The TFOS DEWS II Pathophysiology Subcommittee reviewed the mechanisms involved in the initiation and perpetuation of dry eye disease. Its central mechanism is evaporative water loss leading to hyperosmolar tissue damage. Research in human disease and in animal models has shown that this, either directly or by inducing inflammation, causes a loss of both epithelial and goblet cells. The consequent decrease in surface wettability leads to early tear film breakup and amplifies hyperosmolarity via a Vicious Circle. Pain in dry eye is caused by tear hyperosmolarity, loss of lubrication, inflammatory mediators and neurosensory factors, while visual symptoms arise from tear and ocular surface irregularity. Increased friction targets damage to the lids and ocular surface, resulting in characteristic punctate epithelial keratitis, superior limbic keratoconjunctivitis, filamentary keratitis, lid parallel conjunctival folds, and lid wiper epitheliopathy. Hybrid dry eye disease, with features of both aqueous deficiency and increased evaporation, is common and efforts should be made to determine the relative contribution of each form to the total picture. To this end, practical methods are needed to measure tear evaporation in the clinic, and similarly, methods are needed to measure osmolarity at the tissue level across the ocular surface, to better determine the severity of dry eye. Areas for future research include the role of genetic mechanisms in non-Sjogren syndrome dry eye, the targeting of the terminal duct in meibomian gland disease and the influence of gaze dynamics and the closed eye state on tear stability and ocular surface inflammation.

TFOS DEWS II pathophysiology report

Non-invasive wearable electrochemical sensors: a review

The tarsal glands of Meibom (glandulae tarsales) are large sebaceous glands located in the eyelids and, unlike those of the skin, are unassociated with hairs. According to Duke-Elder and Wyler,1 they were first mentioned by Galenus in 200 AD and later, in 1666, they were described in more detail by the German physician and anatomist Heinrich Meibom, after whom they are named.

Lipids produced by the meibomian glands are the main component of the superficial lipid layer of the tear film that protects it against evaporation of the aqueous phase and is believed also to stabilize the tear film by lowering surface tension.2 Hence, meibomian lipids are essential for the maintenance of ocular surface health and integrity.

Although they share certain principal characteristics with ordinary sebaceous glands, they have several distinct differences in anatomy, location, secretory regulation, composition of their secretory product, and function.

Functional disorders of the meibomian glands, referred to today as meibomian gland dysfunction (MGD),3 are increasingly recognized as a discrete disease entity.4–8 In patients with dry eye disease, alterations in the lipid phase that point to MGD are reportedly more frequent than isolated alterations in the aqueous phase. In a study by Heiligenhaus et al.,9 a lipid deficiency occurred in 76.7% of dry eye patients compared with only 11.1% of those with isolated alterations of the aqueous phase. This result is in line with the observations by Shimazaki et al.10 of a prevalence of MGD in the absolute majority of eyes with ocular discomfort defined as dry eye symptoms. These observations noted that 64.6% of all such eyes and 74.5% of those excluding a deficiency of aqueous tear secretion were found to have obstructive MGD, or a loss of glandular tissue, or both.10 Horwath-Winter et al.11 reported MGD in 78% of dry eye patients or, if only non-Sjogren patients are considered, in 87% compared with 13% with isolated aqueous tear deficiency. It may thus be accepted that MGD is important, conceivably underestimated, and possibly the most frequent cause of dry eye disease due to increased evaporation of the aqueous tears.5,9–12

After some excellent reviews of MGD4,7,8,13,14 in the past, many new findings have been reported in recent years, and other questions remain to be identified and resolved. A sound understanding of meibomian gland structure and function and its role in the functional anatomy of the ocular surface15 is needed, to understand the contribution of the meibomian glands to dysfunction and disease. Herein, we seek to provide a comprehensive review of physiological and pathophysiological aspects of the meibomian glands.

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The International Workshop on Meibomian Gland Dysfunction: Report of the Subcommittee on Anatomy, Physiology, and Pathophysiology of the Meibomian Gland

The members of the Management and Therapy Subcommittee undertook an evidence-based review of current dry eye therapies and management options. Management options reviewed in detail included treatments for tear insufficiency and lid abnormalities, as well as anti-inflammatory medications, surgical approaches, dietary modifications, environmental considerations and complementary therapies. Following this extensive review it became clear that many of the treatments available for the management of dry eye disease lack the necessary Level 1 evidence to support their recommendation, often due to a lack of appropriate masking, randomization or controls and in some cases due to issues with selection bias or inadequate sample size. Reflecting on all available evidence, a staged management algorithm was derived that presents a step-wise approach to implementing the various management and therapeutic options according to disease severity. While this exercise indicated that differentiating between aqueous-deficient and evaporative dry eye disease was critical in selecting the most appropriate management strategy, it also highlighted challenges, based on the limited evidence currently available, in predicting relative benefits of specific management options, in managing the two dry eye disease subtypes. Further evidence is required to support the introduction, and continued use, of many of the treatment options currently available to manage dry eye disease, as well as to inform appropriate treatment starting points and understand treatment specificity in relation to dry eye disease subtype.

