Ocular Surface Disease: Accurately Diagnose & Effectively Treat Your Surgical Patients

Transcription

1 Supplement April 2018 Ocular Surface Disease: Accurately Diagnose & Effectively Treat Your Surgical Patients Supported by an unrestricted educational grant from

2 Prevalence of Ocular Surface Disease and Its Impact on Surgical Outcomes Accurate diagnosis of dry eye disease is critical before cataract or refractive surgery By Elisabeth M. Messmer, MD Dry eye is a common disease, but it may remain undetected. If it is not treated before cataract or refractive surgery, patients may have suboptimal visual outcomes from their procedures. IMPACT ON CATARACT SURGERY There are a number of triggering factors for dry eye (Figure 1). Cataract surgery worsens or causes dry eye in approximately 10% to 20% of patients (Figure 2). 1-4 In a study of 136 patients with a mean age of 71 years who were having cataract surgery, 22% had a prior diagnosis of dry eye that was not treated. 5 Thirty-one percent complained of stinging, burning or other symptoms of dry eye when asked about their symptoms, and 41% reported a foreign body sensation. When the patients were examined, 77% had corneal staining and 50% had central staining. Denervation is probably the most important factor in the pathogenesis of dry eye after cataract surgery. A corneal incision in the temporal area leads to decreased corneal sensation, but this also occurs in other parts of the cornea, such as the incision site for the second port. 6 The central cornea also showed decreased sensation on day 1, day 7 and day 15 after cataract surgery. Cataract surgery worsens or causes dry eye in approximately 10% to 20% of patients Elisabeth M. Messmer, MD After cataract surgery, the meniscus may decrease, and we may find a decreased Schirmer s test and tear film breakup time, as well as ocular surface staining. 2 The incidence of meibomian gland dysfunction may increase after cataract surgery. A prospective, observational case series of 58 eyes of 48 patients showed changes in lid margin abnormalities after cataract surgery. 3 This population already has a high incidence of meibomian gland dysfunction at baseline, before surgery, and meibomian gland dysfunction increases after surgery. INTRINSIC Age Gender TRIGGERING FACTORS FOR DRY EYE Hormones (esp. menopause and reduced androgen levels) Autoimmune disorders (rheumatoid arthritis, systemic lupus erythematosus, thyroid disease) Inflammatory bowel disease Dermatological disorders (Rosacea, psoriasis, pemphigus, pemphigoid etc.) Figure 1 EXTRINSIC Local environment (low humidity, windy conditions, seasonal influences) Dietary imbalance in omega 3/6 intake Use of video display Contact lens use Exposure to medications/ preservatives Ocular surgery EPIDEMIOLOGY OF DRY EYE SYNDROME AFTER CATARACT SURGERY 1-4 Very limited data available, mostly small descriptive/ non-randomised studies 10-20% of patients: DED induced or worsened after uncomplicated cataract surgery In all studies: Signs and symptoms of dry eye increase after surgery In most studies: gradual improvement of signs and symptoms of dry eye within 3 months In some studies: signs and symptoms persist > 3 months Figure 2 Research comparing femtosecond laser-assisted cataract surgery (FLACS) vs. conventional phacoemulsification surgery showed an increase in dry eye symptoms and ocular surface staining in both groups. 4 However, in the FLACS group, ocular surface staining increased significantly 1 day, 1 week and 1 month after surgery. However, approximately 50% of the study population had preexisting dry eye. The incidence of dry eye increased to approximately 70% at 1 week and approximately 60% at 1 month. In the FLACS group, there was more severe dry eye in patients with pre-existing dry eye. This clearly shows that our cataract surgery patients will have pre-existing dry eye that will worsen after surgery. We also need to consider that dry eye can affect intraocular lens (IOL) calculations. Epitropoulos et al. reported that dry eye and increased tear hyperosmolarity were associated with more variability in average K readings and anterior corneal astigmatism. 7 As a result, there were significant differences in IOL power calculations. In a study by Szakáts et al., examining factors associated with patient satisfaction, 50% were satisfied with their cataract surgery and 50% were dissatisfied. 8 The following factors were associated with dissatisfaction: decreased tear film stability, changes in the ocular surface disease index and the visual function index and worse results on the anxiety questionnaire. When Woodward et al. examined patient dissatisfaction after multifocal IOL implantation, dry eye especially played a major role. 9 IMPACT ON CORNEAL REFRACTIVE SURGERY Jabbur et al. reported that dry eye was one of the major reasons patients were not satisfied after refractive surgery. 