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.

Tofacitinib (CP-690,550), a Janus kinase inhibitor for dry eye disease: results from a phase 1/2 trial.

OBJECTIVE: To evaluate safety and efficacy of topical ophthalmic tofacitinib (CP-690,550), a novel Janus kinase inhibitor, in treating dry eye disease (DED). DESIGN: A phase 1/2 prospective, randomized, double-masked, multicenter, vehicle- and comparator-controlled trial (NCT00784719). PARTICIPANTS: Patients (n = 327) 18 years of age and older with a DED diagnosis for 6 months or more. METHODS: Tofacitinib (0.0003% twice daily, n = 46; 0.001% in both eyes twice daily, n = 47; 0.003% twice daily, n = 48; 0.005% twice daily, n = 48; 0.005% once daily, n = 44) results were compared with those of groups receiving active treatment cyclosporine ophthalmic emulsion 0.05% twice daily (n = 47) and vehicle twice daily (n = 47). Safety and efficacy evaluations were performed at baseline and throughout the 8-week study. MAIN OUTCOME MEASURES: Schirmer wetting, corneal staining, tear film break-up time, conjunctival staining, Ocular Comfort Index (OCI), and Ocular Surface Disease Index (OSDI). RESULTS: All tofacitinib doses were well tolerated, exhibiting better patient-reported ocular tolerability than cyclosporine. For the proportion of patients achieving 10 mm or more Schirmer wetting (without anesthesia) at week 8 (primary end point), greater response rates were observed in the tofacitinib 0.001% twice daily (27.3%), 0.005% twice daily (25.5%), and 0.005% once daily (26.1%) groups versus vehicle (20.0%); however, the differences were not statistically significant. Mean increase in Schirmer wetting (without anesthesia) from baseline was statistically significant (P<0.2, 2-sided) for all tofacitinib doses (1.7-3.1 mm), cyclosporine (3.9 mm), and vehicle (1.4 mm). For corneal staining (total score), significant improvement (reduction) from baseline was observed for all tofacitinib doses (-0.9 to -1.9) and vehicle (-2.0), but not for cyclosporine. The proportion of patients with complete corneal clearing (CCC; 100%) at week 8 was greatest with tofacitinib 0.005% once daily (15.9%) versus vehicle (6.7%). Symptom scores (OCI, OSDI) at week 8 showed significant improvements from baseline for all tofacitinib groups, and tofacitinib demonstrated greater improvements than cyclosporine. The tofacitinib 0.005% once daily group showed significant improvements in both a sign (Schirmer wetting without anesthesia) and symptom (OSDI environmental triggers subscale) versus vehicle and also demonstrated the highest response rate for CCC (16.7%) at week 8. CONCLUSIONS: This phase 1/2 study of tofacitinib demonstrated a trend for improving both signs and symptoms of dry eye. All doses of tofacitinib exhibited a reasonable safety profile and were well tolerated by patients with DED.

Improving awareness, identification, and management of meibomian gland dysfunction.

Ocular surface disorder--and dry eye, in particular--is a leading reason for visits to eye care professionals. It has been generally accepted that meibomian gland dysfunction (MGD) is a leading cause of evaporative dry eye, as well as being associated with aqueous-deficient dry eye. Yet, researchers and clinicians have lacked a global consensus on the definition of MGD, its epidemiology, pathophysiology, and management. Various systemic diseases and medications have been associated with the progression of both dry eye and MGD, as have several ocular disorders beyond those directly affecting the surface. It is in the best interest of patients for clinicians to be able to better identify and diagnose MGD, differentiating it from other ocular surface disorders, and to recognize the effects of MGD on the ocular surface, and thus initiate appropriate therapy. This CME activity provides expert insight into the Tear Film and Ocular Surface Society's International Workshop on MGD consensus report, offering practical application of its findings to better manage MGD patient care, particularly for those patients facing or undergoing ocular surgery.

Wax-tear and meibum protein, wax-ß-carotene interactions in vitro using infrared spectroscopy.

