified and overlapped as required by reach patients with DED, the TFOS DEWS II Clinical Trials Sub- practitioners based on an individual patient profile. committee made the following recommendations. The expected treatment trial duration before concluding failure First, that studies be conducted consistent with Good Clinical to improve is related both to the individual's response and to the Practice (GCP). While this may be a daunting task, clinical trialists therapy being considered. Most commonly, treatment effects are should consult colleagues and drug development experts who are observed within one to three months, although some therapies (e.g. familiar with this system of controls. This includes appropriate cyclosporine A) may take longer. protections for the study subjects. GCP also requires compliance Overall, the treatment of DED remains something of an art, not with appropriate regulatory requirements in the jurisdiction of easily lending itself to a rigid, evidence-based algorithm that ac- study conduct, and may require additional regulatory filings if the commodates all patients with DED symptoms or signs. All eye care investigational shipment is prepared and sent from another state or providers who treat patients with DED must exercise their clinical country. skills to judge the significance of each of the varied pathogenic The Consolidated Standards of Reporting Trials (ConSORT) processes that may manifest similar subjective complaints and statement is useful to review prior to planning and starting a study. similar signs of ocular surface dysfunction. Next, the Subcommittee recommended that the design, treatments, and sample size be consistent with the investigational treatment,

Please cite this article in press as: Craig JP, et al., TFOS DEWS II Report Executive Summary, The Ocular Surface (2017), http://dx.doi.org/10.1016/ j.jtos.2017.08.003 J.P. Craig et al. / The Ocular Surface xxx (2017) 1e11 11 the objectives of the study, and the phase of development. For example, a crossover or paired-comparison design may be appropriate for a comfort study in normal volunteers, but not for a long- lasting treatment with potential for systemic or contralateral effects. Also, the dose of a drug or biologic should not only be less than that which was toxic or not tolerated in nonclinical or previous clinical studies, but must be sufficient, in dose and frequency, to deliver therapeutic concentrations at the intended site of action. The duration of treatment, at least for a pivotal study, should also be consistent with the mechanism of action and time course of effect. For pivotal studies, sample size is key to the potential validity of the study. Outcome measures are critical to determine the efficacy of the treatment and, if possible, should include minimally invasive objective metrics that align with the expected mechanism of action of the treatment. Exploration of new ways to evaluate DED, such as biomarkers, may lead to improvement in DED clinical trial design and increased clarity on the efficacy of new treatments. Fig. 6. TFOS DEWS II™ report. Dedication References This TFOS DEWS II report is dedicated to the late Professor Juha Holopainen (Helsinki Eye Lab and Department of Ophthalmology, [1] Nelson JD, Craig JP, Akpek E, Azar DT, Belmonte C, Bron AJ, et al. TFOS DEWS II University of Helsinki and Helsinki University Hospital, Helsinki, introduction. Ocul Surf 2017;15:269e75. [2] Craig JP, Nichols KK, Akpek EK, Caffery B, Dua HS, Joo CK, et al. TFOS DEWS II Finland), who served on the Steering Committee and Tear Film definition and classification report. Ocul Surf 2017;15:276e83. Subcommittee, in recognition of his outstanding scientific contri- [3] Stapleton F, Alves M, Bunya VY, Jalbert I, Lekhanont K, Malet F, et al. TFOS butions to the field of the ocular surface and tear film. DEWS II epidemiology report. Ocul Surf 2017;15:334e65. [4] 2007 TFOS report of the international dry eye workshop (DEWS). Ocul Surf 2007:65e204. Acknowledgments [5] Sullivan DA, Rocha EM, Aragona P, Clayton JA, Ding J, Golebiowski B, et al. TFOS DEWS II sex, gender, and hormones report. Ocul Surf 2017;15:284e333. The authors thank Amy Gallant Sullivan (TFOS Executive Di- [6] Institute of Medicine (US) Committee on Understanding the Biology of Sex and Gender Differences. Exploring the biological contributions to human rector, USA) for raising the funds that made this TFOS DEWS II health: does sex matter?. Washington, DC: The National Academies Press; possible; Amy and Rose M. Sullivan (TFOS Operations Manager, 2001. USA) for their help in the organization of this Workshop; Nino [7] Bron AJ, dePaiva CS, Chauhan SK, Bonini S, Gabison EE, Jain S, et al. TFOS DEWS II pathophysiology report. Ocul Surf 2017;15:438e510. Longo (Catania, Italy) and Sabrina Zappia (Rome, Italy) for their [8] Willcox MDP, Argüeso P, Georgiev G, Holopainen J, Laurie G, Millar T, et al. illustrative expertise (e.g. Figs. 1, 5 and 6); Stephanie Wong TFOS DEWS II tear film report. Ocul Surf 2017;15:366e403. (University of Waterloo, Canada) for her technical assistance; and [9] Belmonte C, Nichols JJ, Cox SM, Brock JA, Begley CG, Bereiter DA, et al. TFOS DEWS II pain and sensation report. Ocul Surf 2017;15:404e37. all participants of TFOS DEWS II for their contributions to this [10] Gomes JAP, Azar DT, Baudouin C, Efron N, Hirayama M, Horwath-Winter J, report. et al. TFOS DEWS II iatrogenic dry eye report. Ocul Surf 2017;15:511e38. The TFOS DEWS II was supported by unrestricted donations [11] Wolffsohn JS, Arita R, Chalmers R, Djalilian A, Dogru M, Dumbleton K, et al. e þ TFOS DEWS II diagnostic methodology report. Ocul Surf 2017;15:539 74. from Alcon, Novartis, Shire, Allergan, Bausch Lomb, Akorn, [12] Jones L, Downie LE, Korb D, Benitez-del-Castillo JM, Dana R, Deng SX, et al. CooperVision, Dompe, Horus Pharma, Lmbris Biopharma, Oculeve, TFOS DEWS II management and therapy report. Ocul Surf 2017;15:575e628. TearLab, Laboratoires Thea, SIFI, Sun Pharma, Johnson & Johnson [13] Novack GD, Asbell P, Barabino B, Bergamini MVW, Ciolino JB, Foulks GN, et al. TFOS DEWS II clinical trial design report. Ocul Surf 2017;15:629e49. VisionCare, Carl Zeiss Meditec, Quint Health, Scope Ophthalmics and Senju.

Please cite this article in press as: Craig JP, et al., TFOS DEWS II Report Executive Summary, The Ocular Surface (2017), http://dx.doi.org/10.1016/ j.jtos.2017.08.003 SUFFERING FOR BEAUTY: HARMFUL INGREDIENTS AND TRENDS IN COSMETICS BEAUTY AND AESTHETICS BEAUTY Dirty secrets inside the beauty bag.

BY LESLIE E. O’DELL, OD; AMY GALLANT SULLIVAN, BS; AND LAURA M. PERIMAN, MD

The United States has the largest cosmetics market in the world, and its revenue is expected to exceed $62 billion in 2016.1 According to the consulting company Kline, natural cosmetics and skincare is estimated to be worth $33 billion, accounting for 13% of the overall global beauty market.2 There is also a growing demand for safe cosmetics. Part one of this four-part series (“Beauty Does Not Have Figure 1. Eyelash length should be one-third of eye width. to Hurt,” page 42, AOC’s July/August 2016 issue) discussed Eyelashes help limit tear evaporation from the surface of the lack of regulatory oversight by the US Food and Drug the eye. Administration over the use of terms such as safe in the labeling of cosmetics. With cosmetics being a large and mineral. They are used not only as gemstones, but also as growing market, it is necessary for eye care providers to industrial abrasives for cutting hard materials. On your face, know the habits of our patients, both men and women, it is claimed that diamond dust acts like a magic wand, eras- and to educate them about proper ocular health and cos- ing sun damage, scars, blotchiness, and lines. metic use. In part two of the series, we explore potential Diamond dust is most often found in luxury eye cosmet- harms from ingredients in commonly used cosmetics, and ics, making their prices out of reach for younger consumers. we uncover some potentially harmful beauty trends. Therefore, the demographic most attracted to diamond- infused products is women in middle-age; this happens to NATURALLY ORGANIC OCULAR SURFACE coincide with the time many women begin to develop ocu- OFFENDERS lar surface disease (OSD).3 “Nature” is all the rage in beauty and wellness products. Can diamond dust exacerbate dry eye symptoms? Crushed Particularly trendy at the moment are earthy ingredients— rocks in the tear film? Yes, perhaps that might cause some like rocks. And the rocks that are very popular are diamonds, instability. On slit-lamp examination, these crushed rocks look and not just those for sparkling adornment. like shards of glass piercing the conjunctival tissue. Actress Elizabeth Taylor once professed “Big girls need big Adding flame to this inflammatory fire, many luxury diamonds.” However, Ms. Taylor was referring to diamonds cosmetic brands have now expanded their natural mineral as jewels, not the crushed rocks we now find in luxury beau- ingredients to include not only diamond dust, but also ty products. Diamonds are a form of carbon, a very hard hematite and tourmaline in their products.

12 ADVANCED OCULAR CARE | SEPTEMBER 2016 BEAUTY AND AESTHETICS

Ms. Taylor might opine that these precious stones should be adorning fingers, ears, and throats, not the eyelids or eye A contours. Another natural mineral ingredient that should raise an eyebrow is kohl. Kohl has been popular since ancient times, used by the queens and nobles of Egypt as early as 3100 BCE.4 Historically, people used kohl to protect their eyes from the harsh rays of the sun, as well as for treatment of eye ailments. In India, mothers applied kohl to their infants’ eyes soon after birth, purportedly to strengthen the children’s eyes, and others believed it could prevent children from being cursed by the evil eye.5-10 The Food and Drug Administration points out, however, that many people may be unaware of the lead-poisoning risk, for both adults and children, from this traditional eye cosmetic, known variously as kohl, kajal, al-kahl, and surma. B Kohl is predominantly used as an eyeliner or mascara, both for beautification and as part of cultural tradition. Concerns about kohl’s safety should be addressed with patients.