10 In a study of SMILE vs. LASIK, there was a high incidence of mild to moderate dry eye 1 month after both procedures, but it remained significantly higher in the LASIK group vs. the SMILE group 6 months after surgery. 11 One month after surgery, corneal sensitivity was better in patients who had SMILE vs. LASIK, but it was normal at 6 months in both groups. Pre-existing dry eye is a risk factor for postoperative dry eye; therefore, it is important to identify patients at risk before surgery. Ophthalmologists should identify risk factors, ask patients about their symptoms and diagnose dry eye by performing a comprehensive examination. It is important to inform patients about the possibility of postoperative dry eye before refractive surgery. 1

3 CONCLUSION Although preoperative dry eye is common, surgeons may overlook signs and symptoms when preparing a patient for ocular surgery. Consequently, patients may be dissatisfied with their surgical outcomes. Therefore, it is important to treat dry eye before surgery because it may affect IOL calculations and postoperative outcomes. Treatment of preoperative dry eye is particularly important in patients receiving premium IOLs. REFERENCES 1. Kasetsuwan N, et al. Incidence and pattern of dry eye after cataract surgery. PLoS One. 2013; 8:e Li XM, et al. Investigation of dry eye disease and analysis of the pathogenic factors in patients after cataract surgery. Cornea. 2007; 26(9 Suppl 1):S Han KE, et al. Evaluation of dry eye and meibomian gland dysfunction after cataract surgery. Am J Ophthalmol. 2014; 157: Yu Y, et al. Evaluation of dry eye after femtosecond laser-assisted cataract surgery. J Cataract Refract Surg. 2015; 41: Trattler WB, et al. The Prospective Health Assessment of Cataract Patients Ocular Surface (PHACO) study: the effect of dry eye. Clin Ophthalmol. 2017; 11: Sitompul R, et al. Sensitivity change in cornea and tear layer due to incision difference on cataract surgery with either manual small-incision cataract surgery or phacoemulsification. Cornea. 2008; 27 (suppl 1):S Epitropoulos AT, et al. Effect of tear osmolarity on repeatability of keratometry for cataract surgery planning. J Cataract Refract Surg. 2015; 41: Szakáts I, et al. Dry eye symptoms, patient-reported visual functioning, and health anxiety influencing patient satisfaction after cataract surgery. Curr Eye Res 2017; 42: Woodward MA, Randleman JB, Stulting RD. Dissatisfaction after multifocal intraocular lens implantation. J Cataract Refract Surg. 2009; 35: Jabbur NS, et al. Survey of complications and recommendations for management in dissatisfied patients seeking a consultation after refractive surgery. J Cataract Refract Surg. 2004; 30: Denoyer A, et al. Dry eye disease after refractive surgery: comparative outcomes of small incision lenticule extraction versus LASIK. Ophthalmology. 2015; 122: Dr. Messmer is professor of ophthalmology, Ludwig Maximilian University, Munich, Germany. She may be reached at Elisabeth. Messmer@med.uni-muenchen.de. Dr. Messmer is a speaker or adviser for the following companies: Alcon Pharma GmbH, Dompé, Pharm-Allergan GmbH, Santen GmbH, Shire, Théa Pharma GmbH, TRB-Chemedica, Ursapharm Arzneimittel GmbH, and Visufarma. Understanding of Physiopathology: Diagnosing and Treating OSD based on DEWS II International workshop offers new insights in defining and managing dry eye disease Christophe Baudouin, MD, PhD, FARVO The International Dry Eye Workshop (DEWS) II gathered 150 members from 23 countries, bringing new concepts, definitions, and aetiological approaches to dry eye disease, as well as the concept of the vicious circle of dry eye disease that I introduced during the first Dry Eye Workshop (DEWS I). 1,2 The workshop also covered neuropathic pain, iatrogenic dry eye, new diagnostic technologies, and new etiology-based therapies. DEFINING THE DISEASE A decade ago, DEWS I introduced new concepts in dry eye, defining it as a disease of the tears and ocular surface (rather than as a syndrome) that causes symptoms and visual disturbances. Figure 1. Severe tear film instability The new definition still includes hyperosmolarity and inflammation, but it also introduced neural sensory abnormalities Christophe Baudouin, MD, PhD, FARVO That workshop also defined the role of hyperosmolarity and inflammation in dry eye. The second workshop changed the definition to a certain extent. Dry eye is a disease of the ocular surface resulting from loss of homeostasis (Figures 1 to 3). It is a question of regulation of the ocular surface in contact with the environment, a concept that is more useful in understanding dry eye. The new definition still includes hyperosmolarity and inflammation, but it also introduced neurosensory abnormalities, which are important. However, I am disappointed that the new definition no longer describes the influence of dry eye on vision. Dry eye is not only a stinging or irritated eye. Its impact on quality of vision is also very important, especially when a patient is having refractive or cataract surgery. 