Michael A. Lemp

Tear Physiology and Dry Eyes

The conditions of tear film formation and stability are governed by the surface chemical characteristics of the tear film system and by the proper functioning of the lacrimal apparatus. The tear film has to remain continuous between blinks in order to fulfill it function. The presence of an abnormal tear film results in dry eye states that can be detrimental to vision. The diagnostic tests presently available are limited mainly to approximately determining tear secretion rate and estimating epithelial damage by staining techniques. The only test that directly measures tear film stability is one which determines tear film breakup time. The treatment modalities depend on the type of irregularity causing the dry eye state and range from the application of artificial tear substitutes or the obstruction of the puncta to surgical alterations of the lacrimal system.

Dysfunctional Tear Syndrome A Delphi Approach to Treatment Recommendations

Purpose: To develop current treatment recommendations for dry eye disease from consensus of expert advice. Methods: Of 25 preselected international specialists on dry eye, 17 agreed to participate in a modified, 2-round Delphi panel approach. Based on available literature and standards of care, a survey was presented to each panelist. A two-thirds majority was used for consensus building from responses obtained. Treatment algorithms were created. Treatment recommendations for different types and severity levels of dry eye disease were the main outcome. Results: A new term for dry eye disease was proposed: dysfunctional tear syndrome (DTS). Treatment recommendations were based primarily on patient symptoms and signs. Available diagnostic tests were considered of secondary importance in guiding therapy. Development of algorithms was based on the presence or absence of lid margin disease and disturbances of tear distribution and clearance. Disease severity was considered the most important factor for treatment decision-making and was categorized into 4 levels. Severity was assessed on the basis of tear substitute requirements, symptoms of ocular discomfort, and visual disturbance. Clinical signs present in lids, tear film, conjunctiva, and cornea were also used for categorization of severity. Consensus was reached on treatment algorithms for DTS with and without concurrent lid disease. Conclusion: Panelist opinion relied on symptoms and signs (not tests) for selection of treatment strategies. Therapy is chosen to match disease severity and presence versus absence of lid margin disease or tear distribution and clearance disturbances.

Tear osmolarity in the diagnosis and management of dry eye disease.

PURPOSE To evaluate the use of tear osmolarity in the diagnosis of dry eye disease. DESIGN A prospective, observational case series to determine the clinical usefulness of tear osmolarity and commonly used objective tests to diagnose dry eye disease. METHODS A multicenter, 10-site study consisting of 314 consecutive subjects between 18 and 82 years of age. Bilateral tear osmolarity, tear film break-up time (TBUT), corneal staining, conjunctival staining, Schirmer test, and meibomian gland grading were performed. Diagnostic performance was measured against a composite index of objective measurements that classified subjects as having normal, mild or moderate, or severe dry eye. The main outcome measures were sensitivity, specificity, area under the receiver operating characteristic curve, and intereye variability. RESULTS Of the 6 tests, tear osmolarity was found to have superior diagnostic performance. The most sensitive threshold between normal and mild or moderate subjects was found to be 308 mOsms/L, whereas the most specific was found at 315 mOsms/L. At a cutoff of 312 mOsms/L, tear hyperosmolarity exhibited 73% sensitivity and 92% specificity. By contrast, the other common tests exhibited either poor sensitivity (corneal staining, 54%; conjunctival staining, 60%; meibomian gland grading, 61%) or poor specificity (tear film break-up time, 45%; Schirmer test, 51%). Tear osmolarity also had the highest area under the receiver operating characteristic curve (0.89). Intereye differences in osmolarity were found to correlate with increasing disease severity (r(2) = 0.32). CONCLUSIONS Tear osmolarity is the best single metric both to diagnose and classify dry eye disease. Intereye variability is a characteristic of dry eye not seen in normal subjects.