EYELASHES: BALANCING BEAUTY AND FUNCTION In most Western cultures, long eyelashes are deemed aesthetically pleasing. However, when we alter the ratio that Mother Nature intended, we create unwanted consequences. The long eyelashes of babies have an adorable appeal, but babies do not experience the same effects of altered lash/lid ratio as adults. Perhaps the incredible tear stability of the young and the long lashes of infancy are designed to maximally deflect debris, an advantage given the relative lack of neurologic coordination and mobility of infancy. Or perhaps it is an illusion that the lashes are Figure 2. This young patient had false lashes applied (A). longer in the young and that the ideal protective lash/lid She developed a severe chemical conjunctivitis from the length ratio is preserved in infancy. glue used during the application process (B). Alterations of length have been found to limit the eyelashes’ unique protective features against turbulent air and debris.11 Additionally, the degree of VKC severity was positively cor- When individuals artificially lengthen their eyelashes with related with longer lash length.13 cosmetics, stiff methacrylate eyelash extension glues, and syn- Eyelash extensions are popular, but for OSD specialists thetic lash extension fibers, the natural lash cilia flexion and there are concerns about the consequences. As noted, resultant tear evaporation and debris-deflecting attribute may altering the ideal lash/lid ratio results in altered evapora- also be detrimentally altered (Figure 1). tive and debris protective abilities, but in addition the Amador et al found that, among 22 mammalian spe- adhesives used for these extensions also create havoc for cies studied in wind tunnel experiments, the optimal lash/ the ocular surface. These adhesives are cyanoacrylate- like lid ratio of 0.34 cuts the tear evaporation rate and particle adhesives, with mixtures of methacrylates, volatile organic deposition rate by half.11 Eyelashes become thinner, shorter, compounds, and formaldehyde (a preservative and known and lighter as women age,12 and this may contribute to the ocular irritant). Methacrylates are considered inert once evaporative load in older patients with OSD. they polymerize, but the accompanying chemicals needed Alterations in the ideal lash/lid ratio are also seen in to keep the acrylates in liquid form during application children with significant ocular allergies such as vernal contribute to evaporative stress, irritation, and allergenic- keratoconjunctivitis (VKC). In a series of 93 children with ity. Additionally, these chemicals can leech onto the ocu- VKC, Pucci et al found the eyelash length to be significantly lar surface during application of the adhesive, creating a longer than in normal age- and gender-matched controls.13 chemical conjunctivitis (Figure 2).

SEPTEMBER 2016 | ADVANCED OCULAR CARE 13 eyeliner application is influenced by fashion trends, which A have included application close to the lash line, posterior to the lash line, and on the inner lid margin or waterline. Trends have also included the addition of bright pigments, glitter, and even gems. It is important to make your make-up wearing patients aware of their eyelid anatomy, particularly the meibomian glands and their orifices. To the eye care practitioner, the lid is an area of great concern for overall tear film stability, but to patients this is the perfect place to apply eyeliner. Pencil eyeliner, when applied on the inner portion of the lash line, has been shown to migrate into the eye 15% to 17

BEAUTY AND AESTHETICS BEAUTY 30% of the time. Although eyeliner entering the ocular surface has not been shown to induce ocular inflammation, use on consecutive days has been shown to increase lipid 17 B layer thickness and the incidence of dry eye symptoms. Conjunctival pigmentation has also been noted in patients using eyelash cosmetics, including both mascara and eyeliner.18 This can be seen on slit-lamp examination as small brown or black flecks within the inferior palpebral conjunctival tissue. Some women who want the luxury of waking up with makeup may elect to obtain permanent eyeliner in the form of tattoos (Figure 3). A recent study found that permanent eyeliner tattooing shortened tear film breakup time, increased corneal staining, and induced meibomian gland loss significantly in comparison with a control group with no eyeliner tattoos.19 Eyelash dying or tinting is another beauty trend that can cause severe allergic reactions, as many hair dyes contain para-phenylenediamine, or PPD.20 This is a chemical found Figure 3. Permanent eyeliner in the form of a tattoo is com- in plastics such as Kevlar (Dupont) and also used in the mon in the United States (A). This practice can affect tear recent trend in henna temporary tattoos. Many individu- film quality and meibomian gland function (B). Education als have reported severe conjunctival reactions, swelling, about the risks of these permanent procedures is key for watering, and acute inflammation due to allergy to PPD in patients with dry eye disease. dyes used around the eyes for eyelash tinting.21-22

Based on the available literature and clinical observations, DIRTY SECRETS: INSIDE THE BEAUTY BAG eye care providers should advise OSD patients to avoid eyelash You can recommend that your patients use cosmetics extensions and growth serums. Many patients with severe containing safer ingredients, and you can educate them OSD stop using eyelid and eyelash cosmetics due to irritation. about the proper application of cosmetics. The next prob- Eyelash growth products such as Latisse (bimatoprost ophthal- lem is assuring their compliance. One common way in which mic solution 0.03%, Allergan), although shown to be “safe and patients may fall short of our expectations is in the timely effective”,14 the incidence of conjunctival and eyelid hyperemia replacement of cosmetics. was significantly greater in subjects using 0.03% bimatoprost Quarterly replacement of eyelash (mascara and eyeliner) than subjects randomized to a vehicle control.15 Also, accord- and eyelid (primers and eye shadow) cosmetics is a common ing to a very recent study, prostaglandin analogues (eg, bima- recommendation. How many of your patients do this? Have toprost) may induce meibomian gland dysfunction.16 you discussed their cosmetic hygiene routines with them? Cosmetics are not like the bottle of milk in your refrigera- EYELIDS: NO SILVER LINING tor: They do not have a “use by” date stamped on them. Lining the eyelid is another common way to enhance the Nonetheless, these makeup products do have built-in expira- eyes. Eyeliners can be found in the form of pencils, cakes, tion dates. Tell your patients to treat products such as mascara liquids, and even permanent options. The location of and liquid eyeliner like eggs, as they have the shortest shelf lives.

14 ADVANCED OCULAR CARE | SEPTEMBER 2016 BEAUTY AND AESTHETICS

MAKEUP TIPS IN THE YOUTUBE ERA Young women and men often turn to YouTube to learn the latest trends in beauty and to find how-to guides for makeup application. In the past 10 years, more than 5 billion hours of beauty tutorials and explainers have been uploaded to YouTube.

Some of the videos offering tips on makeup application may be quite alarming to eye care providers. There are makeup challenges, such as applying 100 layers of mascara or foundation. There are do-it-yourself guides for making cosmetics— using anything from blueberries to crushed Oreo cookies.

Thanks to tips from celebrities like Taylor Swift, we have to be concerned about young women using Sharpie markers as liquid eyeliner. The Kardashian family is not much help either, having made false eyelashes and heavy use of eyeliner mainstream.

Stay vigilant to new beauty trends, and start conversations about proper cosmetic use early with your young patients.

Mascaras and eyeliners are made up of oil, waxes, preser- cara, particularly with an old applicator, the cornea should vatives, and pigments. Most of our female patients use eye be treated immediately and the mascara cultured to detect makeup; it has been estimated that 87% of women younger Pseudomonas. This is important to remember, as mascara than 55 years use eye cosmetics.23 It has been estimated that wand injuries are common with makeup application in 9 out of 10 women 18 to 54 years of age use mascara.24 moving vehicles, another dirty secret of our cosmetic-loving These oils and waxes can not only clog the meibomian patients. Aged mascara wands, tubes, and eyeliners can easi- glands, they can also supplement the diet of Demodex. ly become contaminated with one or more species of micro- Optometrists should make patients aware of Demodex organisms including the genera Bacillus spp., Staphylococcus before an infestation can occur. Not only should you discuss spp., Pseudomonas spp., Proteus vulgaris, and Serratia marc- Demodex and the need for lid hygiene with your patients, escens.27 Patients should also be made aware that they must but you should address bacterial growth and contamination wash their hands before makeup application. Contaminants of makeup tubes and containers and how this can affect can appear from multiple sources. vision. You might point out that, every time they put the Traditionally, the contents in your patient’s purse should wand back into the tube, bacteria enter and contaminate not be public knowledge, however, what’s in their beauty the makeup. bag can be detrimental to their eye health. Please discuss Microbial organisms are normally present on human eye- your patients’ cosmetic routine and OSD implications. Stay lashes. Application of eye makeup to lashes has the poten- vigilante to new beauty trends and start the conversation tial to inoculate the mascara tube or eyeliner with these early about cosmetic use with your patients, what’s hiding in microbes.25 Mascaras are generally contaminated more than their beauty bag can hurt the ocular surface. n eye shadows. In a study of 150 samples, 15% of mascaras were rated as heavily contaminated (more than 104 cfu/mL 1. MarketResearch.com http://www.prnewswire.com/news-releases/marketresearchcom-the-us-beauty-and-cosmetics- market-expected-to-exceed-62-billion-in-2016-300209081.html 26 of bacteria). 2. http://www.cosmeticsdesign-europe.com/Market-Trends/The-lowdown-on-all-that-s-new-in-the-natural-and-organic- Pack et al, upon finding microbial presence in 36.4% of market. 3. Schaumberg DA, Sullivan DA, Buring JE, Dana MR. Prevalence of dry eye syndrome among US women. Am J Ophthalmol. mascara tubes cultured after 3 months of use, recommend- 2003:136;318-326. ed keeping a mascara tube, used on a daily basis, for no more 4. Lucas A. Cosmetics, perfumes and incense in ancient Egypt. J Egypt Archaeol. 1930;16(1/2):41-53. 25 5. Al-Hazzaa SA, Krahn PM. Kohl: a hazardous eyeliner. Int Ophthalmol. 1995;19(2):83-88. than 3 months. 6. Alkhawajah AM. Alkohl use in Saudi Arabia: extent of use and possible lead toxicity. Trop Geogr Med. 1992;44(4):373-377. Pseudomonas corneal ulcers have also been associated 7. Hardy AD, Walton RI, Myers KA, Vaishnav R. Availability and chemical composition of traditional eye cosmetics (“kohls”) 27 used in the United Arab Emirates of Dubai, Sharjah, Ajman, Umm Al-Quwain, Ras Al-Khaimah, and Fujairah. J Cosmet Sci. with mascara contaminated with P aeruginosa. If the cor- 2006;57(2):107-125. neal epithelium is scratched during the application of mas- 8. Jallad KN, Hedderich HG. Characterization of a hazardous eyeliner (kohl) by confocal Raman microscopy. J Hazard Mater.