3 CLASSIFYING DRY EYE Although we classify dry eye as aqueous-deficient vs. evaporative dry eye and quality vs. quantity of tears, we still do not know why so many different diseases cause many different manifestations. I proposed the concept of the vicious circle to explain this. It begins with tear deficiency or tear abnormalities, leading to 2

4 Figure 2. Severe keratitis Figure 3. Lissamine green staining of the conjunctiva hyperosmolarity via tissue damage to neurogenic inflammation that destroys goblet cells and leads to further tear film abnormalities. The same type of concept applies to meibomian gland disease, but it is a double vicious circle with one involving the eyelids and one related to the tear film. Patients enter the circle with different risk factors or an acute stress. You may understand why an acute stress may cause a patient to enter the circle. It also may help you understand why, when the cause of stress is removed (for example, time has passed since the surgery), the patient still experiences discomfort because the consequence is disconnected from the cause. DEWS II introduced neuropathic dry eye. Patients with neuropathic pain have symptoms but no signs of dry eye. Carlos Belmonte MD, PhD, described very complex nerve systems in the cornea that are connected to the brain stem and that peripheral pain can become central neuropathic pain, and some receptors can be activated in a noxious way. 4 Therefore, they can cause pain, irritation, or discomfort. Another interesting concept is iatrogenic dry eye, which can result from eyedrops or refractive or eyelid surgeries. 5 If dry eye is caused by preservatives, and the clinician treats dry eye but continues treating the patient with antibiotics because of slight corneal staining or nonsteroidal drops for chronic inflammation, it will induce dry eye and toxicity. If we do not remove the cause, dry eye will not improve. Therefore, when the cornea does not heal and the patient s discomfort does not lessen, we need to search for the cause. If long-term eyedrops are causing dry eye, for example, we should consider an alternative. Twenty percent of people in the general population have dry eye, but 50% of patients with glaucoma have dry eye. Glaucoma alone does not increase the incidence of dry eye. The treatment can cause dry eye. DIAGNOSING DRY EYE New technologies allow clinicians to perform measurements, visualise glands, evaluate markers and perform other assessments. To manage dry eye, we begin by obtaining information from the patient, perform assessments with advanced diagnostics and treat the case based on the cause of dry eye. I propose examining the vicious circle of dry eye disease for diagnosis. In a series of events, we can control each event individually. We can control the environment. We can use tear substitutes or insert punctal plugs to keep tears in the eye. We can control meibomian gland disease with lid hygiene and tetracyclines. We can target dry eye at its source. If we understand dry eye disease well, we have a range of techniques we can use to identify the cause of dry eye and effectively treat it. REFERENCES 1. Report of the Definition and Classification Subcommittee of the International Dry Eye Workshop. Ocul Surf. 2007; 5: Nelson JD, et al. TFOS DEWS II: Introduction. Ocul Surf. 2017; 15: Benitez-Del-Castillo J, et al. Visual acuity and quality of life in dry eye disease: Proceedings of the OCEAN group meeting. Ocul Surf. 2017; 15: Belmonte C, et al. What causes eye pain? Curr Ophthalmol Rep. 2015; 3: Gomes JAP, et al. TFOS DEWS II iatrogenic report. Ocul Surf. 2017; 15:511e538. Dr. Baudouin is professor and chair of ophthalmology, Quinze-Vingts National Ophthalmology Hospital, and Vision Institute, University Paris 6, Paris, France. He may be reached at cbaudouin@quinze-vingts.fr. He has received consultant and research fees from Allergan, Alcon, Dompé, Horus Pharma, Santen, Shire, and Thea. 3