The International Workshop on Meibomian Gland Dysfunction: Executive Summary

DOI:10.1167/iovs.10-6997a Investigative Ophthalmology & Visual Science, Special Issue 2011, Vol. 52, No. 4 Copyright 2011 The Association for Research in Vision and Ophthalmology, Inc. 1922 ドライアイ疾患の原因としては、マイボーム腺機能不全 (MGD)がおそらく最も多い。この疾患によって数百万人 もの健康と幸福が損なわれているにもかかわらず、MGD の定 義、分類、診断、治療について世界的なコンセンサスはない。 そうしたコンセンサスに達する目的で、非営利団体である Tear Film and Ocular Surface Society( TFOS; http://www. tearfilm.org)が International Workshop on Meibomian Gland Dysfunction(国際マイボーム腺機能不全ワークショップ、 www.tearfilm.org/mgdworkshop/index.html)を起ち上げた。こ のワークショップの目的は以下の通りである:

An objective approach to dry eye disease severity.

PURPOSE A prospective, multisite clinical study (10 sites in the European Union and the United States) evaluated the clinical utility of commonly used tests and tear osmolarity for assessing dry eye disease severity. METHODS Three hundred fourteen consecutive subjects between the ages of 18 and 82 years were recruited from the general patient population, 299 of which qualified with complete datasets. Osmolarity testing, Schirmer test without anesthesia, tear film breakup time (TBUT), corneal staining, meibomian dysfunction assessment, and conjunctival staining were performed bilaterally. A symptom questionnaire, the Ocular Surface Disease Index (OSDI), was also administered to each patient. Distributions of clinical signs and symptoms against a continuous composite severity index were evaluated. RESULTS Osmolarity was found to have the highest correlation coefficient to disease severity (r(2) = 0.55), followed by conjunctival staining (r(2) = 0.47), corneal staining (r(2) = 0.43), OSDI (r(2) = 0.41), meibomian score (r(2) = 0.37), TBUT (r(2) = 0.30), and Schirmer result (r(2) = 0.17). A comparison of standard threshold-based classification with the composite severity index revealed significant overlap between the disease severities of prospectively defined normal and dry eye groups. Fully 63% of the subjects were found to be poorly classified by combinations of clinical thresholds. CONCLUSIONS Tear film osmolarity was found to be the single best marker of disease severity across normal, mild/moderate, and severe categories. Other tests were found to be informative in the more severe forms of disease; thus, clinical judgment remains an important element in the clinical assessment of dry eye severity. The results also indicate that the initiation and progression of dry eye is multifactorial and supports the rationale for redefining severity on the basis of a continuum of clinical signs. (ClinicalTrials.gov number, NCT00848198.).

Meibomian Gland Dysfunction

Blepharitis is probably the most common disease entity seen in the general ophthalmologists office. A significant proportion of these cases are secondary to meibomian gland disease. This review outlines our knowledge of the histopathology, lipid abnormalities and role of microorganisms in meibomian gland dysfunction. We will also review the physiology of meibomian gland secretion and present models of meibomian gland dysfunction which have enhanced our knowledge of this condition. The importance of diagnosing associated conditions such as aqueous tear deficiency, contact lens intolerance, rosacea, and seborrheic dermatitis is emphasized. Although this condition causes significant morbidity in the population, there are effective treatments available and these will be discussed.

Wettability and wetting of corneal epithelium.