SEPTEMBER 2016 | ADVANCED OCULAR CARE 15 BEAUTY AND AESTHETICS 25. PackLD,WickhamMG,EnloeRA,HillDN.Microbialcontaminationassociatedwithmascarause. 24. https://www.npd.com/wps/portal/npd/us/news/press-releases/pr_081125/ Jul;42(4):211-20. doi:10.1097/ICL.0000000000000181. 23. NgA,EvansK,NorthRV,etal.Impactofeyecosmeticsontheeye,adnexa,andocularsurface. 2003;11:149-151. 22. KaisermanI.Severeallergicblepharoconjunctivitisinducedbyadyeforeyelashesandeyebrows. eyelashes andeyebrows. for dye cream a in phenylenediamine 21. HanssonC,Thorneby-AnderssonK.Allergiccontactdermatitisfrom2-chloro-p Dermatitis 20. TeixeiraM,deWachterL,RonsynE,GoossensA.Contactallergytopara-phenylenediamineinapermanenteyelashdye. 755. 19. LeeYB,KimJJ,HyonJY,etal.Eyelidtattooinginducesmeibomianglandlossandtearfilminstability. Ophthalmol. 18. SugarHS,KobernickS.Subconjunctivalpigmentation;associatedwiththeuseofeyecosmeticscontainingcarbon-black. 17. NgA,EvansK,NorthRV,PurslowC.Migrationofcosmeticproductsintothetearfilm. bimatoprost regulatehumanmeibomianglandepithelialcells? 16. KamWR,LiuY,DingJ,SullivanDA.DocyclosporineA,anIL-1receptorantagonist,uridinetriphosphate,rebamipide,and/or masked, vehicle-controlled,parallel-groupstudy. 15. SmithS,FagienWhitcupSM,etal.Eyelashgrowthinsubjectstreatedwithbimatoprost:amulticenter,randomized,double- Dermatol. 14. WoodwardJA,HaggertyCJ,StinnettSS,etal.Bimatoprost0.03%gelforcosmeticeyelashgrowthandenhancement. 2005;115(1):e86-e91. 13. Pucci,N,NovembreE,Lombardietal.Longeyelashesinacaseseriesof93childrenwithvernalkeratoconjunctivitis. population ofhealthywomen. 12. GlaserDA,JonesD,CarruthersJ,etal.Epidemiologicanalysisofchangeineyelashcharacteristicswithincreasingagea 20141294. 11. AmadorGJ,MaoW,DeMercurioP,etal.Eyelashesdivertairflowtoprotecttheeye. 1991;94:121-123. 10. ParryC,EatonJ.Kohl:alead-hazardouseyemakeupfromthethirdworldtofirstworld. 9. NirA,TamirZelnikN,IancuTC.Iseyecosmeticasourceofleadpoisoning? 2005;124(1-3):236-240. . 2006;55(2):92-94. 2010;9(2): 96-102. 1966;62(1):146-149. Contact Dermatol Surg

Dermatitis . 2001;45:235-236. . 2014;40(11):1208-1213. . J AmAcadDermatol. Invest OphthalmolVisSci 2012;66(5):801-6. Isr JMedSci. . 2016;57(10):4287-4294. Eye ContactLens. J RSocInterface 1992;28(7):417-421. Environ Health Perspect. EnvironHealthPerspect. Contact Lens Ocul Immunol Inflamm. Ocul ImmunolInflamm. Optometry Cornea 2015;41(5):304-309. . 2015;12(105). pii: . 2015;12(105).pii: . 2015;34(7):750- . 2016 . 2016 . Pediatrics J Cosmet J Cosmet Contact Am J Am J .

Ophthalmol. 27. WilsonLA,AhearnDG.Pseudomonas-inducedcornealulcersassociatedwithcontaminatedeyemascaras. 1975;79(4):596-601. 26. WilsonLA,JulianAJ,AhearnDG.Thesurvivalandgrowthofmicroorganismsinmascaraduringuse. 2008;79(10):587-593. n n n Laura M. Periman, MD n n n n Leslie E. O’Dell, OD n n Amy Gallant Sullivan, BS TearScience; consultanttoAllergan sultant toBruderandParagonBioTeck Manchester, Pennsylvania Surface Society(TFOS),Boston Financial disclosure: speaker for Allergan, BioTissue, and Financial disclosure:speakerforAllergan,BioTissue,and [email protected]; (206)2349846 Specialist incorneaandexternaldisease,Seattle Financial disclosure:speakerforAllergan,RPS,andShire;con [email protected]; Twitter@helpmydryeyes 717) 266-5661;(717)521-7161;[email protected] Director ofDryEyeCenterPA,WheatlynCare, [email protected]; Twitter@Eyeppl@DryEyeMakeup Executive DirectorandBoardmember,Tear Film&Ocular 1977;84:112-119. Am J Ophthalmol. Am JOphthalmol. - Am J BEAUTY DOES NOT HAVE TO HURT Ocular surface disease can be exacerbated by chemicals hiding in plain sight in everyday products. This is the first of a three part series.

BY LESLIE E. O’DELL, OD; AMY GALLANT SULLIVAN, AND LAURA M. PERIMAN, MD COVER FOCUS COVER The US Food and Drug Administration (FDA) requires that The Breast Cancer Fund ocular prescription reported that the average medications scientifi- cally demonstrate a “ woman in the United States statistically significant uses 12 cosmetic products daily, improvement in the signs and symptoms of disease. Without demonstrating and the average man uses six. efficacy and safety, new pharmaceuticals do not receive FDA approval. Prescription medications that we recommend for our patients with dry eye disease (DED) have proven safety and efficacy documented through rigorous at a concentration not exceeding 1% may be listed in clinical trial studies. Unfortunately, the cosmetics that any order after the listing of the ingredients present at our patients use in and around their eyes daily are not more than 1% in descending order of predominance.” required to meet such high standards. “The Federal Food, Drug and Cosmetics Act (FFDCA) The Breast Cancer Fund reported that the average includes 112 pages of standards for food and drugs, but woman in the United States uses 12 cosmetic products just a single page for cosmetics. The cosmetics title of the daily, and the average man uses six.1 More than 10,000 chemicals are used to create these products, and less than 20% of these ingredients have been proven to be safe. These chemicals, many of them synthetic and industrial chemicals, when absorbed into the body, can act as car- cinogens, endocrine disruptors, neurotoxins, and reproductive toxins. The FDA regulates makeup, products such as lipstick, blush, foundation, eyeliner, eye shadow, and mascara, as cosmetics under the Federal Food, Drug, and Cosmetic Act. In 1938, this statute was enacted after 100 patients died from using a sulfanilamide medication. In the manu- facture of this medication, diethylene glycol, a cousin of poisonous antifreeze, had been used to dissolve it into liquid form.2 The FDA defines cosmetics by their intended use: that is, “articles intended to be rubbed, poured, sprin- Figure 1. Diagram adapted from the TFOS Dry Eye kled, or sprayed on, introduced into, or otherwise applied WorkShop 2007 report illustrates the problem of cosmetics to the human body ... for cleansing, beautifying, promot- ingredients and detergent loads for the DED patient. The ing attractiveness, or altering the appearance.”3 stars have been added to highlight the multiple mechanisms Cosmetics labeling laws available on the FDA’s website by which cosmetics and detergents have the potential to note that “ingredients must be declared in descend- contribute to the mechanisms of DED. ing order of predominance” and “ingredients present

42 ADVANCED OCULAR CARE | JULY/AUGUST 2016 COVER FOCUS

Figure 2. Online survey results: Most respondents are not aware Figure 3. Online survey results: About a third of respondents of the potential effects of retinols on the eyes. said they buy products because they are labeled hypoallergenic.

FFDCA ... provides virtually no power to perform even the sodium laureth sulfates that over-strip the delicate oils of most rudimentary functions to ensure the safety of an the eyelids, contributing to the evaporative burden of the estimated $71 billion cosmetic industry.” This according ocular surface. Mouse models of desiccating stress showed to the Campaign for Safe Cosmetics, a Project of Breast that the protein-to-lipid ratio of mature meibum suffered Cancer Fund. In 2015, Senators Dianne Feinstein (D-CA) under the increased demands of desiccating stress in a and Susan Collins (R-ME) introduced legislation to update controlled adverse environment.5 Imagine the desiccating the regulations covering cosmetics and personal care stress of iatrogenically stripping your oil reservoir every day, products for the first time in 75 years. sometimes twice a day, with facial cleansers. The synthetic In the United States, 11 chemicals are banned from use skin conditioners of most facial cleansers make the skin feel in cosmetics (see Chemicals Banned from Use in Cosmetics moisturized, but the oils that nature intended are stripped in the United States). This is a remarkably low number in away. Makeup removers fall into this category of concern comparison with the situations in the European Union for our patients as well. With so many available, it is impor- (EU), Canada, and Japan. The EU Cosmetic Directive, tant to ask patients, especially DED patients, what they use enacted in 2003 and updated in 2013, bans 1,328 chemi- around their eyes. cals from cosmetics due to risks of cancer, genetic muta- tion, reproductive harm, or birth defects. The EU also Preservatives requires premarket safety assessment and mandatory Preservatives are important to prevent bacterial and registration of cosmetics, neither of which are required in fungal contamination in cosmetics and hygiene products. the United States. However, they also are problematic for the delicate ocular Figure 1 illustrates the problem of cosmetics ingredients surface. Common preservatives used in cosmetics include and detergent loads for the DED patient. formaldehyde-donating preservatives such as parabens and phenoxyethanol (more later). HIDING IN PLAIN SIGHT Remember when you started reading food labels? Formalin Your eyes were opened to all of the additives present in Formalin, a cousin of formaldehyde, is particularly toxic processed foods. Similarly, reading cosmetics labels can in cell culture.6 Formaldehyde is released from formalde- be overwhelming at first. Once you learn the chemical hyde-donating preservatives and is a well-known allergen.7 vocabulary, however, you begin to understand the scope However, you will not see formaldehyde listed in cosmetics. and extent of the problem. Formaldehyde-donating preservatives in cosmetics hide in plain sight under the cloak of organic-chemistry-nightmare Sodium Laureth Sulfates names such as DMDM-hydantoin, quaternium-15, imid- A top selling, “dermatologist recommended” facial wash azolidinyl urea, diazolidinyl urea, and 2-bromo-2-nitropro- may not be ideal for use around the delicate and specialized pane-1,3-diol. skin of eyelids. Many facial washes and cleansers contain Formaldehyde is a known ocular irritant at levels of

JULY/AUGUST 2016 | ADVANCED OCULAR CARE 43 0.05 ppm and 0.5 ppm, producing a sensation of irritation in the eyes with burning, itching, redness, and tearing. An CHEMICALS BANNED FROM USE IN increased rate of blinking and eye closure generally protects the eye from damage at low levels.8 These protective COSMETICS IN THE UNITED STATES mechanisms may be insufficient for the DED patient with • Bithionol compromised aqueous production and/or evaporative • Chlorofluorocarbon propellants protection, allowing formaldehyde to contribute to ocular • Chloroform surface damage. • Halogenated salicylanilides • Hexachlorophene Parabens • Mercury compounds The detrimental effects of estrogen and progester- • Methylene chloride one hormones on the meibomian glands have been well • Prohibited cattle materials

COVER FOCUS COVER 9 described. Parabens have a weak estrogenic effect and have • Sunscreens in cosmetics the potential to inhibit the function of human meibomian • Vinyl chloride gland cells. Methylparaben demonstrates significant toxicity • Zirconium-containing complexes similar to that of benzalkonium chloride (BAK) in human conjunctival and corneal cell cultures.10 Other Potential Tear Film-Disrupting Ingredients Phenoxyethanol Alcohols speed the drying times of cosmetics, but they What smells like a rose, in this case, is not a rose, it is also dry out the native oils and moisture of the lids and phenoxyethanol. Phenoxyethanol is an alternative non– ocular surface. Waxes and pine tar derivatives in eyelin- formaldehyde-donating preservative. With it, the amount of ers have the potential to physically obstruct the meibo- parabens needed in a product for adequate contamination mian gland terminal orifices, thereby limiting meibum control is reduced. The phrase “paraben-free” is used as a delivery to the lid margin lipid reservoirs and subsequent marketing tag, and phenoxyethanol is one of the main ways delivery onto the tear film. This effect can increase the cosmetics companies get around using parabens to cater to inflammation-inducing evaporative load of patients with the “natural” and “vegan” markets. A strong rose or perfume- ocular surface disease (OSD), particularly when eyeliners like smell is prevalent among mascaras at the drug store, the are used along the eyelid margin covering the meibo- department store, and the natural foods store. Although a mian gland orifices in a practice known as “tight-lining” seemingly rose-scented, non–formaldehyde-donating preser- or “waterlining.” Although this should not be confused vative may sound like a good idea, watch out for the thorns. with waterboarding, we suspect this so-called beauty According to Japan’s Standards for Cosmetics, phenoxyetha- practice is torture to the meibomian glands and an unre- nol is restricted to a level of 1% in cosmetics.11 alized hazard among many of our OSD patients. We see

Figure 4. Significant buildup on the lash margin indicates Figure 5. LipiView II images show meibomian gland truncation makeup residue despite makeup removal with a commonly in both eyes of a 20-year-old-patient. used makeup remover.