5 Exploring OSD Diagnostic Testing: From Simple to Sophisticated Techniques Range of tests can help surgeons pinpoint dry eye preoperatively By Béatrice Cochener, MD, PhD The ocular surface plays a key role in visual outcomes after refractive surgery, so it is important to accurately diagnose ocular surface disease (OSD) preoperatively. Surgeons have access to a range of diagnostic tests to accomplish this task, ranging from simple tests to increasingly sophisticated techniques. IMPACT OF OSD ON SURGICAL OUTCOMES Refractive surgery has driven the progress of ocular surface research and investments by industry. We recognise that by improving the ocular surface, we can improve refractive surgery outcomes. OSD is the main complication after cataract and refractive surgery. Most cases of severe postoperative dry eye can be attributed to preoperative dry eye that was underestimated previously. It is important to keep in mind that most patients who seek refractive surgery are doing so because they cannot tolerate their contact lenses, a potential sign of dry eye. As with other medical conditions, we know it is more effective to prevent OSD than to treat it. OSD DIAGNOSTICS In diagnosing dry eye preoperatively, we need to identify risk factors, such as allergies, contact lens intolerance, medications, autoimmune disease, hormonal changes and age (combining many of these factors). By examining the eyelids and the skin, we also can find useful information about conditions such as lupus or meibomian gland disease with rosacea (Figure 1). The patient questionnaire, such as the OSDI, SPEED and others, is an important screening tool to evaluate dry eye and document the patient s response to treatment over time. 1 Figure 1. The routine examination should include evaluation of gland expression and A comprehensive quality of the meibum slit lamp examination Figure 2. Irregularities of the tear film can be seen as a decrease in tear breakup time and dry spots on the cornea Refractive surgery has driven the progress of ocular surface research and investments by industry Béatrice Cochener, MD, PhD includes checking each area of the cornea, limbus, conjunctiva, eyelids and tear film. Meibomian gland dysfunction is the most common cause of evaporative dry eye. We express the meibomian glands, and we can use a transilluminator or meibography to quantify the disorder. We also need to look for signs of inflammation, with anterior blepharitis, telangiectasias and other abnormalities. Everyone should consider how much we can learn from properly instilling one drop of fluorescein. Tear breakup time demonstrates tear film stability (Figure 2). 2 Although a score less than 5 is considered abnormal, it is very subjective. It can be highlighted with a yellow filter (Figure 3). Fluorescein also is used to check for epithelial lesions, which are graded conventionally on the Oxford scale. Lissamine green 1% stains membrane-damaged and devitalised epithelial cells. It may be useful where there is a loss of mucin in the tear film and it may be more sensitive for milder forms of dry eye. For the last several years, there has been controversy over the use of Schirmer s test, but it provides a quantitative analysis of reflex tear secretion. We are moving to point-of-care tests because despite the value of traditional tests, they have shown low specificity, they are subjective, and they have some limitations, particularly if they are not performed correctly. In addition, traditional tests quite commonly are not correlated to clinical findings. If the ocular surface is unstable, the quality of vision is unstable. Decreased central visual acuity from tear film instability can induce higher-order aberrations, blurred vision and ocular fatigue. 3 These complaints are related to ocular surface abnormalities and not the surgery itself. If the decrease in tear film thickness is uniform, it modestly affects refraction, but if there are irregular variations, there are more power variations. This is why it is important to focus on the quality of blinking. 4 A number of qualitative tests used to evaluate surface stability are already in routine practice, such as Placido topography and elevation topography. We can also quantify the ocular surface with advanced optical coherence tomography. 5 We can measure the height of the meniscus and tear film thickness and perform epithelial mapping. Eyelid dynamics and the lipid layer are important, including the frequency and time of blink, meibography, and automated tear breakup time. Aberrometry allows us to examine the entire optical system, from the tear film to the retina. We can use these technologies, but we need to know where the abnormalities are originating. Among aberrometers, the double-pass aberrometer (OQAS) provides a specific index ocular scatter index which reflects, when greater than 2, an alteration of light diffusion in the eye. This may be related to OSD if the lens and retina are normal. 4