Protein-meibum and terpenoids-meibum lipid interactions could be important in the etiology of meibomian gland dysfunction (MGD) and dry eye symptoms. In the current model studies, attenuated total reflectance (ATR) infrared (IR) spectroscopy was used to determine if the terpenoid ß-carotene and the major proteins in tears and meibum affect the hydrocarbon chain conformation and carbonyl environment of wax, an abundant component of meibum. The main finding of these studies is that mucin binding to wax disordered slightly the conformation of the hydrocarbon chains of wax and caused the wax carbonyls to become hydrogen bonded or experience a more hydrophilic environment. Lysozyme and lactoglobulin, two proteins shown to bind to monolayers of meibum, did not have such an effect. Keratin and ß-carotene did not affect the fluidity (viscosity) or environment of the carbonyl moieties of wax. Based on these results, tetraterpenoids are not likely to influence the structure of meibum in the meibomian glands. In addition, these findings suggest that it is unlikely that keratin blocks meibomian glands by causing the meibum to become more viscous. Among the tear fluid proteins studied, mucin is the most likely to influence the conformation and carbonyl environment of meibum at the tear film surface.

Changes in human meibum lipid with meibomian gland dysfunction using principal component analysis.

Changes in the phase transition temperatures and conformation of human meibum lipid with age and meibomian gland dysfunction have been quantified but with analysis of less than 1% of the infrared spectral range. The remaining 99% of the spectral range was analyzed with principal component analysis (PCA) and confirms our previous studies and reveal further insights into changes that occur in meibum with age and disease. Infrared spectra of meibum from 41 patients diagnosed with meibomian gland dysfunction (Md) and 32 normal donors (Mn) were measured. Principal component analysis (PCA) was used to quantify the variance among the spectra and meibum protein was quantified using the infrared carbonyl and amide I and II bands. A training set of spectra was used to discriminate between Mn and Md with an accuracy of 93%. This shows that certain spectral regions (eigenvectors) contain compositional and structural information about the changes that occur with the principal component (variable), meibomian gland dysfunction. The spectral features of the major eigenvector indicate that Md contains more protein and relatively less CH(3) and cis = CH band intensity compared to Mn. The amount of protein was confirmed from relative infrared band intensities. Our study supports the idea that compositional differences result in meibum that is less fluid and more viscous with meibomian gland dysfunction so that less lipid flows out of the meibomian gland orifice as observed clinically. This study also demonstrates the power of the combination of infrared spectroscopy and PCA as a diagnostic tool that discriminates between Mn and Md.

Ocular surface effects of thyroid disease.

The orbital manifestations of ophthalmic Graves' disease have been appreciated since the first description of the disease many years ago. The effects of ophthalmic Graves' disease on the ocular surface, although some of the most bothersome and potentially damaging features of the disease, are often not as well appreciated. This review identifies and summarizes the manifestations of ocular surface disease attendant to ophthalmic Graves' disease and provides recommendations for clinical evaluation and management options to control the ocular surface problems.

Physical changes in human meibum with age as measured by infrared spectroscopy.

Both lipids and mucins contribute to the stability of the tear film and lipids may inhibit tears from evaporating. Younger people have lower lipid viscosity, higher lipid volume, and a lower rate of tear evaporation. Since age-related changes in human meibum composition and conformation have never been investigated, as a basis for the study of lipid-associated changes with meibomian gland dysfunction, we used the power of infrared spectroscopy to characterize hydrocarbon chain conformation and packing in meibum from humans without dry eye symptoms in relation to age and sex. Meibum from normal human donors ranging in age from 3 to 88 years was studied. Meibum phase transitions were quantified by fitting them to a 4-parameter 2-state sigmoidal equation. Human meibum order and phase transition temperatures decrease with age and this trend may be attributed to lipid compositional changes. If meibum has the same thermodynamic properties on the surface of the tears as it does on the lid margin, a decrease in lipid-lipid interaction strength with increasing age could decrease the stability of tears since lipid-lipid interactions on the tear surface must be broken for the tear film to break up. This study also serves as a foundation to examine meibum conformational differences in meibum from people with meibomian gland dysfunction.