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Figure 6. The patient reported using a waterproof eyeliner and Figure 7. Online survey results: Almost 90% of respondents are mascara daily and applying her eyeliner to the “waterline.” not talking to their eye care providers about their cosmetic use. cosmetics-associated iatrogenic meibomian gland block- patients to avoid products that claim antiaging effects, as age in our OSD patients routinely, as outlined in the case the antiaging ingredient is likely to be one of these sub- reports below. stances toxic to the meibomian glands. The best antiaging Teaching patients to care for their eyelids like their product is a paraben-free sunscreen. grandmother’s best cast iron frying pan helps drive the point home. Eyelids are delicate, and they need gentle Botox and “Botox in a Jar” care. Tell patients to lightly soak (with warm compresses), The neuromuscular blocking agent onabotulinum- gently scrub, avoid soaps and detergents, and gently con- toxinA (Botox; Allergan), injected into the crow’s feet area, dition (eg, with hyaluronic acid–containing moisturizers). has a wrinkle-relaxing effect. However, it is also known to Hyaluronic acid moisturizers are excellent humectants correlate with DED.13 for the skin and lashes, but watch out for detrimental Acetyl-hexapeptide 3, a peptide that is a fragment of co-ingredients such as parabens (weakly estrogenic) and SNAP-25, a substrate of botulinum toxin, is a common retinols (toxic to the meibocytes), particularly in so-called antiaging additive to luxury products that is often enthu- antiaging formulations. When lid hygiene and over- siastically promoted at the cosmetics counter as “Botox the-counter product details are optimized for the OSD in a Jar.” The problem is that this neurotoxic chemical patient, whether a woman or a man, the patient’s daily may weaken the orbicularis muscle, creating the prom- desiccating stress load is reduced. ised wrinkle-smoothing effect but also thereby potentially working counter to our blink exercise counseling efforts. ANTIAGING PRODUCTS AND OSD These exercises are important to promote tear wetting Tretinoin (also known as Retin A; available from mul- and spreading, lid-to-lid contact, and mechanical expres- tiple manufacturers) and its retinoic, retinol, and retinyl sion of meibum into the lipid reservoir and precorneal cousins are wonderful antiaging products for the face, but tear film. their application anywhere near the eyes should be avoid- ed. Skin products are thought to migrate up to 1 cm, so Hypoallergenic: Just a Buzzword when tretinoin-like products are applied at bedtime to As noted previously, the FDA does not require all the face they become potential nightly offenders to the ingredients to be listed on a product if they are present health of the meibomian glands. at a level of 1% or less. This is of particular relevance for The keratinizing, apoptotic, interleukin 1 beta–, and patients allergic to certain ingredients in cosmetics, as a matrix metalloproteinase–inducing effects of retinoic potential allergen may not be listed. acid have been described in human meibomian gland We conducted a recent online survey of 169 cosmetic cell culture.12 This potential for harm to the meibomian users that uncovered some interesting trends. When glands is a public health issue that eye care providers looking to purchase cosmetics, about one in three survey must address, as, according to an online survey we con- respondents said they buy products because they are ducted, most consumers do not understand the potential labeled hypoallergenic (Figure 3). The designation hypoal- of retinols to harm the eyes (Figure 2). We must educate lergenic is not determined by any federal standards or

JULY/AUGUST 2016 | ADVANCED OCULAR CARE 45 definitions; it is simply a term companies use to make their products more appealing to these sensitive consumers. Dermatologists agree that the label hypoallergenic has HELPFUL WEBSITES very little value. • Think Dirty Other words used to attract sensitive consumers include www.thinkdirtyapp.com herbal, natural, vegan, and organic. These terms have no FDA backing and are simply used as marketing tactics to • EWG’s Skin Deep Cosmetics Database attract consumers. Consumers and the patients we serve www.ewg.org/skindeep need to understand that there is no guarantee that a cosmetic will not cause an allergic reaction. • GoodGuide www.goodguide.com REAL-WORLD SCENARIOS

COVER FOCUS COVER Patient No. 1. (Dr. Periman) • FDA MedWatch Online Voluntary Reporting Form I began to realize the scope of the cosmetics and OSD www.accessdata.fda.gov/scripts/medwatch/index. problem years ago while taking care of a delightful and cfm?action=reporting.home beautiful 73-year-old woman with severe DED and stage 3+ meibomian gland loss who was referred for severe DED nonresponsive to treatment. She had received last crow’s feet injection of neurotoxin. She was surprised appropriate therapies for years and was still miserable to realize this connection upon history questioning. from her DED. Her makeup was full and expertly done, Although correlations between DED and eyelid tattoos, and she even had waterproof eyeliner on the lid margins lid and facial cosmetic surgeries, and botulinum toxin are in addition to tattoo eyeliner under the lashes done years known,13 her disease was more severe than other patients before. I had seen with similar risk factors. Upon request, at At the slit lamp, she had significant debris in the tear follow-up she brought her full arsenal of beauty products. film that looked like eye shadow had dropped in. She had Particularly impressive was her luxury brand, expensive, pigmented micro-shards imbedded under her inferior department store eye makeup remover. This incredibly palpebral conjunctiva that also looked like eyeshadow effective eye makeup remover probably also removed pigments. Her history included cosmetic surgical proce- more than makeup. It also likely removed the healthy oils dures, 10-plus years of injectable neurotoxins (botulinum of the lipid reservoir, creating a nightly drying and strip- toxin) to the forehead and crow’s feet, as well as daily ping effect. application of full makeup (including applying eyeliner The actual percentage of BAK in the product was not to the eyelid margin) and nightly removal with makeup mentioned on the package or online, but BAK was listed removers. Notably, she reported that her DED flare-ups after benzyl alcohol (drying) and quaternium-15 (form- occurred 3 to 4 times a year, within 1 to 2 weeks after her adelhyde donor preservative), implying that its level was above 1%. This is significantly more BAK exposure than anyone in eye care would dream of prescribing for use around the eyes. BAK is known to damage goblet cells, thereby decreasing mucin production, compromising tear-film stability, and furthering desiccating stress—a core mechanism of DED as outlined in the 2007 report of the TFOS Dry Eye WorkShop.14 Her waterproof eyeliners had waxes, pine tar extracts, and alcohols that were likely contributing to terminal ductule obstruction and irritation of the already severely diseased meibomian glands.

Patient No. 2. (Dr. O’Dell) I transilluminate every patient at the slit lamp, and, when it is indicated, I use LipiView II (TearScience) to produce meibography images. Based on my observation, Figure 8. Online survey results: About 70% of respondents there are a surprising number of patients with meibomian said they do not look at ingredients when deciding what gland truncation, atrophy, and tortuosity. One patient cosmetics products to purchase. stands out, a 20-year-old white woman, an emmetrope, who came to our office complaining of fluctuating vision.

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the Tear Film & Ocular Surface Society (www.tearfilm. org). A patient version, to be available in multiple lan- Our online survey showed that guages, will also be published. 89% (150/169) of respondents If a patient has adverse reaction to eye cosmetics, the “ FDA encourages us to report it much like we would are not talking to their eye care report adverse events to medications we prescribe. A link providers about their cosmetic use. to the MedWatch Online Voluntary Reporting Form is shown in an accompanying box. Beauty does not have to hurt. The more we understand the dangers lurking in plain sight, and the more we can guide our deserving patients in their daily use of prod- Significant findings during examination included make- ucts, the more effective our OSD-fighting strategies and up residue on the lashes, although, when questioned, she therapeutics will become. n said she did not apply fresh makeup on the day of her 1. The Campaign for Safe Cosmetics. Breast Cancer Fund. http://www.breastcancerfund.org/big-picture-solutions/ exam and had removed it the night before (Figure 4). She campaign-for-safe-cosmetics.html. Accessed June 29, 2016. also had significant meibomian gland changes (Figure 5), 2. Federal Food, Drug, and Cosmetic Act (FD&C Act. http://www.fda.gov/RegulatoryInformation/Legislation/Federal- FoodDrugandCosmeticActFDCAct/default.htm. Accessed June 29,2016. with almost 50% truncation of the glands in both eyes. 3. FDA Authority Over Cosmetics: How Cosmetics Are Not FDA-Approved, but Are FDA-Regulated. US Food and Drug Regarding her daily cosmetic use, the patient reported Administration website. August 3, 2013. http://www.fda.gov/Cosmetics/GuidanceRegulation/LawsRegulations/ ucm074162.htm#What_kinds. Accessed June 29, 2016. using a waterproof eyeliner and mascara daily and apply- 4. Cosmetic Labeling Guide. US Food and Drug Administration website. January 2, 2015. http://www.fda.gov/ ing her eyeliner to the “waterline” (Figure 6), thereby cov- Cosmetics/Labeling/Regulations/ucm126444.htm#clga. Accessed June 29, 2016. 5. Suhalim JL, Parfitt GJ, Xie Y, et al. Effect of desiccating stress on mouse meibomain gland function. Ocul Surf. ering the meibomian gland orifices with waxes and other 2014;12(1):59-68. offending chemicals. Her removal habits were equally 6. Songur A1, Ozen OA, Sarsilmaz M. The toxic effects of formaldehyde on the nervous system. Rev Environ Contam Toxicol. 2010;203:105-118. concerning, as her makeup remover contained chemi- 7. de Groot, AC, Flyvholm, MA, Lensen, G, et al. Formaldehyde-releasers: relationship to formaldehyde contact allergy. cals found in paint, acetone derivatives, and alcohol, all Contact allergy to formaldehyde and inventory of formaldehyde-releasers. Contact Dermatitis. 2009;61(2): 63-85. 8. US Department of Labor. Occupational Safety and Health Standards. https://www.osha.gov/pls/oshaweb/owadisp. of which had the potential to strip her oil reservoir and show_document?p_table=STANDARDS&p_id=10078. Accessed June 29, 2016. potentially harm her meibomian glands. 9. Knop E, Knop N, Millar T, et al. The International Workshop on Meibomian Gland Dysfunction: Report of the subcommittee on anatomy, physiology and pathophysiology of the meibomian gland. Invest Ophthalmol Vis Sci. The patient’s comfort improved significantly after she 2011;52(4):1938-1978. was educated as to the ingredients to avoid in her cosmet- 10. Epstein SP, Ahdoot M, Marcus E, Asbell PA. Comparative toxicity of preservatives on immortalized corneal and conjunctival epithelial cells. J Ocul Pharmacol Ther. 2009;25(2):113-119. ics, the proper placement of her cosmetics to avoid the 11. Japan Ministry of Health, Labour and Welfare. 2006. Standards for Cosmetics. Evaluation and Licensing Division. waterline, and recommendations for less OSD-offending Pharmaceutical and Food Safety Bureau. 12. Ding J, Kam WR, Dieckow J, Sullivan DA. The influence of 13-cis retinoic acid on human meibomian gland makeup removers. epithelial cells. Invest Ophthalmol Vis Sci. 2013;54:4341-4350 13. Ozgur O, Murariu D, Parsa AA, Parsa FD. Dry eye syndrome due to botulinum toxin type-A injection: guideline for prevention. Hawaii J Med Pub Health. 2012;71(5):120-1237 CONCLUSIONS 14. Tear Film and Ocular Surface Society. 2007 Report of the Dry Eye WorkShop (DEWS). http://www.tearfilm.org/ Our online survey showed that 89% (150/169) of dewsreport/index.html. Accessed June 30, 2016. respondents are not talking to their eye care providers about their cosmetic use (Figure 7). In addition 70% Leslie E. O’Dell, OD (119/169) said they do not look at ingredients when n Director of Dry Eye Center of PA, Wheatlyn Eye Care, deciding what products to purchase (Figure 8). With so Manchester, Pennsylvania many chemicals with the potential to harm the ocular n (717) 266-5661; (717) 521-7161;[email protected] surface hiding in the cosmetics our patients are using n [email protected]; Twitter @helpmydryeyes daily, we need to start a conversation with our patients. n Financial disclosure: speaker for Allergan and RPS; consultant to We must educate patients that the delicate eyelids and Bruder and Paragon BioTeck ocular surface need thoughtful and special care. What is Laura M. Periman, MD good for the face and skin may be detrimental to the lac- n Specialist in cornea and external disease, Seattle rimal functional unit. n [email protected]; (206) 234 9846 The conversation with patients should include informa- n Financial disclosure: speaker for Allergan, BioTissue, and tion about dry eye and how the cosmetics, soaps, facial TearScience; consultant to Allergan cleansers, and make-up removers they use daily can affect their eye health. A few websites that can help are listed in Amy Gallant Sullivan the sidebar, Helpful Websites. Another resource that will n Executive director and board member, Tear Film & Ocular be available in 2017, is a report from the TFOS Dry Eye Surface Society (TFOS), Boston n [email protected]; Twitter @Eyeppl @DryEyeMakeup WorkShop II, which will update the seminal report from the first TFOS Dry Eye WorkShop in 2007, sponsored by

