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.

PURPOSE: Prisms used for field expansion are limited by the optical scotoma at a prism apex (apical scotoma). For a patient with two functioning eyes, fitting prisms unilaterally allows the other eye to compensate for the apical scotoma. A monocular patient's field loss cannot be expanded with a conventional or Fresnel prism because of the apical scotoma. A newly invented optical device, the multiplexing prism (MxP), was developed to overcome the apical scotoma limitation in monocular field expansion. METHODS: A Fresnel-prism-like device with alternating prism and flat elements superimposes shifted and see-through views, thus creating the (monocular) visual confusion required for field expansion and eliminating the apical scotoma. Several implementations are demonstrated and preliminarily evaluated for different monocular conditions with visual field loss. The field expansion of the MxP is compared with the effect of conventional prisms using calculated and measured perimetry. RESULTS: Field expansion without apical scotomas is shown to be effective for monocular patients with hemianopia or constricted peripheral field. The MxPs are shown to increase the nasal field for a patient with only one eye and for patients with bitemporal hemianopia. The MxPs placed at the far temporal field are shown to expand the normal visual field. The ability to control the contrast ratio between the two images is verified. CONCLUSIONS: A novel optical device is demonstrated to have the potential for field expansion technology in a variety of conditions. The devices may be inexpensive and can be constructed in a cosmetically acceptable format.

Genetic associations for keratoconus could be useful for understanding disease pathogenesis and discovering biomarkers for early detection of the disease. We conducted a systematic review and meta-analysis to summarize all reported genetic associations for the disease. We searched in the MEDLINE, Embase, Web of Science, and HuGENET databases for genetic studies of keratoconus published from 1950 to June 2016. The summary odds ratio and 95% confidence intervals of all polymorphisms were estimated using the random-effect model. Among 639 reports that were retrieved, 24 fulfilled required criteria as eligible studies for meta-analysis, involving a total of 53 polymorphisms in 28 genes/loci. Results of our meta-analysis lead to the prioritization of 8 single-nucleotide polymorphisms (SNPs) in 6 genes/loci for keratoconus in Whites. Of them 5 genes/loci were originally detected in genome-wide association studies, including FOXO1 (rs2721051, P = 5.6 × 10(-11)), RXRA-COL5A1 (rs1536482, P = 2.5 × 10(-9)), FNDC3B (rs4894535, P = 1.4 × 10(-8)), IMMP2L (rs757219, P = 6.1 × 10(-7); rs214884, P = 2.3 × 10(-5)), and BANP-ZNF469 (rs9938149, P = 1.3 × 10(-5)). The gene COL4A4 (rs2229813, P = 1.3 × 10(-12); rs2228557, P = 4.5 × 10(-7)) was identified in previous candidate gene studies. We also found SNPs in 10 genes/loci that had a summary P value < 0.05. Sensitivity analysis indicated that the results were robust. Replication studies and understanding the roles of these genes in keratoconus are warranted.

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.

OBJECTIVE: To examine the efficacy of various disinfection methods for reusable tonometer prisms in eye care and to highlight how disinfectants can damage tonometer tips and cause subsequent patient harm. METHODS: Literature searches were conducted last in October 2016 in the PubMed and the Cochrane Library databases for original research investigations. Reviews, non-English language articles, nonophthalmology articles, surveys, and case reports were excluded. RESULTS: The searches initially yielded 64 unique citations. After exclusion criteria were applied, 10 laboratory studies remained for this review. Nine of the 10 studies used tonometer prisms and 1 used steel discs. The infectious agents covered in this assessment include adenovirus 8 and 19, herpes simplex virus (HSV) 1 and 2, human immunodeficiency virus 1, hepatitis C virus, enterovirus 70, and variant Creutzfeldt-Jakob disease. All 4 studies of adenovirus 8 concluded that after sodium hypochlorite (dilute bleach) disinfection, the virus was undetectable, but only 2 of the 4 studies found that 70% isopropyl alcohol (e.g., alcohol wipes or soaks) eradicated all viable virus. All 3 HSV studies concluded that both sodium hypochlorite and 70% isopropyl alcohol eliminated HSV. Ethanol, 70% isopropyl alcohol, dilute bleach, and mechanical cleaning all lack the ability to remove cellular debris completely, which is necessary to prevent prion transmission. Therefore, single-use tonometer tips or disposable tonometer covers should be considered when treating patients with suspected prion disease. Damage to tonometer prisms can be caused by sodium hypochlorite, 70% isopropyl alcohol, 3% hydrogen peroxide, ethyl alcohol, water immersion, ultraviolet light, and heat exposure. Disinfectants can cause tonometer tips to swell and crack by dissolving the glue that holds the hollow tip together. The tonometer tip cracks can irritate the cornea, harbor microbes, or allow disinfectants to enter the interior of the tonometer tip. CONCLUSIONS: Sodium hypochlorite (dilute bleach) offers effective disinfection against adenovirus and HSV, the viruses commonly associated with nosocomial outbreaks in eye care. Tonometer prisms should be examined regularly for signs of damage.

