Gerd Geerling

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.).

Autologous serum eye drops for ocular surface disorders

Tears have antimicrobial, nourishing, mechanical, and optical properties. They contain components such as growth factors, fibronectin, and vitamins to support proliferation, migration, and differentiation of the corneal and conjunctival epithelium. A lack of these epitheliotrophic factors—for example, in dry eye, can result in severe ocular surface disorders such as persistent epithelial defects. Recently, the use of autologous serum in the form of eye drops has been reported as a new treatment for severe ocular surface disorders. Serum eye drops may be produced as an unpreserved blood preparation. They are by nature non-allergenic and their biomechanical and biochemical properties are similar to normal tears. In vitro cell culture experiments showed that corneal epithelial cell morphology and function are better maintained by serum than by pharmaceutical tear substitutes. Clinical cohort studies have reported its successful use for severe dry eyes and persistent epithelial defects. However, the protocols to prepare and use autologous serum eye drops varied considerably between the studies. As this can result in different biochemical properties protocol variations may also influence the epitheliotrophic effect of the product. Before the definitive role of serum eye drops in the management of severe ocular surface disease can be established in a large randomised controlled trial this has to be evaluated in more detail. In view of legislative restrictions and based upon the literature reviewed here a preliminary standard operating procedure for the manufacture of serum eye drops is proposed.

The International Workshop on Meibomian Gland Dysfunction: Report of the Subcommittee on Management and Treatment of Meibomian Gland Dysfunction

The goals of the subcommittee were to review the current practice and published evidence of medical and surgical treatment options for meibomian gland dysfunction (MGD) and to identify areas with conflicting, or lack of, evidence, observations, concepts, or even mechanisms where further research is required. To achieve these goals, a comprehensive review of clinical textbooks and the scientific literature was performed and the quality of published evidence graded according to an agreed on standard, using objective criteria for clinical and basic research studies adapted from the American Academy of Ophthalmology Practice Guidelines1 (Table 1). It should be noted that, in many of the clinical textbooks and previous reports, terminology is often interchanged and the management of anterior and posterior blepharitis and/or meibomitis is often considered concurrently. Thus, a broad scope of documents was reviewed in this process. Consistency in terminology and global adoption of the term “meibomian gland dysfunction” would significantly aid clinical research and clinical care in MGD going forward. Table 1. Grading Level of Evidence of Clinical and Basic Research Studies1

Role of Hyperosmolarity in the Pathogenesis and Management of Dry Eye Disease: Proceedings of the OCEAN Group Meeting

Dry eye disease (DED), a multifactorial disease of the tears and ocular surface, is common and has a significant impact on quality of life. Reduced aqueous tear flow and/or increased evaporation of the aqueous tear phase leads to tear hyperosmolarity, a key step in the vicious circle of DED pathology. Tear hyperosmolarity gives rise to morphological changes such as apoptosis of cells of the conjunctiva and cornea, and triggers inflammatory cascades that contribute to further cell death, including loss of mucin-producing goblet cells. This exacerbates tear film instability and drives the cycle of events that perpetuate the condition. Traditional approaches to counteracting tear hyperosmolarity in DED include use of hypotonic tear substitutes, which have relatively short persistence in the eye. More recent attempts to counteract tear hyperosmolarity in DED have included osmoprotectants, small organic molecules that are used in many cell types throughout the natural world to restore cell volume and stabilize protein function, allowing adaptation to hyperosmolarity. There is now an expanding pool of clinical data on the efficacy of DED therapies that include osmoprotectants such as erythritol, taurine, trehalose and L-carnitine. Osmoprotectants in DED may directly protect cells against hyperosmolarity and thereby promote exit from the vicious circle of DED physiopathology.

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.

Keratin films for ocular surface reconstruction

Human amniotic membrane (AM) is frequently used as a substrate for ocular surface reconstruction. Its disadvantages (e.g., reduced transparency and biomechanical strength, heterogeneity depending on donor) create the need for standardized alternatives. Keratin from hair or wool has been proposed as an appropriate material for producing films or cell cultivation scaffolds. The current study was performed to develop transparent, stable and transferable films based on human hair keratin that support cellular adhesion and proliferation. The films were engineered by a multi-step procedure including keratin extraction, neutral and alkaline dialysis, drying and a curing process. Keratin films were investigated by SDS-PAGE, SEM and X-ray analyses. Furthermore, swelling and water absorption of the films were studied, as were tensile strength and light transmission (UV/VIS). Finally, the growth behavior of corneal epithelial cells on the keratin films and AM was estimated in proliferation studies. In addition, we assessed the seeding efficiency and cell detachment behavior during trypsinization. The film-forming process resulted in transparent films composed of nanoparticulate keratin structures. The film characteristics could be varied by changing the protein composition, adding softening agents or varying the curing temperature and duration. Based on these findings, an optimized protocol was developed. The films showed improved light transmission and biomechanical strength in comparison to AM. Furthermore, cell behavior on the films was similar to that found on AM. We conclude that keratin films may represent a new, promising alternative for ocular surface reconstruction.

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.

