Validation of a Modified National Eye Institute Grading Scale for Corneal Fluorescein Staining.

Purpose: Validation of the novel Lexitas modified NEI scale for use in assessment of corneal fluorescein staining. Patients and Methods: A series of 18 illustrations and 14 clinical photographs depicting varying severity levels of corneal fluorescein staining were assessed by 3 independent examiners. Regions of the cornea were graded for staining severity based on 3 different grading scales: the original NEI staining scale (density-based scoring; 0-3 scale), a structured version of the NEI scale (dot-count scoring; 0-3 scale), and the Lexitas modified NEI staining scale (0-4 scale with half-point increments). Kappa statistics (simple and weighted) were computed to determine intra-examiner image grading repeatability for each examiner over 2 separate assessments. Inter-examiner assessment reliability utilized the scores from the first read of each examiner, and pairs of examiners to compute kappa statistics. Results: Data was analyzed from the scores provided by the examiners from each gradable corneal region on 32 images (18 illustrations and 14 photographs) for a total of 154 corneal regions across the 3 grading scales for each validation run. The mean intra-examiner simple/weighted kappa values using the NEI density, NEI dot count, and the Lexitas modified NEI staining scales were 0.67/0.72, 0.91/0.94, 0.80/0.92 for the graded illustrations, and 0.83/0.88, 0.76/0.85, 0.77/0.88 for the graded photographs, respectively. The mean inter-examiner simple/weighted kappa values using the NEI density, NEI dot count, and the Lexitas modified NEI staining scales were 0.59/0.65, 0.86/0.90, and 0.78/0.91 for the graded illustrations, and 0.80/0.88, 0.84/0.89, 0.69/0.88 for the graded photographs, respectively. Conclusion: The expanded scale of the Lexitas modified NEI staining scale demonstrated a high degree of reliability and repeatability of grading assessments within and across individual examiners, comparing favorably with the original NEI staining scale. A future investigation into the in-office utility of the Lexitas modified NEI staining scale is warranted.

Perspective on Systematic Medical Literature Reviews and Meta-Analyses.

PURPOSE: This study sought to identify factors contributing to the inadequacies of systematic reviews and meta-analyses (SRMAs) published in the ophthalmology literature. DESIGN: Perspective. METHODS: Review and synthesis of selective literature, with interpretation and perspective. RESULTS: Although recommendations for the design, conduct, assessment of quality, and risk of bias of systematic reviews have been widely available, some recent publications illustrate a serious potential failing in this domain: inclusion of refuted science, lack of citation of post-publication correspondence and failure to use ≥1 alternative search strategy. CONCLUSIONS: Examples of inadequacies of peer review in medical literature and perpetuation of erroneous science by unfiltered inclusion in subsequent systematic reviews have been identified, and the problem can be traced to authors, peer reviewers, and editors of journals. This perspective identifies and analyzes several possible causes of the problem and recommends some specific corrective actions to improve the quality and accuracy of such reviews.

Human Meibum Cholesteryl and Wax Ester Variability With Age, Sex, and Meibomian Gland Dysfunction.

Purpose: Relationships between tear film lipid (TFL) layer composition, structure, and function could provide insight into the etiology of dry eye. The molar ratio of cholesteryl ester (CE)/wax ester (WE) was measured in meibum from normal donors (Mn) and compared with meibum from donors with meibomian gland dysfunction (MMGD). Methods: CE/WE was measured using nuclear magnetic resonance spectroscopy. Results: CE/WE was distributed into two populations with 81% distributed near 0.55 and 19% near 0.3. CE/WE were higher in donors 13 to 19 years old compared with donors 1 to 12 years old and 20 to 88 years old. CE/WE for MMGD was 30% lower, 0.34 ± 0.04, compared with Mn, 0.49 ± 0.04. There were no sex differences in CE/WE. There were no significant racial differences between the CE/WE ratios for Asians and Caucasians. The CE/WE ratio was higher for blacks and lower for Hispanics compared to Caucasians. Due to the small number sampled, confirmation of the later racial results is needed. The packing of CE and WE in the TFL layer was proposed. Conclusions: Although MMGD contains much less CE than Mn, factors other than the CE content, such as the levels of saturation and/or proteins, may be responsible for the higher order of MMGD. In addition to saturation, CE could contribute to the increase in order of Mn between 0 and 20 years of age. Observed changes in the meibum content of CE alone is not likely to influence tear film stability.

TFOS DEWS II Clinical Trial Design Report.