6 CHARACTERISING THE OCULAR SURFACE When characterising the ocular surface, we need to define thresholds, as well as the specificity, repeatability and sustainability of our new measurements. Hyperosmolarity, biomarkers, automated conjunctival prints and meibography (interferometry) all play a role in characterizing the ocular surface. 6,7 With the point-of-care test for hyperosmolarity, if osmolarity is greater than 308 mosm/l, the patient is considered to have dry eye. This platform has evolved into another technology that integrates testing of tear fluid biomarkers using fluorescent immunoassay detection technology, testing for osmolarity and inflammation (MMP-9 and IL-1Ra). Lactoferrin a glycoprotein secreted by the lacrimal gland could be a new test. Low levels of lactoferrin occur when patients have aqueous-deficient dry eye. It is a sign of lacrimal gland dysfunction, and in these cases, there is a high suspicion for Sjögren s syndrome. Interferometry enables us to quantify and qualify the lipid layer and evaluate the meibomian glands. Dynamic meibomian gland imaging allows us to check the functionality of the meibomian glands, and using different light sources, we can take multiple images and combine them. CONCLUSION Examining and treating the ocular surface before surgery helps improve surgical outcomes from refractive surgery and decrease the number of unhappy patients. The diagnosis of OSD does not contraindicate surgery but guides the surgeon in choosing the procedure, preparing the eye for operation, and informing the patient about this specific risk. We know that in medicine, it is always better to prevent than to cure. REFERENCES 1. Ngo W, et al. Psychometric properties and validation of the standard patient evaluation of eye dryness questionnaire. Cornea. 2013; 32: Abelson M., et al. Alternative reference values for tear film break up time in normal and dry eye populations. Adv Exp Med Biol. 2002; 506(Part B): Figure 3. The yellow filter emphasises the point of rupture of the tear film 3. Koh S. Mechanisms of visual disturbance in dry eye. Cornea 2016; 35(suppl 1):S Montés-Micó R. Role of the tear film in the optical quality of the human eye. J Cataract Refract Surg. 2007; 33: Shen M, et al. Upper and lower tear menisci in the diagnosis of dry eye. Invest Ophthalmol Vis Sci. 2009; 50: Sullivan BD, et al. An objective approach to dry eye disease severity. Invest Ophthalmol Vis Sci. 2010; 51: Chotikavanich S, et al. Production and activity of matrix metalloproteinase-9 on the ocular surface increase in dysfunctional tear syndrome. Invest Ophthalmol Vis Sci. 2009; 50: Dr. Cochener is chair and professor of the Ophthalmology Department at Brest University Hospital, France, general secretary of EuCornea, and president-elect of ESCRS. She may be reached at beatrice.cochener-lamard@chu-brest.fr. Dr. Cochener has financial interests in Alcon, Zeiss, Johnson & Johnson Vision, PhysIOL, RVO, Staar, Thea, Santen, and Cutting Edge. Management of Ocular Surface in the Context of Surgery The field of dry eye treatments continues to expand José M. Benitez del Castillo, MD To manage ocular surface disease before refractive or cataract surgery, ophthalmologists have a range of treatment options to consider. TEAR SUBSTITUTES Tear substitutes include artificial tears, dissolvable inserts and combination medications. 1 We now have intelligent artificial tears with osmoprotectants because the tear film in dry eye is hyperosmolar. Antioxidants such as acetylcysteine, vitamin A, quercetin, gallic acid and selenoprotein P play a role because there is oxidative stress in dry eye. It is important to consider the inactive agents, such as buffers and electrolytes. If phosphate levels are too high, they can cause calcic keratopathy. Because meibomian gland dysfunction is the most We now have intelligent artificial tears with osmoprotectants because the tear film in dry eye is hyperosmolar José M. Benitez del Castillo, MD frequent cause of evaporative dry eye, there is a role for lipid supplementation. Autologous serum has anti-inflammatory effects and stimulates nerve regeneration. When we cannot use autologous serum, we can use adult allogenic serum, umbilical cord serum, and platelet preparations. We have mucolytics for patients with mucus strands. We can 5