JULY/AUGUST 2016 | ADVANCED OCULAR CARE 47 CORNEA/EXTERNAL DISEASE “IF I COULD TURN BACK TIME…” Beauty practices that wreak havoc on the ocular surface: part three of a four-part series.

BY LESLIE E. O’DELL, OD; AMY GALLANT SULLIVAN, BS; AND LAURA M. PERIMAN, MD

Over the centuries, body.3 Evaluation of and care for the eyelids are very important many have misquoted functions of eye care providers. The eyelid protects the ocu- Shakespeare thus: lar surface, which would otherwise be vulnerable as the only “Vanity, thy name is mucous membrane exposed during all waking hours to the woman.” Shakespeare’s environment.4 Hamlet actually said, “Frailty, thy name is THE TERRIFYING TEENS woman.” The only During the acne-prone teenage years, oil-gland targeting weak female aspect is the ocular surface when it is aggressed therapies are often used for acne control. These have a negative with makeup, serums, and cosmetic enhancements. The impact on the crucial, specialized meibomian oil glands of the misquoted vanity image, however, may be quite applicable eyelids. Ingredients causing ocular surface disease (OSD) include in this day and age, when aesthetics is a growing industry for salicylic acid, benzoyl peroxide, tretinoin, acne face washes, both women and men.1 and oral medications such as spironolactone and isotretinoin.5 Aging comes in two varieties: intrinsic aging, controlled by Note that the branded version of isotretinoin, Accutane, was our genes, and extrinsic aging, influenced by our environment withdrawn from the market in 2009 by its manufacturer, Roche and lifestyle. The antiaging and facial rejuvenation sectors of der- Pharmaceuticals, after reports of side effects. However, generic matology and eye care are growing rapidly. According to statis- versions remain available. tics on plastic surgery procedures from the American Society of As seen with retinoic acid, what is good for the skin may not Plastic Surgeons, there were 15.9 million surgical and minimally always be good for the eyes.6 When considering more aggres- invasive cosmetic procedures performed in the United States in 2015, a 2% increase over 2014.2 The same report2 listed these procedure numbers for 2015 and percent changes from previous years: • Botox (onabotulinumtoxinA; Allergan) injections: 6.7 million procedures, up 1% percent from 2014 and 759% since 2000; • soft tissue fillers: 2.4 million procedures, up 6% from 2014; • chemical peels: 1.3 million procedures, up 5 % from 2014; • eyelid surgery: 204,000, down 38% since 2000; • microdermabrasion: 800,000 procedures, down 9%. Extrinsic aging factors, including decades of sun exposure damage, poor nutrition, and lack of healthy activities, accelerate one’s intrinsic aging processes. Because of their youthful reserves, young people do not immediately see the impacts from tanning, junk food, poor sleep and hygiene: The consequences come later. The people now entering this consequence phase are helping to drive the increasing popularity and acceptance of Be skeptical of before and after pictures. Lighting changes antiaging cosmetic products and procedures. give the appearance of improved skin tone and fewer under- As aesthetic procedures have gained popularity over the eye wrinkles in the bottom photo. One easy way to compare recent decades, we have learned that what is good for the skin, enhancements with lighting is noting the pupil reflex, if a flash our largest organ, is not always friendly to the eyelid. The eye- is used there will be a pinpoint of light centrally in the pupil. lid is a specialized structure, and also the thinnest skin on the

NOVEMBER/DECEMBER 2016 | ADVANCED OCULAR CARE 25 THE PROBLEM WITH PIXELS AND PROOF A picture may be worth a thousand words, but what is that picture actually saying? In the world of cosmetic marketing and advertising, “before” and “after” photos are commonly used to show the benefits of a product. However, the US Food and Drug Administration does not require clinical proof of over-the-counter cosmetics claims. That before-after photo comparison that impresses your patients at the cosmetics counter or online may simply be clever leveraging of photographic tricks that create or enhance the illusion of a product’s effect. Asa Mathat (asamathat.com), a world-renowned portrait photographer who has captured the essences of world lumi-

CORNEA/EXTERNAL DISEASE naries such as the Dalai Lama, shared some insights into creating the best image possible (Figure).

1 POSTPRODUCTION WORK A cosmetics company wants to promote the best possible effects, so postphotographic alterations with common programs such as PhotoShop are likely present in nearly every “after” photo. Pixel adjustments of the “before” photo could also be used to make the original look worse, thereby enhancing the delta between the before and after images.

2 REDUCED AND RELOCATED LIGHTING Single-source overhead lighting highlights shadows and contours. This would accentuate the appearance of undereye bags. If the “after” image has diffuse, multiple light sources, the shadows are filled in, creating the illusion of greater effect.

3 OBSERVATION ANGLE Look carefully at the position of the head and chin tilt. This trick can improve the appearance of nuchal skin laxity, an effect that some firming creams may claim.

4 OPTICS A photographer may use a high millimeter lens in the “before” photo to magnify the subject’s supposed defects. The “after” photo may then be taken with a lower millimeter lens for a wider field of view along with less detail, creating the illusion of improvement.

5 FOCUS AND FILTERS Defocus and diffractive filters can fill in fine lines and create the illusion of softer skin with fewer wrinkles. Combined with diffuse lighting tricks before and after, the effects of a skin care product can be significantly enhanced. Subtle photography color gels can filter certain wavelengths and add to a glowing appearance. Pay close attention to the overall color, looking for cool or warm overtones that may have been leveraged to enhance the illusion of effect.

sive oral retinoic acid treatments, such as isotretinoin, there are ucts only to the acne-affected areas of the face and not within many variables to weigh beyond its acne-treating effects. With the orbital rim.9 This rapid and significant negative impact on use of isotretinoin comes many risks including cataracts,6 mei- the ocular surface despite a lack of direct contact with the bomian gland atrophy and dysfunction,7 increased osmolarity,8 treatment is of concern. We must start incorporating patients’ and symptoms of dry eye disease (DED). complete facial care routine and product use into our care for Topical acne treatments may also be OSD-exacerbating OSD patients. agents, a consequence underappreciated and unknown by Use of botulinum toxin by teenagers, or “teen toxing,” is patients and eye care providers alike. In a recent study by increasing around the globe. According to the American Bayhan et al, after just 1 month of use, topical isotretinoin Society for Aesthetic Plastic Surgery, in 2009 botulinum toxin plus erythromycin was associated with a highly statistically injections were the fifth most often performed cosmetic pro- significant increase in osmolarity and DED symptoms based on cedure for patients 18 years and younger. This raises several Ocular Surface Disease Index or OSDI scores.9 More than half of questions: Is this young generation of botulinum toxin users patients using the compound were found to have punctate epi- more appearance-conscious due to the rise of social media, or theliopathy, even though they were presumably applying prod- are they more prevention-aware and antiaging savvy? Do they