The development of novel therapies for Dry Eye Disease (DED) is formidable, and relatively few treatments evaluated have been approved for marketing. In this report, the Subcommittee reviewed challenges in designing and conducting quality trials, with special reference to issues in trials in patients with DED and present the regulatory perspective on DED therapies. The Subcommittee reviewed the literature and while there are some observations about the possible reasons why so many trials have failed, there is no obvious single reason other than the lack of correlation between signs and symptoms in DED. Therefore the report advocates for conducting good quality studies, as described, going forward. A key recommendation for future studies is conduct consistent with Good Clinical Practice (GCP), including use of Good Manufacturing Practice (GMP) quality clinical trial material. The report also recommends that the design, treatments, and sample size be consistent with the investigational treatment, the objectives of the study, and the phase of development. Other recommendations for pivotal studies are a priori selection of the outcome measure, and an appropriate sample size.

Clinical guidelines for management of dry eye associated with Sjögren disease.

PURPOSE: To provide a consensus clinical guideline for management of dry eye disease associated with Sjögren disease by evaluating published treatments and recommending management options. DESIGN: Consensus panel evaluation of reported treatments for dry eye disease. METHODS: Using the 2007 Report of the International Workshop on Dry Eye (DEWS) as a starting point, a panel of eye care providers and consultants evaluated peer-reviewed publications and developed recommendations for evaluation and management of dry eye disease associated with Sjögren disease. Publications were graded according to the American Academy of Ophthalmology Preferred Practice Pattern guidelines for level of evidence. Strength of recommendation was according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines. RESULTS: The recommendations of the panel are briefly summarized herein. Evaluation should include symptoms of both discomfort and visual disturbance as well as determination of the relative contribution of aqueous production deficiency and evaporative loss of tear volume. Objective parameters of tear film stability, tear osmolarity, degree of lid margin disease, and ocular surface damage should be used to stage severity of dry eye disease to assist in selecting appropriate treatment options. Patient education with regard to the nature of the problem, aggravating factors, and goals of treatment is critical to successful management. Tear supplementation and stabilization, control of inflammation of the lacrimal glands and ocular surface, and possible stimulation of tear production are treatment options that are used according to the character and severity of dry eye disease. SUMMARY: Management guidelines for dry eye associated with Sjögren's disease are presented.

Rethinking dry eye disease: a perspective on clinical implications.

Publication of the DEWS report in 2007 established the state of the science of dry eye disease (DED). Since that time, new evidence suggests that a rethinking of traditional concepts of dry eye disease is in order. Specifically, new evidence on the epidemiology of the disease, as well as strategies for diagnosis, have changed the understanding of DED, which is a heterogeneous disease associated with considerable variability in presentation. These advances, along with implications for clinical care, are summarized herein. The most widely used signs of DED are poorly correlated with each other and with symptoms. While symptoms are thought to be characteristic of DED, recent studies have shown that less than 60% of subjects with other objective evidence of DED are symptomatic. Thus the use of symptoms alone in diagnosis will likely result in missing a significant percentage of DED patients, particularly with early/mild disease. This could have considerable impact in patients undergoing cataract or refractive surgery as patients with DED have less than optimal visual results. The most widely used objective signs for diagnosing DED all show greater variability between eyes and in the same eye over time compared with normal subjects. This variability is thought to be a manifestation of tear film instability which results in rapid breakup of the tearfilm between blinks and is an identifier of patients with DED. This feature emphasizes the bilateral nature of the disease in most subjects not suffering from unilateral lid or other unilateral destabilizing surface disorders. Instability of the composition of the tears also occurs in dry eye disease and shows the same variance between eyes. Finally, elevated tear osmolarity has been reported to be a global marker (present in both subtypes of the disease- aqueous-deficient dry eye and evaporative dry eye). Clinically, osmolarity has been shown to be the best single metric for diagnosis of DED and is directly related to increasing severity of disease. Clinical examination and other assessments differentiate which subtype of disease is present. With effective treatment, the tear osmolarity returns to normal, and its variability between eyes and with time disappears. Other promising markers include objective measures of visual deficits, proinflammatory molecular markers and other molecular markers, specific to each disease subtype, and panels of tear proteins. As yet, however, no single protein or panel of markers has been shown to discriminate between the major forms of DED. With the advent of new tests and technology, improved endpoints for clinical trials may be established, which in turn may allow new therapeutic agents to emerge in the foreseeable future. Accurate recognition of disease is now possible and successful management of DED appears to be within our grasp, for a majority of our patients.