7 Aqueous - Diquafosol - Lacritin Mucin - Rebamipide - Galectin-3 - MMF - NGF TOPICAL SECRETAGOGUES Lipid - ILG-1 - Topical testosterone Oral Nasal neurostimulation (TrueTear ) TRPM8 stimulation use oral preparations, such as ambroxol and bromhexine, and acetylcysteine topical drops. For patients with symptoms but no signs of ocular surface disease, we studied TRPVI receptor antagonist, which reduced discomfort. 2 ADDITIONAL STEPS To help preserve tears in aqueous-deficient dry eye, we can use punctal plugs or perform surgical punctal occlusion. We can also decrease evaporation with moisture chamber spectacles and humidifiers. Topical secretagogues can increase the production of aqueous, mucin and lipids; however, topical aqueous and mucin secretogogues are not available in Europe or the United States (Figure 1). Nasal neurostimulation also can increase tear production. We are also studying TRPM8 stimulation. There are a number of treatments for lid abnormalities. Lid hygiene is very important to reduce bacteria, and tea tree oil and ivermectin are used to treat Demodex. Warm compresses help liquefy the lipids of the meibomian glands, thermal pulsation facilitates meibomian gland expression and debridement scaling helps remove debris. Patients also may benefit from wearing contact lenses to prevent tear evaporation. Management of dry eye disease is still an art José M. Benitez del Castillo, MD To treat inflammation, which is a main component of dry eye, we can use short-term unpreserved steroids and cyclosporine. Lubricin, a biologic agent, helps reduce friction of the eyelid against the globe, and other biologics are being studied. Lifitegrast 5% is a new approach to dry eye. It binds to integrin receptor LFA-1 and blocks interaction between LFA-1 with ICAM-1 that signals the start of the inflammatory cycle. It may inhibit T-cell activation, T-cell migration and secretion of inflammatory cytokines. Lifitegrast treats signs and symptoms of dry eye. The onset of action is as early as 2 weeks. It can be used in combination with cyclosporine. Surgical approaches include tarsorrhaphy, surgery for conjunctivochalasis, botulinum toxin, treatment for dermatochalasis, amniotic membrane grafts, dacryoreservoirs and salivary gland transplantation. Dietary modifications, including improved hydration, lactoferrin, calorie restriction for weight reduction and omega 3, 6, and 3 + 6, also may be useful. 3 CASE REPORT A 65-year-old woman was referred by her ophthalmologist. She originally sought medical help for poor near vision after a premium intraocular lens was implanted. She hadcataract surgery in her right eye 5 months previously with no complications. She used unpreserved artificial tears. Her distance visual acuity was 0.7 and near visual acuity J5. Corneal sensitivity (Cochet-Bonnet aesthesiometer) was 5 cm (central). Other results were as follows: Schirmer test: 5 mm; tear film break-up time: 1 second; corneal staining (Oxford score): 3 (central localisation); and corneal topography: central irregularity. Slit lamp examination showed central corneal epithelial irregularity and no conjunctival hyperemia (Figure 2). She was treated with preservative-free artificial tear gel in the afternoon and at night, as well as cyclosporine 0.1% drops once a day. Patient satisfaction improved after 2 months of treatment. Superficial punctate keratopathy healed and her near visual acuity was J2. It also is helpful to avoid drying medications, desiccating conditions, and pollutants. In addition, we need to manage the psychological aspects of the disease because these patients are more likely to have depression and anxiety. In patients with dry eye, cataract surgery and refractive surgery produce aqueous-deficient and evaporative dry eye resulting from the use of speculums and medications, and many patients have lower lid ptosis, altering the relationship between the puncta and globe. These patients have decreased tear clearance and a greater likelihood of evaporative dry eye. CONCLUSION Management of dry eye disease is still an art. Patients with symptoms but no signs have neuropathic pain, and patients with signs but no symptoms have neuropathic keratopathy. REFERENCES 1. Pucker AD, Ng SM, Nichols JJ. Over the counter (OTC) artificial tear drops for dry eye syndrome. Cochrane Database Syst Rev 2016; 2:CD Benitez-Del-Castillo JM, et al. Safety and efficacy clinical trials for syl1001, a novel short interfering RNA for the treatment of dry eye disease. Invest Ophthalmol Vis Sci. 2016; 57: Ng SM, Lindsley K, Akpek EK. Omega-3 and omega-6 polyunsaturated fatty acids for dry eye syndrome (Protocol). Cochrane Database Syst Rev 2014; 3:CD Dr. Benitez-del-Castillo, MD, is chairman of ophthalmology UCM, Hospital Clinico San Carlos, Clinica Rementeria, Madrid, Spain. He may be reached at benitezcastillo@gmail.com. He has financial interests in Allergan, Santen, Bausch + Lomb, Abbvie, Angelini, Farmamix, Horus, Alcon, Thea, Esteve, Dompé, Novartis, Sylentis, and Brill. 6

8 Supplement April 2018 Supported by an unrestricted educational grant from Shire, Novartis & TearLab