PURPOSE: To determine sensitivity and specificity of laser-scanning in vivo confocal microscopy (LS-IVCM) for detection of filamentous fungi in patients with microbial keratitis and to evaluate the effect of observer's imaging experience on these parameters. DESIGN: Retrospective reliability study. METHODS: This study included 21 patients with filamentous fungal keratitis and 24 patients with bacterial keratitis (as controls). The etiology of infection was confirmed based on the response to specific therapy regardless of culture results. All patients had undergone full-thickness corneal imaging by a LS-IVCM (Heidelberg Retina Tomograph 3 with Rostock Cornea Module; Heidelberg Engineering, Heidelberg, Germany). The images were evaluated for the presence of fungal filaments by 2 experienced observers and 2 inexperienced observers. All observers were masked to the clinical and microbiologic data. RESULTS: The mean number of images obtained per eye was 917 ± 353. The average sensitivity of LS-IVCM for detecting fungal filaments was 71.4% ± 0% for the experienced observers and 42.9% ± 6.7% for the inexperienced observers. The average specificity was 89.6% ± 3.0% and 87.5% ± 17.7% for these 2 groups of observers, respectively. Although there was a good agreement between the 2 experienced observers (κ = 0.77), the inexperienced observers showed only a moderate interobserver agreement (κ = 0.51). The LS-IVCM sensitivity was higher in patients with fungal infections who had positive culture or longer duration of the disease. CONCLUSIONS: Although LS-IVCM has a high specificity for diagnosing filamentous fungal keratitis, its sensitivity is moderate and highly dependent on the level of the observer's experience and training with this imaging modality.

The National Eye Institute launched the Audacious Goals Initiative (AGI) in 2013 with the aim "to restore vision through the regeneration of neurons and neural connections in the eye and visual system." An AGI Town Hall held at the Association for Research in Vision and Ophthalmology Annual Meeting in 2016 brought together basic, translational, and clinical scientists to address the clinical implications of the AGI, with a particular emphasis on diseases amenable to regenerative medicine and strategies to deal with barriers to progess. An example of such a barrier is that replacement of lost neurons may be insufficient because damage to other neurons and non-neuronal cells is common in retinal and optic nerve disease. Reparative processes such as gliosis and fibrosis also can make it difficult to replenish and regenerate neurons. Other issues include choice of animal models, selecting appropriate endpoints, ethics of informed consent, and regulatory issues. Another area critical to next steps in the AGI is the choice of target diseases and the stage at which early development studies should be focused. For example, an advantage of doing clinical trials in patients with early disease is that supporting cellular and structural constituents are still likely to be present. However, regenerative studies in patients with late disease make it easier to detect the effects of replacement therapy against the background of severe visual loss, whereas it may be harder to detect incremental improvement in visual function in those with early disease and considerable remaining visual function. Achieving the goals of the AGI also requires preclinical advances, new imaging techniques, and optimizing translational issues. The work of the AGI is expected to take at least 10 years but should eventually result in therapies to restore some degree of vision to the blind.

Pathological angiogenesis in the eye is an important feature in the pathophysiology of many vision-threatening diseases, including retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration, as well as corneal diseases with abnormal angiogenesis. Development of reproducible and reliable animal models of ocular angiogenesis has advanced our understanding of both the normal development and the pathobiology of ocular neovascularization. These models have also proven to be valuable experimental tools with which to easily evaluate potential antiangiogenic therapies beyond eye research. This review summarizes the current available animal models of ocular angiogenesis. Models of retinal and choroidal angiogenesis, including oxygen-induced retinopathy, laser-induced choroidal neovascularization, and transgenic mouse models with deficient or spontaneous retinal/choroidal neovascularization, as well as models with induced corneal angiogenesis, are widely used to investigate the molecular and cellular basis of angiogenic mechanisms. Theoretical concepts and experimental protocols of these models are outlined, as well as their advantages and potential limitations, which may help researchers choose the most suitable models for their investigative work.-Liu, C.-H., Wang, Z., Sun, Y., Chen, J. Animal models of ocular angiogenesis: from development to pathologies.