26 ADVANCED OCULAR CARE | NOVEMBER/DECEMBER 2016 CORNEA/EXTERNAL DISEASE

know that, when neurotoxins are injected to the crow’s feet medicine and lifestyle coaching with discussion about cosmetic area, a DED-associated insult occurs?10 Moreover, what are the use, application, and removal, as well as clinical evaluation of potential impacts of additional OSD risk factors such as acne the ocular surface, lid margins, meibomian gland health, and therapies and teen toxing for this generation of heavy users of tear film. Consider adding allergy testing to your clinic services smartphones and computers? (Doctors Allergy Formula; Bausch + Lomb) or reaching out to local dermatologists to collaboratively care for patients, as these THE 20s: MILLENNIALS specialists often have access to specialized allergy testing such as As patients mature into their 20s, extrinsic aging factors are a cosmetic panel to help identify irritants for patients experienc- at the forefront, and lifestyle risks threaten the skin’s youthful ing atopic dermatitis of the eyelids.15 appearance. First jobs enable more buying power and routine aesthetic enhancements, while media and marketing campaigns THE 30s: THIRTY AND FLIRTY further lure these youths into believing that aging prevention is Antiaging efforts require a definite routine. For patients in key. their 30s, higher salaries now permit them to visit the derma- Establishing good habits during these years can improve the tologist regularly for assorted treatments including botulinum appearance of the skin for years to come. We should encourage toxin injections, peels, and microdermabrasion. Their medicine our patients to think of their 20s as ‘facial’ boot camp. cabinets are also becoming packed full with a collection of A lifetime of decreased squinting from sun glare can be high-end serums, creams, and cosmetics to smooth the texture achieved through establishing the habit of regular sunglasses of skin and lighten dark spots caused by melasma and exac- use. This decreases the repetitive squinting facial expression that erbated by regular birth control pill consumption or years of can lead to unwelcome dynamic lines, especially to the skin neglecting sunscreen application.16 overlying the orbicularis muscles (crow’s feet) corrugator (frown For women, altered hormone levels can start to cause a lines) and glabellar (“eleven” lines between the brows) muscles. decrease in the water-storing properties of the epidermis. During the 20s, we should encourage patients to eliminate These skin changes are often seen first in the thin eyelids. There bad habits such as tanning, smoking, excessive alcohol con- is a decline in cell turnover and collagen production during sumption, and ubiquitous all-nighters. Moreover, just as ciga- this decade, causing many to focus on techniques to hide the rette smoking has long been known to accelerate aging,11 recent emerging dark circles and fine lines under their eyes. For others, research also shows its negative impact on the ocular surface, fluctuating hormones combined with elevated stress levels can with decreased Schirmer test scores and goblet cell density in create the environment for adult-onset acne. smokers compared with nonsmoking control subjects.12 For many, the solution for dark circles is the use of a multi- For many, daily cleansing routines are focused on twice-daily tude of under-eye creams that promise a more youthful coun- facial washes. Many of the available facial cleansers have harm- tenance. Some turn to minimally invasive procedures with soft- ful chemicals that can strip the natural oils from the face and tissue fillers. These fillers vary in their type of material, duration around the eyelids.13 It is important for patients to avoid ingre- of effect, and placement of injection (Table). dients such as drying alcohols and aggressive detergents and Juvéderm injectable gels (Allergan), a popular suite of facial surfactants such as sodium lauryl sulfate in order to retain the fillers, are not ideal for use around the ocular adnexa due skin’s natural oils. Over time, simply applying and removing the to their hydrophilic properties, which attract fluids and cre- facial cleanser gently and precisely, avoiding the delicate area ate more puffiness under the eye17 as well as a discoloration inside the orbital rim, can help prevent overstripping. Clinically, termed the Tyndall effect. Other complications with fillers can a patient with significant meibomian gland dysfunction who is include nodules and bruising or swelling of the injection site struggling with excess evaporative stresses (insufficient or poor and eyelid. quality meibum) may benefit from daily cleansing strategies that Puffiness is another concern, often caused by dehydration, do not strip the oils that the overworked meibomian glands bloating, allergy, fatigue, genetics, or hormones. To shrink labor to create. A landmark paper demonstrated the meibo- tissue, some turn to over-the-counter products such as mian gland upregulating effects of desiccating stress in a mouse Preparation H (Pfizer Consumer Healthcare), containing active model.14 The meibocytes upregulated activity in response to ingredients such as phenylephrine, shark liver oil, and hydro- the desiccating stress, however, the protein/lipid ratios suffered cortisone. Using Preparation H under the eyes will reduce the negatively suggesting altered meibocyte differentiation and size of veins and constrict blood flow to shrink swollen veins meibum biosynethesis. and quickly diminish puffiness, due to the effects of phenyl- Our dermatology colleagues recommend annual exams for ephrine.18 It is not ophthalmologically formulated. Additional those over 25 years to assist in their fight against aging. How concerns arise from chronic use of hydrocortisone, as it further does this translate to eye care? Recommending annual ocular thins the skin and causes redness and breaks in the capillaries.19 wellness exams is a great opportunity to grow your practice and Solutions for fine lines can include retinols, hyaluronic acid, your subspecialty in DED. These visits should include preventive vitamin C, and microdermabrasion. Of particular concern is

NOVEMBER/DECEMBER 2016 | ADVANCED OCULAR CARE 27 TABLE. SOFT TISSUE FILLERS Soft tissue fillers are often used for facial and orbital cosmetic procedures. Most of these fillers are absorbed by the body over time. Some of the injectables also contain lidocaine to lessen the injection pain and discomfort. This table outlines the materials used for dermal fillers as well as the duration of the filler in the tissue.

Absorbable Materials Description of Filler Duration Collagen A type of protien, typically for bovine or 3-4 months human cells Hyaluronic Acid A type of sugar (polysaccharide) often from 6-12 months rooster combs CORNEA/EXTERNAL DISEASE Calcium hydroxylapatite A type of mineral commonly found in teeh 18 months and bones. Poly-L-lactic acid (PLLA) A material found also in absorbable stitches. Up to 2 years Nonabsorbable Materials Description of filler Duration Polymethylmethacrylate beads (PMMA A nonbiodegradable manmade polymer Permanent microspheres)

the use of retinols around the eye area given the hyperkeratotic otulinumtoxinA; Ipsen Biopharmaceuticals and Galderma effects and demonstrated meibomian gland cell culture toxic- Laboratories) for decreasing dynamic aging lines. Our OSD ity.7 Microdermabrasion makes one blink, as it uses a spray of patients who cease using these products in the crow’s feet aluminum oxide, magnesium oxide, sodium chloride or sodium area report improved OSD symptoms. bicarbonate crystals under pressure and vacuum, adjusted Weakly neurotoxic topicals such as Argireline solution (ace- according to the patient’s condition. tyl hexapeptide-8; Lipotec) are touted as “Botox in a bottle” and marketed as “antiaging peptides.” The wrinkle-reducing THE 40s: FORTY AND FABULOUS effects of these products may be detrimental to the orbicularis Patients in their 40s are a dream demographic for cosmetic muscle and the blink forces necessary for a healthy ocular companies and dermatologists—not to mention eye care surface. providers, who will see more of their 40-something patients due to Mother Nature’s new vision tricks, such as the onset of THE 50s: OVER THE HILL? presbyopia and the likelihood of newly developed symptoms Individuals in their 50s are in the prime demographic for the of DED. onset of DED.20 This is often the decade when patients try to The focus of antiaging efforts remains on the continued reverse years of extrinsic aging with procedures such as intense thinning of the skin and eyelids, with increases in facial and pulsed light (IPL) therapy, radiofrequency skin tightening, and

eyelid margin redness, breaking of capillaries, and worsening CO2 laser skin resurfacing. of under-eye darkness. Several antiaging products and ingredi- Some researchers have noted the improvement of rosacea- ents can have unwanted effects at this stage of life. related OSD signs and symptoms with IPL therapy21 and as an Among chemicals added to age-defying cosmetics, the reti- effective procedural treatment in MGD associated DED.22 In noid family is particularly compromising to the ocular surface. addition to its well-known clinical effect of restoring a more When we review the products our patients with OSD are youthful evenness to the skin tone, IPL has been found to have using around their eyes, we search carefully for retinoic acid collagen- and hyaluronic acid–stimulating properties in human and its cousins. Retinoic acid, in particular, damages meibo- fibroblast culture.22 IPL also coagulates Demodex mites,23 which cytes in cell culture7 and theoretically contributes to MGD. may contribute to its benefit for patients with facial or ocular Clinically, we observe that cessation of retinoid use around the rosacea. eyes helps our MGD patients. Radiofrequency devices are nonablative and have rejuvenat- Neurotoxin injections are also associated with DED.10 The ing biostimulatory effects. Even when performed at low energy most familiar of these are neuromuscular junction–block- and frequency levels, radiofrequency treatment is associated ing injectables such as Botox Cosmetic and Dysport (abob- with increases in dermal-firming hyaluronic acid, tissue-remod-