Meibomian gland dysfunction: the past, present, and future.

OBJECTIVE: To recount the historic evaluation of meibomian gland dysfunction (MGD) and describe new techniques to monitor disease and therapy. METHODS: A review of the literature regarding the description of MGD and the role of abnormalities of meibomian gland secretion in health and disease. RESULTS: Meibomian gland dysfunction is a common clinical condition and is a major cause of evaporative dry eye with associated discomfort, visual disturbance, and contact lens intolerance. Despite the early description of the anatomy and physiology of the meibomian gland, recognition of the importance of the MGD and particularly therapeutic options to treat it has been limited. CONCLUSIONS: Improved methods of spectroscopic and chemical analysis of the meibomian gland secretion in health and disease are providing a better understanding of the physical and chemical abnormalities of the meibomian gland secretions and are allowing better evaluation of medical therapies.

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.

MUC1 and estrogen receptor alpha gene polymorphisms in dry eye patients.

Dry eye syndrome is a collection of common disorders of multifactorial etiology. Although the epidemiology of dry eye has been well studied, reports of genetic patterns that might influence susceptibility to dry eye are few. We reported that the frequency of non-Sjögren's aqueous-deficient dry eye patients expressing only the MUC1/A splice variant of the mucin MUC1 may be lower than that of a normal control group [Imbert, Y., Darling, D.S., Jumblatt, M.M., Foulks, G.N., Couzin, E.G., Steele, P.S., Young, W.W., Jr., 2006. MUC1 splice variants in human ocular surface tissues: possible differences between dry eye patients and normal controls. Exp. Eye Res. 83, 493-501]. Also, He et al. [He, Y., Li, X., Bao, Y., Sun, J., Liu, J., 2006. The correlation of polymorphism of estrogen receptor gene to dry eye syndrome in postmenopausal women. Yan. Ke. Xue. Bao. 22, 233-236] reported a difference between Chinese dry eye and control groups in the frequency of a polymorphism in estrogen receptor alpha (ERalpha). In the present study we determined the statistical significance and generality of these observations and tested if the MUC1 splice variant difference between subject groups reflected a difference in the MUC1 variable number of tandem repeat (VNTR) size class. There was a perfect correlation between the MUC1/A or MUC1/B splice variant pattern and the SNP genotype frequency of the SNP (rs4072037) controlling that splicing event. In contrast, western and Southern blotting indicated that MUC1 VNTR size class corresponded to the MUC1 SNP genotype in only 80% of cases. We determined the status of the MUC1 SNP in normal and dry eye populations all of whom were female Caucasians. The MUC1 SNP genotype frequency of the normal control group was statistically different from both the non-Sjögren's aqueous-deficient dry eye group with ocular surface staining (P=0.017) and the evaporative dry eye group (P=0.015). We also tested SNP rs2234693 to analyze the polymorphism in the ERalpha gene and found no significant difference in the SNP genotype frequency between the control group and either of the dry eye subtypes. Thus, among Caucasians there is no evidence for an association of the ERalpha gene polymorphism with dry eye syndrome as previously described in a Chinese population. In conclusion, the etiologies of evaporative dry eye and non-Sjögren's aqueous-deficient dry eye are known to be different. However, our results suggest that both of these subtypes of dry eye disease may share a common mechanism or factor related to MUC1 genotypic differences that affects susceptibility to ocular surface damage. This altered susceptibility may not be related to the MUC1 VNTR size class. Therefore, mechanisms influencing protection of the ocular surface against inflammation and damage in different types of dry eye disease warrant further investigation particularly in relation to MUC1 genotype.

Factors affecting evaporation rates of tear film components measured in vitro.