Cancer stem-like cell (CSC) model has been established to investigate the underlying mechanisms of tumor initiation and progression. The imbalance between acetylation and deacetylation of histone or non-histone proteins, one of the important epigenetic modification processes, is closely associated with a wide variety of diseases including cancer. Acetylation and deacetylation are involved in various stemness-related signal pathways and drive the regulation of self-renewal and differentiation in normal developmental processes. Therefore, it is critical to explore their role in the maintenance of cancer stem-like cell traits. Here, we will review the extensive dysregulations of acetylation found in cancers and summarize their functional roles in sustaining CSC-like properties. Additionally, the use of deacetyltransferase inhibitors as an effective therapeutic strategy against CSCs is also discussed.

Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a neurological syndrome characterized by small vessel disease (SVD), stroke, and vascular cognitive impairment and dementia caused by mutations in NOTCH3 No therapies are available for this condition. Loss of mural cells, which encompass pericytes and vascular smooth muscle cells, is a hallmark of CADASIL and other SVDs, including diabetic retinopathy, resulting in vascular instability. Here, we showed that Notch3 signaling is both necessary and sufficient to support mural cell coverage in arteries using genetic rescue in Notch3 knockout mice. Furthermore, we show that systemic administration of an agonist Notch3 antibody prevents mural cell loss and modifies plasma proteins associated with Notch3 activity, including endostatin/collagen 18α1 and Notch3 extracellular domain in mice with the C455R mutation, a CADASIL variant associated with Notch3 loss of function. These findings open opportunities for the treatment of CADASIL and other SVDs by modulating Notch3 signaling.

PURPOSE: To provide current estimates of the prevalence of diagnosed dry eye disease (DED) and associated demographics among US adults aged ≥18 years. DESIGN: Cross-sectional, population-based survey. METHODS: Data were analyzed from 75,000 participants in the 2013 National Health and Wellness Survey to estimate prevalence/risk of diagnosed DED overall, and by age, sex, insurance, and other demographic factors. We weighted the observed DED prevalence to project estimates to the US adult population and examined associations between demographic factors and DED using multivariable logistic regression. RESULTS: Based on weighted estimates, 6.8% of the US adult population was projected to have diagnosed DED (∼16.4 million people). Prevalence increased with age (18-34 years: 2.7%; ≥75 years: 18.6%) and was higher among women (8.8%; ∼11.1 million) than men (4.5%; ∼5.3 million). After adjustment, there were no substantial differences in prevalence/risk of diagnosed DED by race, education, or US census region. However, there was higher risk of diagnosed DED among those aged 45-54 years (odds ratio [OR]: 1.95; 95% confidence interval [CI]: 1.74-2.20) and ≥75 years (OR: 4.95; 95% CI: 4.26-5.74), vs those aged 18-34 years. Risk was also higher among women vs men (OR: 2.00; 95% CI: 1.88-2.13) and insured vs uninsured participants (OR: 2.12; 95% CI: 1.85-2.43 for those on government and private insurance vs none). CONCLUSIONS: We estimate that >16 million US adults have diagnosed DED. Prevalence is higher among women than men, increases with age, and is notable among those aged 18-34 years.

Current treatments for choroidal neovascularization, a major cause of blindness for patients with age-related macular degeneration, treat symptoms but not the underlying causes of the disease. Inflammation has been strongly implicated in the pathogenesis of choroidal neovascularization. We examined the inflammatory role of Toll-like receptor 2 (TLR2) in age-related macular degeneration. TLR2 was robustly expressed by the retinal pigment epithelium in mouse and human eyes, both normal and with macular degeneration/choroidal neovascularization. Nuclear localization of NF-κB, a major downstream target of TLR2 signaling, was detected in the retinal pigment epithelium of human eyes, particularly in eyes with advanced stages of age-related macular degeneration. TLR2 antagonism effectively suppressed initiation and growth of spontaneous choroidal neovascularization in a mouse model, and the combination of anti-TLR2 and antivascular endothelial growth factor receptor 2 yielded an additive therapeutic effect on both area and number of spontaneous choroidal neovascularization lesions. Finally, in primary human fetal retinal pigment epithelium cells, ligand binding to TLR2 induced robust expression of proinflammatory cytokines, and end products of lipid oxidation had a synergistic effect on TLR2 activation. Our data illustrate a functional role for TLR2 in the pathogenesis of choroidal neovascularization, likely by promoting inflammation of the retinal pigment epithelium, and validate TLR2 as a novel therapeutic target for reducing choroidal neovascularization.