28 ADVANCED OCULAR CARE | NOVEMBER/DECEMBER 2016 CORNEA/EXTERNAL DISEASE

eling matrix metalloproteinase 9, and rejuvenating collagen,24 expertise about beauty practices and aesthetic procedures and a positive effect on OSD signs and symptoms.25 and the impact they have on your patients. Educating yourself n Fractional CO2 laser resurfacing is more invasive and associ- about antiaging trends and products never looked so good. ated with longer recovery time, but it is an effective treatment 1. Furnham A, Levitas J. Factors that motivate people to undergo cosmetic surgery. Can J Plast Surg. 2012;20(4):e47-e50. for skin aging. These aesthetic laser modalities may be more 2. New statistics reflect the changing face of plastic surgery [press release]. American Society of Plastic Surgeons. https://www. expensive than other options, but they also seem to be less plasticsurgery.org/news/press-releases/new-statistics-reflect-the-changing-face-of-plastic-surgery. Accessed October 19, 2016. 26 3. Kersten RC. Orbit, Eyelids and Lacrimal System. Basic and Clinical Science Course Section 7. San Francisco; Foundation of the DED exacerbating than some topical antiaging products. American Academy of Ophthalmology; 2008. 4. Benitez-del-Castillo JM. How to promote and preserve eyelid health. Clin Ophthalmol. 2012; 6:1689-1698. s 5. Fraunfelder FT, Fraunfelder FW, Edwards R. Ocular side effects possibly associated with isotretinoin usage. Am J Ophthalmol. THE 60 : DON’T GIVE UP THE FIGHT 2001;132(3):299-305. After the turn of the half-century mark, patients may turn to 6. Lerman S. Ocular side effects of accutane therapy. Lens Eye Toxic Res. 1992;9(3-4):429-438. 7. Ding J, Kam WR, Dieckow J, Sullivan DA. The influence of 13-cis retinoic acid on human meibomian gland epithelial cells. Invest blepharoplasty to recontour the eyelids, in order to eliminate Ophthalmol Vis Sci. 2013;54:4341-4350. excess skin and anteriorly displaced orbital fat. This is a tradi- 8. Mathers WD, Shields WJ, Sachdev MS, et al. Meibomian gland morphology and tear osmolarity: changes with Accutane therapy. Cornea. 1991;10(4):286-290. tional way to eliminate the puffy, tired, baggy look around the 9. Aslan Bayhan S, Bayhan HA, Çölgeçen E, Gürdal C. Effects of topical acne treatment on the ocular surface in patients with acne eyes. Upper blepharoplasty is performed through an incision vulgaris [published online ahead of print July 12, 2016]. Cont Lens Anterior Eye. doi: 10.1016/j.clae.2016.06.009. 10. Ozgur O, Murariu D, Parsa AA, Parsa FD. Dry eye syndrome due to botulinum toxin type-A injection: guideline for prevention. in the crease of the upper eyelid. In lower blepharoplasty, the Hawaii J Med Pub Health. 2012;71(5):120-123. lower eyelid can be approached from an infra tarsal conjunc- 11. Jacobs LC, Liu F, Bleyen I, et al. Intrinsic and extrinsic risk factors for sagging eyelids. JAMA Dermatol. 2014;150(8):836-843. 12. Uchino Y, Uchino M, Yokoi N, et al. Impact of cigarette smoking on tear function and correlation between conjunctival goblet tival incision. Often an incision is made in the orbital septum cells and tear MUC5AC concentration in office workers. Sci Rep. 2016;6:27699. to allow the surgeon to remove excess orbital fat. Selective 13. O’Dell LE, Sullivan AG, Periman LM. Beauty does not have to hurt. Advanced Ocular Care. July/August 2016. 14. Suhalim JL, Parfitt GJ, Xie Y, DePaiva CS, Pflugfelder SC, Shah TN, Potma EO, Brown DJ, Jester JV. Effect of desiccating stress on reductions are performed to recontour the eyelid. Clinically, we mouse meibomian gland function. Oc Surf. 2014 12(1): 59-68 have seen overcorrections after blepharoplasty that leave an 15. Schalock PC, Dunnick CA, Nedorost S, et al. American contact dermatitis society core allergen series. Dermatitis. 2013;24(1):7-9. 16. Pietrzak B, Wlazlak E, Zwierzynska E. Long-term use of estrogens: benefit or risk. [Article in Polish]. Postepy Hig Med Dosw incomplete blink or eyelid seal, either of which can significantly (online). 2015;69:285-293. exacerbate OSD. Other eyelid surgeries and their OSD compli- 17. Christensen L. Normal and pathologic tissue reactions to soft tissue gel fillers. Dermatol Surg. 2007;33 Suppl 2:S168-175. 18. Desjardins PJ, Berlin RG. Efficacy of phenylephrine. Br J Clin Pharmacol. 2007;64(4):555-556; author reply 557. cations are beyond the scope of this antiaging and OSD report. 19. Kolbe L, Kligman AM, Schreiner V, Stoudemayer T. Corticosteroid-induced atrophy and barrier impairment measured by non- Blepharoplasty is performed for both cosmetic and func- invasive methods in human skin. Skin Res Technol. 2001;7(2):73-77. 20. Schaumberg DA, Sullivan DA, Buring JE, Dana MR. Prevalence of dry eye syndrome among US women. Am J Ophthalmol. tional reasons. When eyelid dermatochalasis, blepharoptosis, or 2003;136(2):318-326. brow ptosis is clinically significant, loss of superior field of vision 21. Vora GK, Gupta PK. Intense pulsed light therapy for the treatment of evaporative dry eye disease. Curr Opin Ophthalmol. 2015; 26(4):314-318. occurs. When this has progressed to a point at which func- 22. Toyos R, McGill W, Briscoe D. Intense pulsed light therapy for dry eye disease due to meibomian gland dysfunction: a 3-year tional visual field loss has occurred, often third-party insurance retrospective study. Photomed Laser Surg 2015 33(1): 41-46. 23. Cuerda-Galindo E, Díaz-Gil G, Palomar-Gallego MA, Linares-GarcíaValdecasas R. Intense pulsed light induces synthesis of dermal will cover the procedure. By contrast, cosmetic eyelid surgery, extracellular proteins in vitro. Lasers Med Sci. 2015;30(7):1931-1939. primarily intended to improve aesthetic appearance and not 24. Prieto VG, Sadick NS, Lloreta J, et al. Effects of intense pulsed light on sun-damaged human skin, routine, and ultrastructural analysis. Lasers Surg Med. 2002;30:82-85. visual function, is arranged financially between patient and sur- 25. Avantaggiato A, Andreasi Bassi M, Cura F, et al. Non-ablative radio-frequency rejuvenation: a histological and bio-molecular geon and is not covered nor governed by third parties. report. J Biol Regul Homeost Agents. 2016;30(2 Suppl 1):223-230. 26. Meadows D, Christensen M, Grant R, et al. Evaluation of radio frequency thermistor for use in MGD dry eye treatment. Poster Occasionally a blepharoplasty or lid laxity repair patient presented at: 8th International Conference on the Tear Film and Ocular Surface; September 7-10, 2016; Montpellier, France. will have a sudden increase in OSD symptoms. Alterations of 27. Sultan B, Genther DJ, Perkins SW. Measurement of change in lower eyelid position in patients undergoing transcutaneous the lid wiper function, iatrogenic changes in lid closure from skin-muscle flap lower eyelid blepharoplasty. JAMA Facial Plast Surg. 2016;18(6):429-435. overcorrection (microlagophthalmos on light leak testing to frank lagophthalmos on gross examination), and even an Leslie E. O’Dell, OD aggressive wound healing response can push a previously n Director of Dry Eye Center of PA, Wheatlyn Eye Care, compensated OSD patient into a significant increase in signs Manchester, Pennsylvania and symptoms. In a case series of 100 patients undergo- n (717) 266-5661; (717) 521-7161; [email protected] n [email protected]; Twitter @helpmydryeyes ing transcutaneous lower eyelid blepharoplasty, a 0.33 mm n Financial disclosure: speaker for Allergan, RPS, and Shire; mean increase in distance between pupil and lower lid was consultant to Bruder and Paragon BioTeck noted, and 25% of patients reported experiencing new onset of dry eye symptoms.27 Laura M. Periman, MD n Specialist in cornea and external disease, Seattle CONCLUSION n [email protected]; (425) 885-3574; Twitter @dryeyemaster Some may say that Father Time is cruel. Others profess that n Financial disclosure: speaker for Allergan, BioTissue, and aging is beautiful. Whether we support aesthetic procedures TearScience; consultant to Allergan or not, it is best that we be aware of the trends and potential Amy Gallant Sullivan, BS troubles the quest for beauty can inflict upon our patients. n Executive Director and Board member, Tear Film & Ocular As always, education is key. The multibillion-dollar antiaging Surface Society (TFOS), Boston business is only going to grow, and wrinkles will continue to n [email protected]; Twitter @Eyeppl @DryEyeMakeup appear. Arm your practice with the correct knowledge and

NOVEMBER/DECEMBER 2016 | ADVANCED OCULAR CARE 29 WHEN BEAUTY TALK TURNS UGLY The must-have conversation with patients about cosmetic use.

BY LESLIE E. O’DELL, OD; AMY GALLANT SULLIVAN, BS; AND LAURA M. PERIMAN, MD

The fourth and final as part of a proactive approach to ocular surface health. piece in our series on What is used on and around the eyes can affect not only eye CORNEA/EXTERNAL DISEASE cosmetics and ocular health but also overall vision.1 Beauty is literally in the eye of surface disease (OSD) the beholder. We must communicate this to patients: do not focuses on guidelines permit ugly ingredients to compromise your tear film and and recommendations vision just for the sake of beauty. regarding beauty prod- As we have discussed in previous installments, patients use uct use for clinicians eye cosmetics regularly, many on a daily basis. This is an area and patients. Eye makeup and facial care products used by where we must expand our practices by discussing with patients both women and men should be scrutinized as closely as the their habits for choosing products, techniques for application of foods we eat. cosmetics, comfort with cosmetics, usage habits, and removal We advocate label reading and understanding ingredients habits. Just as a diabetes educator must teach diabetic patients

A B Figure 1. A recently conducted online survey of 254 consumers revealed the most commonly used cosmetics on and around the eye as well as their replacement habits for products such as mascara, eyeliners and eye shadow that can become contaminated over time (A) Mascara was the most commonly used eye cosmetic with 87% of respondents stating its use. Replacement habits for (B) D mascara, (C) eyeliner, and (D) eye shadow were found to be well beyond the recommended discard dates with the majority C of consumers using eyeliners and eye shadows until the supply is exhausted.

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about their nutrition and lifestyle habits, we must educate OSD patients regarding the everyday habits that may interfere with their treatment successes and overall well-being. WHO ARE Since writing the previous articles in this series, we have THE DRY EYE DIVAS? again surveyed doctors and patients about their cosmetic use. We found a significant disconnect between how eye care providers think they are educating their patients and what patients actually think they hear about cosmetics from their eye care providers (Figure 1). In fact, many patients come to the office for eye examinations not wearing their full eye makeup, which contributes to “out of sight, out of mind” attitudes in both doctor and patient.

STARTING THE CONVERSATION Your opening lines in this eye health conversation are simple: • Do you wear eye makeup? • Do you use eye cream or antiaging creams? • Do you use skincare products? Consider asking patients to bring a list or a photographic lineup of their regular skincare and cosmetics products to The Dry Eye Divas are Leslie E. O’Dell, OD; Amy Gallant their OSD follow-up visits. These can be helpful to identify Sullivan, BS; and Laura M. Periman, MD. More than 1 year the “bad guys” in a patient’s daily cosmetic or skincare rou- ago, Amy reached out to Leslie, an optometrist and sub- tines. In our clinics, we have uncovered massive exposure committee member for the Tear Film & Ocular Surface to OSD-exacerbating chemicals in some patients’ skin care Society’s Dry Eye WorkShop II, to collaborate on a public products (Figure 2) awareness campaign about cosmetics and dry eye. At the One recent patient brought a gallon-sized plastic kitchen beginning of 2016, Amy and Leslie recruited Laura, a well- bag full of expensive skin care, and each product had from known ophthalmologist who is passionate about dry eye and everything makeup. They coined the term #DryEyeDiva to energize their efforts. They are in the process of recruiting other “divas” to spread the education about how beauty routines can affect the ocular surface.

five to 13 known OSD-exacerbating ingredients. Ironically, her so-called eye cream had the most OSD-exacerbating ingredients, and it was labeled “Not for use around the eye”! Another patient had purchased the most expensive line at a department store beauty counter, naturally thinking this would be better for her eyes and skin. Analysis of the ingredients lists revealed nine to 13 OSD-exacerbating ingredients … per product. Even the authors are not immune to the toxic onslaught. One of our spouses was sent home from the dermatologist with a recommendation to use a top-selling over-the-counter (OTC) moisturizer, only to find this product contained Figure 2. Discussion of facial cleansers with patients. The Dry six OSD-offending ingredients. Eye Divas asked 155 eye care providers via an online survey if We are all consumers. Even men and women who do not they were discussing the use of facial soaps and eyelid cleansers/ use eye makeup may be inadvertently increasing their risk makeup removers regularly with their dry eye patients. The for ocular irritation through their facial cleansing habits. results show only approximately 21% of eye care practitoners We, the Dry Eye Divas (see Who Are The Dry Eye Divas?) are always asking this for their dry eye patients. This is a valuable have spent countless hours researching ingredient lists, peer- conversation to have as many of the cleansing products are reviewed literature, known ocular surface offenders, applica- loaded with OSD harming ingredients. tion trends, and removal habits to develop an educational template for you, the eye care professional, and your patients.