TFOS DEWS II Management and Therapy Report

Most higher animals require sight for survival, yet even minor distortions of the visual axis can cause blindness. For this reason, intraocular inflammation is incompatible with good vision. Nature has found a way to provide the eye with immune protection against pathogens in a manner that greatly reduces the threat of inflammation-induced vision loss. Nature's way — known as 'immune privilege' — arises from anatomical, cellular and molecular specializations of the eye and the immune system. Knowledge of these unique characteristics indicates new ways to prevent and treat autoimmune and immunopathogenic diseases of the eye, as well as other organs and tissues, and to promote acceptance of cornea and other types of solid-tissue allograft.

Ocular immune privilege: therapeutic opportunities from an experiment of nature.

Background. The expression of Fas ligand (FasL) in the eye has been proposed to be an important component of ocular immune privilege. Since the unusually favorable outcome of corneal transplantation is thought to result from the immune privilege of the eye, examination of the function of FasL on corneal allografts would be a test of that hypothesis. Methods. To investigate the role of Fas-FasL interaction in corneal allografts, orthotopic corneal transplantation was performed using C57BL/6 (B6, FasL + ) and B6-gld (FasL - ) mice as cornea donors and BALB/c mice as recipients. The rejection rate of B6-gld grafts (FasL - group) was compared with that of normal B6 control corneas. Results. The rejection rate at the final observation (8 weeks) in the FasL - group (89%) was significantly higher than in the FasL + control group (47%). FasL expression was found on the corneal endothelium by staining with anti-FasL monoclonal antibodies. The TdT-mediated dUTP nick-end labeling assay revealed that apoptotic cells were attached to the endothelium in the control group but not in the FasL - groups. Conclusions. Apoptosis of infiltrating cells on the corneal endothelium resulting from Fas-FasL interaction plays an important role in the high success rate of corneal transplantation.

Role of Fas-Fas ligand interactions in the immunorejection of allogeneic mouse corneal transplants.

Purpose. To further evaluate the role of draining cervical lymph nodes (CLN) in high-risk (HR) corneal allografts performed in vascularized beds. Recently, we have shown that CLN are critical for promotion of allograft rejection in normal-risk corneal allografts. Methods. Fully mismatched HR orthotopic corneal transplantation was performed in BALB/c hosts that had their CLN excised before transplantation (CLN - ). Graft rejection and allospecific delayed-type hypersensitivity (DTH) were used as measures of alloreactivity. Numbers of interferon gamma (IFN-γ)- and interleukin 2 (IL-2)-expressing cells were compared among hosts that retained their native CLN (CLN+) and CLN - hosts. Additionally, splenectomized mice (Sp - ), and hosts without either CLN or spleen (CLN - Sp - ) were evaluated. Results. Within 5 weeks, 100% of HR grafts among CLN+ hosts were rejected, and hosts of these grafts uniformly demonstrated allospecific delayed-type hypersensitivity (DTH). In contrast, 92% of CLN - hosts accepted their HR allografts, and demonstrated suppressed allospecific DTH response. Moreover, significantly lower numbers of IFN-γ- and IL-2-expressing cells were infiltrating corneal grafts in CLN - group. All Sp - hosts rejected corneal allografts in an accelerated manner, whereas 86% of CLN - Sp - hosts accepted their allografts indefinitely. Conclusions. Draining CLN play a critical role in alloimmunity and rejection of HR corneal grafts, suggesting the essential function of CLN in corneal alloimmunization regardless of the degree of preoperative risk. Modulation of factors that regulate access of alloantigens or antigen-laden antigen-presenting cells to draining CLN may offer novel strategies in controlling induction of alloimmunity in corneal transplantation.

Draining lymph nodes play an essential role in alloimmunity generated in response to high-risk corneal transplantation.