OBJECTIVE: Emotion processing is known to be mediated by a complex network of cortical and subcortical regions with evidence of specialized hemispheric lateralization within the brain. In light of prior evidence indicating that lateralization of cognitive functions (such as language) may depend on normal visual development, we investigated whether the lack of prior visual experience would have an impact on the development of specialized hemispheric lateralization in emotional processing. METHOD: We addressed this issue by comparing performance in early blind and sighted controls on a dichotic listening task requiring the detection of specific emotional vocalizations (i.e., suggestive of happiness or sadness) presented independently to either ear. RESULTS: Consistent with previous studies, we found that sighted individuals showed enhanced detection of positive vocalizations when presented in the right ear (i.e., processed within the left hemisphere) and negative vocalizations when presented in the left ear (i.e., right hemisphere). It is interesting to note that although blind individuals were as accurate as sighted controls in detecting the valance of the vocalization, performance was not consistent with any pattern of specialized hemispheric lateralization. CONCLUSIONS: Overall, these results suggest that although the lack of prior visual experience may not lead to impaired emotion processing performance, the underlying neurophysiological substrate (i.e., degree of special hemispheric lateralization) may depend on normal visual development. (PsycINFO Database Record

PURPOSE: To present pre-papillary vitreous opacity as an uncommon manifestation of inflammation in Behçet's disease that may be specific to this uveitic entity. METHODS: We retrospectively reviewed the charts of 67 patients with Behçet's disease examined at our clinic between 2005 and 2016. Behçet's disease was diagnosed based on established clinical criteria of inflammation involving the eyes, mucocutaneous junctions, and skin. Patients with Behçet's disease who presented with papillitis and a pre-papillary vitreous opacity were identified. Response to anti-inflammatory treatment on examination and optical coherence tomography imaging were evaluated. PubMed searches were performed for (1) other cases with pre-papillary vitreous opacities in uveitic entities and (2) reports of optic nerve involvement specifically in Behçet's disease. RESULTS: We identified three patients with Behçet's disease who presented with unilateral papillitis and a pre-papillary vitreous opacity. The pre-papillary vitreous opacity had a funnel-shaped appearance on optical coherence tomography. All patients were initially treated with steroids, which led to resolution of the opacity clinically and on imaging. We identified one previous report of such a pre-papillary opacity in a patient with Behçet's disease, and no reports of this finding in other uveitic entities. CONCLUSION: This study expands the number of Behçet's disease cases presenting with a pre-papillary vitreous opacity and demonstrates novel optical coherence imaging of this finding. This finding may be specific to Behçet's disease as it was not identified in other uveitic entities in a review of the existing literature.

OBJECTIVE: To prospectively examine gait characteristics of participants acutely after concussion with and without receded near point of convergence (NPC), compared with healthy controls. DESIGN: Cross-sectional study. SETTING: Sports-medicine clinic. PARTICIPANTS: Patients examined after concussion (n = 33; mean ± SD = 7.2 ± 3.1 days) and a group of uninjured athletes (n = 31) completed a Postconcussion Symptom Scale, underwent NPC testing, and single/dual-task gait assessments. INDEPENDENT VARIABLES: Near point of convergence was defined as the patient-reported diplopia distance when a fixation target moved toward the nose. Receded NPC was defined as a distance >5 cm from the tip of the nose. MAIN OUTCOME MEASURES: Spatiotemporal gait characteristics in single-task and dual-task conditions were evaluated with analysis of variance; correlations were calculated between NPC and gait measures. RESULTS: Eighteen of 33 (55%) patients with concussion presented with receded NPC. Those with receded NPC exhibited slower gait speed (single-task = 1.06 ± 0.14 m/s vs 1.19 ± 0.15 m/s; dual-task = 0.80 ± 0.13 m/s vs 0.94 ± 0.13 m/s; P = 0.003) and shorter stride lengths (single-task = 1.11 ± 0.10 m vs 1.24 ± 0.11 m; dual-task = 0.97 ± 0.11 m vs 1.09 ± 0.11 m; P = 0.001) than healthy controls. Near point of convergence was moderately correlated with dual-task average walking speed for the normal NPC group (ρ = -0.56; P = 0.05). Postconcussion Symptom Scale scores did not significantly differ between groups (27 ± 18 vs 28 ± 16). CONCLUSIONS: After concussion, adolescents with receded NPC exhibited significant gait-related deficits compared with healthy controls, whereas those with normal NPC did not. Vergence and gross motor system dysfunction may be associated after concussion. Gait and vergence measures may contribute useful information to postconcussion evaluations.