JANUARY/FEBRUARY 2017 | ADVANCED OCULAR CARE 17 Optometrists and ophthalmologists are the guardians of ocular surface health. We must be proactive in addressing eye TOP 10 OCULAR safety with patients and identifying what is safe to use around the eyes. Increasing your knowledge about everyday products SURFACE BEAUTY and habits for both women and men is a rewarding way to expand your already excellent clinical care. BLUNDERS As noted, we advocate label reading. We tell patients that 1. WATERPROOF EYE choosing products with fewer unpronounceable ingredients MAKEUP is a good place to start. Do not trust the claims. Just because 2. EYELID TATTOOING a package says a product is “natural,” “vegan,” “not tested 3. EYELASH EXTENSIONS on animals,” or even “ophthalmologist tested,” this does not guarantee that the product is ocular surface–friendly. 4. EYELASH TINTING Often, rather, these products can be rather ocular surface– 5. OTC EYELASH CORNEA/EXTERNAL DISEASE unfriendly (see Top 10 Ocular Surface-Offending Ingredients). GROWTH SERUMS 6. BOTOX-IN-A-JAR GENERAL EDUCATION RECOMMENDATIONS 7. BOTOX FOR Here are some guidelines to help educate patients and CROW’S FEET consumers about the proper use of cosmetics and cleansers 8. RETIN-A as they pertain to the eye. 9. LOOSE EYESHADOW OR GLITTER Products Patients Must Avoid 10. SHARING MAKEUP • Avoid waterproof makeup, as the same ingredients that make these cosmetics waterproof not only have the potential to block the terminal ductules of the meibomian glands approval of a new topical preparation now in phase 3 but also make the product very difficult to remove without trials meant to specifically address infraorbital bags, also harsh makeup removal products. We have not found an known as “festoons.” Emphasize to patients: Do not com- effective waterproof makeup removal product that did not promise your ocular surface health by using a rectal muco- contain multiple OSD-exacerbating chemicals. sal OTC agent near your eyes. • Avoid eye-area products containing retinol. Antiaging products such as cis-retinoic acid in cosmetics are particu- Things Patients Must Never Do: larly concerning their demonstrated toxicity to human • Do not share cosmetics. Ever. meibomian glands in cell culture.2 Clinically, we have • Do not use products not specified for use on or around seen cases of refractory chronic meibomitis improve with the eyes, such as lip liners or Sharpie markers. The use of mindful elimination of prescription tretinoin (Retin-A and Sharpie markers as a semipermanent eyeliner, along the other brands) and OTC antiaging products with similar lid margin, has been popularized by social media and metabolites. media stars. In addition to the obvious safety issues, the • Avoid products containing benzalkonium chloride. This alcohols, volatile organic compounds, and solvents used preservative ingredient can cause surface epithelial cell in Sharpie marker inks present particularly dangerous and and goblet cell damage, resulting in punctate keratitis and ugly elements to this so-called beauty practice. alterations in surface wettability. • Do not alter products with heat, and be careful where • Avoid use of Botox Cosmetic (onabotulinumtoxinA; cosmetics are stored. Many are not supposed to reach Allergan) for crow’s feet. This application weakens the temperatures above 80°F. orbicularis muscle, leading to incomplete blink, reduced • Do not moisten eye makeup products with saliva, a blink forces, and increased symptoms of dry eye disease.4 bodily fluid with myriad bacterial contaminants with • Avoid the so-called Botox-in-a-jar ingredients found in potential ocular surface pathogenicity. OTC cosmetics: acetyl hexapeptide-8 or acetyl hexapep- • Do not apply makeup while moving, whether in a car, tide-8 (Argireline; Lipotec) bus, taxi, Uber, or walking. • Avoid neurotoxic ingredients such as phenoxyethanol • Do not buy OTC lash enhancers or growth serums. One and acrylamides ingredient in these products, isopropyl cloprostenate, • Avoid periocular use of Preparation H (Pfizer Consumer is a synthetic prostaglandin analogue that can induce Healthcare) near the eyes. If the patient is concerned changes in eye color, changes in eyelid skin (loss of peri- regarding persistent bags under the eyes, recommend orbital fat and darkening of the skin, also known as pros- seeing an oculoplastic surgeon or waiting for regulatory taglandin-associated periorbitopathy), stinging, blurred

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THE FORMIDABLE FORMALDEHYDES TOP 10 OCULAR SURFACE–OFFENDING INGREDIENTS

DMDM Hydantoin Ureas Quaternium-15 Sodium hydroxymethylglycinate 1. BENZALKONIUM CHLORIDE (BAK) 2. ALCOHOL vision, eye redness, itching, and burning. This ingredient is 3. RETINOL not approved by the FDA for OTC cosmetic use, but we 4. PARABENS have found at least one example of its prohibition being 5. ISOPROPYL CLOPROSTENATE ignored. It is recommended to consult with your eye care 6. FORMALDEHYDE & FORMALDEHYDE provider if using the aforementioned products. DONORS • Do not use eyelash extensions. Eyelash glues contain 7. PHENOXYETHANOL volatile organic compounds and ocular surface-irritating 8. BUTYLENE GLYCOL formaldehyde. (Claims that glues are “formaldehyde free” 9. ETHYLENEDIAMINETETRAACETIC are inaccurate). In addition, the abnormal eyelash:eyelid ACID (EDTA) length ratio negatively alters the wind-and-debris– 10. ARGIRELINE (ACETYL HEXAPEPTIDE-3, deflecting properties of the physiologic eyelash. LIPOTEC) • Do not opt for permanent makeup with eyeliner tattooing. Eyeliner tattooing is associated with meibomian ing eye shadow. You would be surprised at how much gland disease.5 debris accumulates at the caruncle. • Do not use eyelash tint. Use of these products can cause • Shop for paraben-free powder eye shadow that has a conjunctivitis and dermatitis.6 high cling and is not easily tapped off the applicator or brush (known as fallout). Alternatively, use a paraben- Things Patients Should Do: free and retinol-free shadow base (primer) or use a The following are some guidelines you can share with paraben-free cream-based eye shadow to prevent fallout patients for proper application and removal of eye cosmetics. into the tear film (Figure 3). • Contact lens wear and cosmetic use is an area of controver- • Never apply makeup on the so-called waterline or tightline sy that need more research. Until more research is available, (the lower and upper lid margins). The waxes and resins in we recommend instructing patients to insert their contact these products can block the meibomian gland terminal lenses prior to makeup application or 10 minutes after ductule orifices. Additionally, the alcohols that dry the liner with clean hands and remove before makeup removal. This in place also dry the delicate tear film (Figure 4). avoids the collection under your lens of debris that can • Use paraben-free and formaldehyde-free eyeliner pencils, irritate the ocular surface and contribute to discomfort. but avoid the eyelash roots and lid margins. This is too Remove contact lenses before makeup removal to avoid close to the meibomian gland orifices, and application damaging the lenses with harsh chemicals. here may cause superficial obstruction of the glands. • If you are not a contact lens wearer, apply a drop of a • Stick with eyeliner pencils, and sharpen them before preservative-free lipid-based artificial tear before apply- every application.

JANUARY/FEBRUARY 2017 | ADVANCED OCULAR CARE 19 OSD symptoms after this treatment, likely due to slight improvements in lid position, blink mechanics, and downward force vectors. • Consider intense pulsed light therapy to the face and periocular structures to even out skin tone, photoco- agulate Demodex, lightly stimulate collagen remodeling, and control the inflammatory load. We call this the “neighborhood cleanup” effect. • Consider radiofrequency rejuvenation procedures to lift and rejuvenate the tissues in a drug-free and cosmetics- free manner.

• Consider CO2 laser resurfacing as a superior method of addressing skin elasticity and fine wrinkles. CORNEA/EXTERNAL DISEASE Figure 3. Commonly used eye cosmetics such as eye shadow CONCLUSION often are found in the tear film and even can be detected in Beauty practices can be ugly for the ocular surface. Eye the conjunctival tissues. This image of a 63 year-old woman care professionals must tell their patients: Do not sacrifice with grade 3 OSD and grade 3 meibomian gland loss with a your eye health for the sake of vanity! SPEED score of 22 was found to have embedded retractile Educate yourself so you can educate your patients about elements, subconjunctival fibrosis and a trace papillary how to age gracefully and safely. Expanding your knowledge reaction attributed to the use of her eye cosmetics. of common ocular-surface–unfriendly practices, exacerbating ingredients, and more ocular-surface–friendly practices is a rewarding way to stake your claim as an ocular surface guardian. Do not neglect the unique opportunity and privi- lege to educate yourself and your deserving patients regarding ocular surface–friendly habits and hygiene practices. n

1. O’Dell L, Periman L, Sullivan, A, et al. An Evaluation of Cosmetic Wear Habits Correlated to Ocular Surface Disease Symptoms. ARVO poster submission 2017. 2. Ding J, Kam WR, Dieckow J, Sullivan DA. The influence of 13-cis retinoic acid on human meibomian gland epithelial cells. Invest Ophthalmol Vis Sci. 2013;54:4341-4350. 3. Tear Film and Ocular Surface Society. 2007 Report of the Dry Eye WorkShop (DEWS). http://www.tearfilm.org/ dewsreport/index.html. Accessed December 12, 2016. 4. Ozgur O, Murariu D, Parsa AA, Parsa FD. Dry eye syndrome due to botulinum toxin type-A injection: guideline for prevention. Hawaii J Med Pub Health. 2012;71(5):120-123. Figure 4. Application of eyeliner to the waterline or 5. Lee YB, Kim JJ, Hyon JY, Wee WR, Shin YJ. Eyelid tattooing induces meibomian gland loss and tear film instability. meibomian gland orifices increases the patient’s risk for mei- Cornea. 2015;34(7):750-755. 6. Teixeira M, de Wachter L, Ronsyn E, Goossens A. Contact allergy to para-phenylenediamine in a permanent eyelash dye. bomian gland dysfunction and even gland obstruction over Contact Dermatitis. 2006;55(2):92-94. time. This is an image of eyeliner residue seen in the yellow circle at the meibomian gland orifices of a young woman Leslie E. O’Dell, OD detected with meibography. n Director of Dry Eye Center of PA, Wheatlyn Eye Care, Manchester, Pennsylvania • Replace moist cosmetics (eg, mascara) monthly. n (717) 266-5661; (717) 521-7161; [email protected] n [email protected]; Twitter @helpmydryeyes • Remove makeup daily. Never use facial cleansers or n Financial disclosure: speaker for Allergan, RPS, and Shire; hand soap to remove eye makeup. consultant to Bruder and Paragon BioTeck • Clean eye makeup brushes regularly. • Talk to their eye care provider about their cosmetic use, Laura M. Periman, MD antiaging regimen, removal products and facial cleansers. n Specialist in cornea and external disease, Seattle n [email protected]; (425) 885-3574; Twitter @dryeyemaster ANTIAGING RECOMMENDATIONS n Financial disclosure: speaker for Allergan, BioTissue, and Following are some tips patients may consider to keep the TearScience; consultant to Allergan periocular area looking young. Amy Gallant Sullivan, BS • Use paraben-free sunscreen daily. Wear a hat. Wear n Executive Director and Board member, Tear Film & Ocular sunglasses. Surface Society (TFOS), Boston • Consider injection of dermal fillers in the midface and n [email protected]; Twitter @Eyeppl @DryEyeMakeup tear trough. Clinically, we have seen improvements in

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