Purpose To evaluate risk factors for graft failure and allograft rejection after penetrating keratoplasty (PK). Methods We retrospectively studied clinical results of PKs in terms of graft survival and rejection-free graft survival rates. PKs were done on 271 eyes between 1987 and 1997. Clinical results were analyzed by Kaplan-Meier's life table method and the log-rank test. Relative risks and adjusted survival probabilities for each value of the factor were compared with the risk for a specified reference value. Results The overall rates of graft survival and rejection-free graft survival in 10 years after PK were 79.3% and 77.9%, respectively. Higher relative risk of graft failure was associated with corneal vascularization (relative risk for within one quadrant = 1.67, two quadrants = 2.37, three or more quadrants = 3.39), regraft (relative risk for one failed previously graft = 2.08, two or more failed previously graft = 2.65), aphakia (relative risk = 2.17) or pseudophakia (relative risk = 3.02), presence of anterior synechia (relative risk = 2.91), presence of posterior synechia (relative risk = 2.56), long (more than 85 minutes) operation time (relative risk = 2.20), and older (more than 50 years) recipient age (relative risk = 2.38). Higher relative risk of rejection was associated with corneal vascularization (relative risk for within one quadrant = 2.35, two quadrants = 2.03, three or more quadrants = 2.63), long (more than 85 minutes) operation time (relative risk = 1.47), and younger (less than 60 years) donor age (relative risk = 2.10). There was no association between graft failure or allograft rejection and graft size or suture technique, respectively. Conclusion The risk factors for graft failure after PK were corneal vascularization, regraft, aphakia or pseudophakia, presence of anterior synechia, presence of posterior synechia, long operation time, and older recipient age. The risk factors after PK for allograft rejection were corneal vascularization, long operation time, and younger donor age.

Risk factors for corneal graft failure and rejection in penetrating keratoplasty

Purpose To evaluate the safety and efficacy of simultaneous Kamra corneal inlay implantation and laser in situ keratomileusis (LASIK) for the treatment of presbyopia in emmetropic, hyperopic, or myopic patients. Setting Private center, Tokyo, Japan. Design Cohort study. Methods Patients had bilateral LASIK with simultaneous implantation of a corneal inlay in the nondominant eye to treat presbyopia and ametropia between September 2009 and April 2010. The efficacy and safety were determined by the spherical equivalent (SE) in the eye with the inlay. Results The study enrolled 360 eyes of 180 patients with a mean age of 52.4 years ± 5.1 (SD) (range 41 to 65 years). Sixty-four patients were available for the 6-month postoperative examination. The mean logMAR uncorrected near visual acuity in the eye with the inlay improved 7 lines in hyperopic eyes, 6 lines in emmetropic eyes, and 2 lines in myopic eyes. The mean logMAR uncorrected distance visual acuity improved by 3 lines, 1 line, and 10 lines, respectively. Conclusions Simultaneous intracorneal inlay implantation and LASIK to treat presbyopia with emmetropia, hyperopia, or myopia was clinically safe and effective, yielding improvement in distance and near visual acuity. Patients were satisfied with decreased dependence on reading glasses regardless of the preoperative SE range. However, postoperative symptoms, such as dry eyes, halo, glare, or night-vision disturbances, occurred occasionally. Financial Disclosure Dr. Waring has a financial interest in and is world surgical monitor for Acufocus. No other author has a financial or proprietary interest in any material or method mentioned.

Simultaneous corneal inlay implantation and laser in situ keratomileusis for presbyopia in patients with hyperopia, myopia, or emmetropia: Six-month results

. We clarified the preoperative risk factors for graft failure in penetrating keratoplasty with fresh donor corneas. This analysis covered 698 consecutive keratoplasty cases in a single center between 1971 and 1992, and was designed to assess the risk factors. The risk factors in penetrating keratoplasty were determined by the Cox multiple regression model which considers the follow-up periods and multiple factors simultaneously. The factors which worsen the prognosis of keratoplasty significantly were found to be preoperative endothelial dysfunction (hazard ratio = 2.3), prior glaucoma/ocular hypertension (hazard ratio = 2.0), preoperative corneal vascularization (hazard ratio for within one quadrant = 1.3, hazard ratio for 2 or more quadrants = 1.6), anterior synechiae of iris (hazard ratio = 1.5), aphakia or pseudophakia (hazard ratio = 1.4), and older donor age (hazard ratio = 1.3 in proportion to the increase of each 10-year period of age). Surgeons must take these risk factors into consideration to obtain a better prognosis for keratoplasty.

Tadahiko Tsuru

Papers

Role of Fas-Fas ligand interactions in the immunorejection of allogeneic mouse corneal transplants.

Draining lymph nodes play an essential role in alloimmunity generated in response to high-risk corneal transplantation.

Risk factors for corneal graft failure and rejection in penetrating keratoplasty

Simultaneous corneal inlay implantation and laser in situ keratomileusis for presbyopia in patients with hyperopia, myopia, or emmetropia: Six-month results

Risk factors for graft failure in penetrating keratoplasty.