Angiogenesis, in which vascular endothelial growth factor receptor (VEGFR) 2 plays an essential role, is associated with a variety of human diseases including proliferative diabetic retinopathy and wet age-related macular degeneration. Here we report that a system of adeno-associated virus (AAV)-mediated clustered regularly interspaced short palindromic repeats (CRISPR)-associated endonuclease (Cas)9 from Streptococcus pyogenes (SpCas9) is used to deplete VEGFR2 in vascular endothelial cells (ECs), whereby the expression of SpCas9 is driven by an endothelial-specific promoter of intercellular adhesion molecule 2. We further show that recombinant AAV serotype 1 (rAAV1) transduces ECs of pathologic vessels, and that editing of genomic VEGFR2 locus using rAAV1-mediated CRISPR/Cas9 abrogates angiogenesis in the mouse models of oxygen-induced retinopathy and laser-induced choroid neovascularization. This work establishes a strong foundation for genome editing as a strategy to treat angiogenesis-associated diseases.Abnormal angiogenesis causes many ocular diseases. Here the authors employ CRISPR/Cas9 gene editing technology to silence VEGFR2, a major regulator of angiogenesis, in retinal endothelium and abrogate angiogenesis in the mouse models of oxygen-induced retinopathy and laser-induced choroid neovascularization.

Ocular adnexal smooth muscle masses/neoplasms are extremely rare. Such lesions are comparatively more common in the conjunctiva than in the orbit and are most unusual in the eyelid. A 58-year-old woman slowly developed over 4 months a firm, movable sausage-shaped lesion in the deep lateral half of the right lower eyelid. The lesion ran parallel to and above the orbital rim. At surgery, the lesion was located between the orbicularis muscle and the inferior orbital septum. The term ellipsoid is used descriptively and does not imply any particular biologic behavior. Immunohistochemical evaluation revealed smooth muscle actin and desmin positivity. Due to the ubiquity of small blood vessels and the absence of smooth muscle bundles in the potential space between the orbicularis striated muscle and the inferior orbital septum, venular smooth muscle emerges as a highly likely source for the lesion.

PURPOSE: To evaluate interobserver concordance in measured ocular redness among a group of raters using an objective computer-assisted method (ocular redness index [ORI]) and a group of clinicians using an ordinal comparative scale. METHODS: We conducted a prospective study to evaluate ocular redness in clinical photographs of 12 patients undergoing pterygium surgery. Photographs were acquired preoperatively, and at 1 week and 1 month postoperatively. One group of clinicians graded conjunctival redness in the photographs using an image-based comparative scale. A second group applied the ORI to measure redness in the same photographs. We evaluated redness change between time points, level of agreement among raters, and assessed redness score differences among observers within each group. RESULTS: Interobserver agreement using the image-based redness scale was 0.458 (P < 0.001). Interobserver agreement with the ORI was 0.997 (P < 0.001). We observed statistically significant differences among clinicians' measurements obtained with the image-based redness scale (P < 0.001). There were no significant differences among measurements obtained with the ORI (P = 0.27). We observed a significant change in redness between baseline and follow-up visits with all scoring methods. Detailed analysis of redness change was performed only in the ORI group due to availability of continuous scores. CONCLUSION: Our findings suggest that the ORI scores provide higher consistency among raters than ordinal scales, and can discriminate redness changes that clinical observers often can miss. TRANSLATIONAL RELEVANCE: The ORI may be a reliable alternative to measure ocular redness objectively in the clinic and in clinical trials.