The wettability of cleansed corneal epithelium by aqueous solutions has been studied. The critical surface tension of corneal epithelium in situ and that of epithelial monolayers cultured from cornea has been determined with pure hydrophobic liquids. Results indicate that corneal epithelium free of adsorbed mucins exhibits a low energy surface as indicated by its critical surface tension value; 28 dyn/cm. The epithelial surface has a certain affinity toward aqueous phases, but it is insufficient for complete wetting. The possible wetting action of mucous glycoproteins has been investigated by using a commercially available glycoprotein mixture, bovine submaxillary mucin. The activity of this mucin at water-air and water-oil interfaces was measured as a function of concentration. The mucin was studied in the form of a surface film spread over water from an aqueous solution. The wettability of mucin adsorbed on various solid surfaces was also studied. Bovine submaxillary mucin lowers the surface tension considerably at both water-air and water-oil interfaces. The average area occupied by one molecule was calculated from the concentration dependence of surface tension to be between 50 and 100 square A. The area occupied by one mucin molecule in a monolayer spread over water was measured to be about 90,000 square A. The mucin adsorbed on low energy solids like polyethylene and corneal epithelium yields a surface with higher critical surface tension and with considerably higher affinity toward water. It is suggested that the primary role of the conjunctival glycoproteins in the eye is to transform the low-energy corneal surface into a higher energy surface via adsorption. This effect combined with increased affinity toward water and with the lowering of the surface tension of the tears is sufficient to achieve the complete wetting of the corneal surface.

Advances in understanding and managing dry eye disease.

PURPOSE To present evidence from the literature and scientific meetings to support fundamental changes in concepts regarding the prevalence, pathogenesis, definition, diagnosis, management of dry eye disease (DED) and the prospects for the development of new therapies. DESIGN Analysis and clinical perspective of the literature and recent presentations. METHODS Review and interpretation of literature. RESULTS The tear film and ocular surface form an integrated physiologic unit linking the surface epithelia and secretory glands via a neural network. This sensory-driven network regulates secretory activity in quantity and composition, supporting the homeostasis of the system. The tear film forms a metastable covering between blinks, subserving clear vision, and maintains the health and turnover of the ocular surface cells. Disturbance of intrinsic factors such as increasing age; hormonal balance; systemic or local autoimmune disease, or both; systemic drugs or extrinsic factors including topical medications; environmental stress; contact lens wear; or refractive surgery result in a final common pathway of events at the tear film and ocular surface, resulting in DED. Diagnosis of DED and the design of clinical trials for new drugs have been hampered by a lack of correlation between signs and symptoms and flawed endpoints; successful new drug applications likely will require new approaches, such as the use of objective biomarkers for disease severity. CONCLUSIONS Recent advances in our knowledge of the causation of DED open opportunities for improving diagnosis and disease management and for developing new, more effective therapies to manage this widely prevalent and debilitating disease state.

Distribution of aqueous-deficient and evaporative dry eye in a clinic-based patient cohort: a retrospective study.

Purpose: To evaluate in a general clinic-based cohort of patients with dry eye disease (DED) the distribution of patients with aqueous-deficient or evaporative subtype of DED. Methods: Schirmer tests and meibomian gland dysfunction (MGD) (Foulks–Bron scoring) were evaluated in both eyes of 299 normal subjects and DED patients (218 women and 81 men) across 10 sites in the European Union and the United States. Using the more severe measurement of the 2 eyes, subjects were considered to have pure aqueous-deficient dry eye (ADDE) with Schirmer values of <7 mm and MGD grades of ⩽5. Patients were classified as purely evaporative dry eye with MGD grades of >5 and Schirmer values of ≥7 mm. Subjects were placed into the mixed (hybrid) category if they exhibited both a low Schirmer value of <7 and evidence of MGD with a grade >5. Results: Of the 224 subjects classified with DED using an objective, composite, disease severity scale, 159 were classified into 1 of 3 categories: 79 were classified with only MGD, whereas only 23 were classified as purely aqueous deficient, and 57 showed evidence of both MGD and aqueous deficiency. Overall, 86% of these qualified DED patients demonstrated signs of MGD. The remaining 65 patients showed evidence of DED through other clinical signs, without overt evidence of MGD or ADDE, possibly because of the inherent variability of these signs. Conclusions: The proportion of subjects exhibiting signs of evaporative dry eye resulting from MGD far outweighs that of subjects with pure ADDE in a general clinic-based patient cohort.

Correlations between commonly used objective signs and symptoms for the diagnosis of dry eye disease: clinical implications

Purpose:  To evaluate the relationship between signs and symptoms of dry eye disease (DED) in a clinic‐based population.