Botulinum toxin treatment for hyperlacrimation secondary to aberrant regenerated seventh nerve palsy or salivary gland transplantation

Aim: To investigate the potential of botulinum toxin A for treating hyperlacrimation. Methods: Three patients with unilateral symptoms of hyperlacrimation (diagnosed as “crocodile tearing”) and one patient with a submandibular salivary gland transplant (SMGT) were studied. Tear production was quantified in the resting and stimulated (chewing or following exercise) state, using Schirmers test and tear clearance. Lacrimal scintigraphy was used to assess outflow. Intraglandular injections (for patients with “crocodile tears”) or periglandular injections (for the SMGT patient) of Dysport were administered in divided doses. Results: Two of the three eyes with reported gustatory lacrimation had a higher Schirmer test result than their fellow eye following gustatory stimulation. Scintigraphy, with and without stimulation, confirmed a patent drainage system in these patients. The other patient demonstrated a functional obstruction to tear flow. After treatment patients with confirmed gustatory lacrimation and the SMGT patient had a marked reduction in tearing at 2 weeks. This effect lasted 3–4 months. There was no demonstrable improvement in the patient with epiphora secondary to functional obstruction. Two patients who had received intraglandular injections developed a ptosis, which resolved spontaneously. Conclusions: This study illustrates that gustatory lacrimation is a difficult diagnosis. In post-facial nerve palsy a functional element must always be considered. However, in confirmed hyperlacrimation botulinum toxin treatment is effective but side effects may occur.

Anterior chamber angle measurement with optical coherence tomography: Intraobserver and interobserver variability

PURPOSE: To assess intraobserver and interobserver variability of anterior segment optical coherence tomography (AS‐OCT) as an objective diagnostic tool to quantify the anterior chamber angle and opening width. SETTING: University Eye Clinic, Lübeck, Germany. METHODS: The anterior chamber angle and opening width were assessed in 18 eyes of 9 healthy volunteers by 2 observers. Intraobserver reproducibility was evaluated by calculating an intraclass correlation coefficient (ICC) in a mixed model. Each observer had a separate model using information from 5 scans. Interobserver variability was determined by Bland‐Altman analysis. The ICC was calculated in a mixed model using a residual maximum likelihood method. The results of 3 and 5 repeated scans were evaluated to indicate the change to 1 measurement application. RESULTS: The mean anterior chamber angle measurement was 35.9 degrees ± 5.7 (SD) for observer A and 36.2 ± 5.7 degrees for observer B. The ICC was 0.94 and 0.91, respectively. The mean opening width was 315 ± 62 μm for observer A and 317 ± 60 μm for observer B. The ICC was 0.97 and 0.93, respectively. Interobserver comparisons showed a mean difference between anterior chamber angle measurements of −0.27 ± 1.6 degrees, a limit of agreement (LOA) interval from −3.52 to 2.98 degrees, and an ICC estimate of 0.96. The mean difference in opening width measurements was 2.40 ± 12.40 μm, the LOA from −27.20 to 22.40 μm, and the estimated ICC 0.96. Using 1 instead of the mean of 5 measurements, the LOA range increased by 3.46 degrees for the anterior chamber angle and 30.0 μm for the opening width. CONCLUSION: Anterior chamber angle and opening width measurements by OCT showed low intraobserver and interobserver variability, indicating OCT is a valuable technique for quantitative assessment that provides reproducible measurements and objective documentation by different examiners.

Evaluation of lipid layer thickness measurement of the tear film as a diagnostic tool for Meibomian gland dysfunction.

Purpose: The LipiView interferometer (TearScience Inc, Morrisville, NC) is capable of delivering quantitative values of the tear-film lipid layer thickness (LLT). The purpose of this study was to investigate whether there is a correlation between the LLT and other diagnostic criteria for Meibomian gland dysfunction (MGD). Methods: We performed a retrospective analysis of 110 patients (199 eyes) from our dry eye clinic. Subjective symptoms, break-up time (BUT), expressible Meibomian glands, and LLT were measured. Results: There was a significant correlation between expressible Meibomian glands and LLT (r = 0.36, P < 0.0001). Also, a possible trend of inverse correlation between subjective symptoms (standard patient evaluation of eye dryness) and the LLT was observed; however, this was not significant (r = −0.13, P < 0.08). Analysis of the whole study collective revealed no correlation between the BUT and the LLT (r = 0.003, P = 0.97). A subgroup analysis of the patients with an LLT ⩽ 60 showed a better correlation between the LLT and the BUT, which was marginally not significant (r = 0.21; P = 0.059). For a cut-off value of ⩽75-nm LLT, we found a sensitivity of 65.8% and a specificity of 63.4% for the detection of an MGD. For a cut-off value of ⩽60, the sensitivity was 47.9%, and the specificity was 90.2%. Conclusions: The positive correlation between the LLT and expressible meibomian glands found in this study suggests a higher probability of MGD in patients with a low LLT. This automated assessment of the LLT might be a suitable screening test for detecting MGD. However, further prospective studies are needed to confirm these results and to identify potential confounders.