New testing options for diagnosing and grading dry eye disease.

PURPOSE: To describe new options for diagnosis and severity grading of dry eye disease. DESIGN: Perspective on technological advancements to identify tear dysfunction and their value in diagnosing and grading dry eye disease. METHODS: Evidence is presented on new and evolving technologies to measure tear stability, composition, and meniscus height and their role in dry eye diagnosis and therapeutic efficacy grading is assessed. RESULTS: Evolving concepts regarding pathogenesis and new technologies to evaluate the tears and ocular surface have improved the ability to diagnose, classify, and grade the severity of dry eye disease. New technologies include noninvasive imaging of tear stability and tear meniscus height as a measure of tear volume and tear composition (osmolarity, lacrimal factors, inflammatory mediators, growth and differentiation factors). Approved tests, such as tear osmolarity and tear imaging, are being integrated into clinical practice and may eventually supplant certain traditional tests that have greater variability and less sensitivity. Other tests, such as molecular assays of tears and conjunctival cells, are currently being used in studies investigating pathogenesis and therapeutic mechanism of action. They may eventually translate to routine clinical practice. CONCLUSIONS: New technologies have emerged that can noninvasively evaluate the tears and measure disease-associated compositional changes. These tests are being integrated into clinical practice and therapeutic trials for diagnosis, classification, and severity grading of dry eye disease.

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. METHODS: In a retrospective analysis, clinical signs and symptoms were evaluated for 344 subjects (n = 82, normal; n = 263, dry eye), across 11 sites from the EU and United States. Pearson correlations between signs and symptoms (r(2) ) and an independent components analysis (ICA) mixing matrix were derived from the data set. Similar analysis was performed on an independent data set from 200 subjects in a previous study in Munich, Germany. RESULTS: No correlations above r(2) = 0.17 were found between any signs and symptoms, except for corneal and conjunctival staining, which reported an r(2) = 0.36. In the multisite study, the average r(2) for osmolarity (0.07), tear breakup time (0.12), Schirmer test (0.09), corneal (0.16) and conjunctival staining (0.17), meibomian grading (0.11) and Ocular Surface Disease Index(®) (0.11) were consistently low. Among patients who showed evidence of DED by consensus of clinical signs, only 57% reported symptoms consistent with a diagnosis of DED. Similar results were observed in the Munich-based study data set. Each component of the ICA mixing matrix exhibited minimal residual information. CONCLUSIONS: No consistent relationship was found between common signs and symptoms of DED. Each type of measurement provides distinct information about the condition of the ocular surface. These results also demonstrate that symptoms alone are insufficient for the diagnosis and management of DED and argue for a consensus of clinical signs that better reflect all aspects of the disease.

Efficacy of an artificial tear emulsion in patients with dry eye associated with meibomian gland dysfunction.

OBJECTIVES: The aim of the study reported here was to assess the efficacy of an artificial tear emulsion for the treatment of dry eye associated with meibomian gland dysfunction (MGD). METHODS: At five clinics, patients completed a 1-week treatment with their habitual topical therapy and then a 4-week treatment with open-label study medication: Systane® Balance Lubricant Eye Drops (Alcon, Alcon Inc, Fort Worth, TX, USA). Subjective assessments included a preference survey, the Impact of Dry Eye in Everyday Life questionnaire, and the Work Productivity and Activity Impairment questionnaire. Objective assessments by unmasked investigators included visual acuity, meibomian gland expression and dropout, tear film breakup time, corneal staining, and dosing frequency. RESULTS: At baseline, the 49 patients had mean meibomian gland expression grades and gland dropout that indicated mild to moderate MGD. Patients administered their habitual therapy 2.5 ± 1.3 times per day. After 4 weeks of study medication, the Impact of Dry Eye in Everyday Life questionnaire results indicated statistically and clinically significant improvements. Fewer than half of the participants were employed, limiting the usefulness of the Work Productivity and Activity Impairment questionnaire. Visual acuity remained statistically similar, while corneal staining and tear film breakup time improved significantly (P < 0.05) but modestly. The outcomes were achieved with 1.9 ± 1.1 doses per day of study medication, a significantly lower frequency than the habitual frequency (P < 0.001). The most common medication-related adverse event was blurred vision (3/49 patients, 6.1%). At study conclusion, 27/44 (61.4%) survey respondents preferred the study medication to their habitual therapy. CONCLUSION: The artificial tear emulsion was effective for treating the signs and symptoms of dry eye in MGD patients.