PURPOSE: To evaluate the associations between optic disc (OD)-related anatomical parameters (interartery angle [IAA] between superior and inferior temporal retinal arteries, OD tilt [TL], rotation [ROT], and torsion [TO], OD surface curvature [CUR], and central retinal vessel trunk entry point location [CRVTL] on OD) and the spherical equivalent of refractive error (SE), and to assess the impact of glaucoma severity on these relationships. METHODS: Cirrus optical coherence tomography (OCT) fundus images and 24-2 visual fields of 438 patients were included. Ellipses were fitted to OD borders. IAA was calculated between marked retinal artery locations on a circle around OD. Blood vessel entry point on OD was marked to locate CRVTL. TL was measured as the angle between the lines fitted to OD clinical boundary and the Bruch's membrane edges on the horizontal B-scans. Ellipse rotation relative to the vertical axis defined ROT. Angle between the long axis of OD and the interartery line defined TO. CUR was determined by the inner limiting membrane on the horizontal B-scans. Linear regression models evaluated by Bayes Factors (BF) were used to determine the covariance structure between the parameters and SE as well as possible impacts of mean deviation (MD). RESULTS: Our results showed that CRVTL had the strongest relationship with SE, followed by ROT, TL, and IAA (BFs: 3.59 × 10(7), 2645, 1126, and 248, respectively). MD did not significantly modulate the relationship between ONH parameters and SE. CONCLUSION: Our results suggest that SE should be considered when interpreting the OD and its circumpapillary region for diagnostic purposes. TRANSLATIONAL RELEVANCE: The reported relationships between OD-related parameters and ametropia may help to decrease false-positive clinical diagnoses of optic neuropathies.

Pain associated with mechanical, chemical, and thermal heat stimulation of the ocular surface is mediated by trigeminal ganglion neurons, while cold thermoreceptors detect wetness and reflexly maintain basal tear production and blinking rate. These neurons project into two regions of the trigeminal brain stem nuclear complex: ViVc, activated by changes in the moisture of the ocular surface and VcC1, mediating sensory-discriminative aspects of ocular pain and reflex blinking. ViVc ocular neurons project to brain regions that control lacrimation and spontaneous blinking and to the sensory thalamus. Secretion of the main lacrimal gland is regulated dominantly by autonomic parasympathetic nerves, reflexly activated by eye surface sensory nerves. These also evoke goblet cell secretion through unidentified efferent fibers. Neural pathways involved in the regulation of meibomian gland secretion or mucin release have not been identified. In dry eye disease, reduced tear secretion leads to inflammation and peripheral nerve damage. Inflammation causes sensitization of polymodal and mechano-nociceptor nerve endings and an abnormal increase in cold thermoreceptor activity, altogether evoking dryness sensations and pain. Long-term inflammation and nerve injury alter gene expression of ion channels and receptors at terminals and cell bodies of trigeminal ganglion and brainstem neurons, changing their excitability, connectivity and impulse firing. Perpetuation of molecular, structural and functional disturbances in ocular sensory pathways ultimately leads to dysestesias and neuropathic pain referred to the eye surface. Pain can be assessed with a variety of questionaires while the status of corneal nerves is evaluated with esthesiometry and with in vivo confocal microscopy.

Human corneal endothelial cells (HCEnCs) are terminally differentiated cells that have limited regenerative potential. The large numbers of mitochondria in HCEnCs are critical for pump and barrier function required for corneal hydration and transparency. Fuchs Endothelial Corneal Dystrophy (FECD) is a highly prevalent late-onset oxidative stress disorder characterized by progressive loss of HCEnCs. We previously reported increased mitochondrial fragmentation and reduced ATP and mtDNA copy number in FECD. Herein, carbonyl cyanide m-chlorophenyl hydrazone (CCCP)-induced mitochondrial depolarization decreased mitochondrial mass and Mfn2 levels, which were rescued with mitophagy blocker, bafilomycin, in FECD. Moreover, electron transport chain complex (I, V) decrease in FECD indicated deficient mitochondrial bioenergetics. Transmission electron microscopy of FECD tissues displayed an increased number of autophagic vacuoles containing degenerated and swollen mitochondria with cristolysis. An elevation of LC3-II and LAMP1 and downregulation of Mfn2 in mitochondrial fractions suggested that loss of fusion capacity targets fragmented mitochondria to the pre-autophagic pool and upregulates mitophagy. CCCP-induced mitochondrial fragmentation leads to Mfn2 and LC3 co-localization without activation of proteosome, suggesting a novel Mfn2 degradation pathway via mitophagy. These data indicate constitutive activation of mitophagy results in reduction of mitochondrial mass and abrogates cellular bioenergetics during degeneration of post-mitotic cells of ocular tissue.

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-Sjögren 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.