OBJECTIVES: With increasing age and in patients affected with dry-eye symptoms, the human tear film becomes more unstable and exhibits shorter tear break-up times. We examined whether the inclusion of proteins and lipids to water affected the evaporation rates measured in vitro and could account for the lower rates reported previously from in vivo measurements. The impact of temperature, air flow, and humidity on the evaporation rate of tears was measured in vitro. METHODS: Lipid-protein interactions were measured using fluorescence spectroscopy and in vitro rates of evaporation were performed gravimetrically. RESULTS: Human reflex tears evaporated at a rate similar to that of water. A temperature increase from 25 degrees C to 34 degrees C caused a threefold increase in the evaporation rates of tears in still air. Further increases were observed under a current of dry air. Wax, mucin, lysozyme, or beta-lactoglobulin did not influence significantly the rates of evaporation measured in vitro. In contrast, lipid layered on the surface resulted in a 23% decrease in the rates. CONCLUSIONS: Environmental factors affect evaporation rates significantly and should be carefully controlled when performing in vivo measurements. The presence of a lipid layer lowers evaporation rates. The significantly lower rates of evaporation of tears measured in vivo suggest that with the lipid layer intact, the high reserve capacity of the lacrimal gland to provide both unstimulated and stimulated tear flow is more than enough to compensate for evaporative loss. However, with dry eye, increased rates of evaporation and decreased lacrimal tear flow could result in decreased break-up times.

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.

Pharmacological management of dry eye in the elderly patient.

Dry eye disease is a common and increasingly prevalent condition particularly associated with advancing age and postmenopausal women. Epidemiological studies identify prevalence rates ranging from 7% in the US to 33% in the Asian population. Research increasingly identifies risk factors of increasing age, female sex, smoking, use of video display terminals and use of certain medications as well as environmental stresses as aggravating factors for the disease. Basic and clinical investigations provide cumulative evidence of hyperosmolarity of the tear film and ocular surface/lacrimal gland inflammation as pathogenic features of dry eye disease. A decline in systemic and local levels of sex hormones is associated with advancing age and advancing disease. Pharmacological therapeutic interventions include enhanced lubricants and anti-inflammatory drugs such as topical corticosteroids and ciclosporin (cyclosporine A). Secretagogues and hormonal supplementation are potential future therapies. The increased understanding of the contributing and pathogenetic factors responsible for dry eye provides a rationale for multiple therapeutic options for this multi-factorial disease. In the elderly patient it is important to recognize the physical and cognitive limitations that will influence the selection of appropriate topical medication.

The correlation between the tear film lipid layer and dry eye disease.

Dry eye, also known as keratoconjunctivitis sicca, can be due either to insufficient tear production or excessive tear evaporation, both resulting in tear hyperosmolarity that leads to symptoms of discomfort and ocular damage. Additionally, the severity of dry eye symptoms appears to be correlated to lipid layer thickness. It is now generally recognized that increased evaporation due to a compromised lipid layer is one of the most common etiologies for hyperosmolarity of the tear film. Thus, therapies targeted at replenishing or stabilizing the lipid layer are key to the treatment of dry eye, either as monotherapy or in conjunction with therapies designed to enhance aqueous production.

Spectroscopic evaluation of human tear lipids.

Infrared and fluorescence spectroscopies were applied to characterize the molecular conformational/structure and dynamics of human meibum (ML) and tear lipids (SSL). ML lipids contained more CC and CH3 moieties than SSL. SSL contained OH groups that were not apparent in the spectra of ML. The CO stretching band observed in the infrared spectra of SSL and ML revealed that the CO groups are not involved in hydrogen bonds. Bands due to the polar moieties CO and PO2- did not change significantly with increasing temperature, suggesting that they may not play an appreciable thermodynamic role in the lipid hydrocarbon chain phase transition. Components in tears bind to SSL and exclude water at the water-lipid boundary where the polar headgroups of phospholipids are located. If similar interactions occur in vivo at the tear film lipid-aqueous interface, they would reduce the rate of evaporation. The results provide a foundation for future studies to assess possible differences with age and sex in tears from normal and dry eye subjects.