In vivo confocal microscopy (IVCM) is becoming an indispensable tool for studying corneal physiology and disease. Enabling the dissection of corneal architecture at a cellular level, this technique offers fast and noninvasive in vivo imaging of the cornea with images comparable to that of ex vivo histochemical techniques. Corneal nerves bear substantial relevance to clinicians and scientists alike, given their pivotal roles in regulation of corneal sensation, maintenance of epithelial integrity, and proliferation and promotion of wound healing. Thus, IVCM offers a unique method to study corneal nerve alterations in a myriad of conditions, such as ocular and systemic diseases and following corneal surgery, without altering the tissue microenvironment. Of particular interest has been the correlation of corneal subbasal nerves to their function, which has been studied in normal eyes, contact lens wearers, and patients with keratoconus, infectious keratitis, corneal dystrophies, and neurotrophic keratopathy. Longitudinal studies have applied IVCM to investigate the effects of corneal surgery on nerves, demonstrating their regenerative capacity. IVCM is increasingly important in the diagnosis and management of systemic conditions such as peripheral diabetic neuropathy and, more recently, in ocular diseases. In this review, we outline the principles and applications of IVCM in the study of corneal nerves in various ocular and systemic diseases.

Angiogenesis is the formation of new blood vessels from pre-existing vasculature. Pathologic angiogenesis in the eye can lead to severe visual impairment. In our review, we discuss the roles of both pro-angiogenic and anti-angiogenic molecular players in corneal angiogenesis, proliferative diabetic retinopathy, exudative macular degeneration and retinopathy of prematurity, highlighting novel targets that have emerged over the past decade.

Optimal vision is contingent upon transparency of the cornea. Corneal neovascularization, trauma and, surgical procedures such as photorefractive keratectomy and graft rejection after penetrating keratoplasty can lead to corneal opacification. In this article we identify the underlying basis of corneal transparency and factors that compromise the integrity of the cornea. With evidence from work on animal models and clinical studies, we explore the molecular mechanisms of both corneal avascularity and its dysfunction. We also seek to review therapeutic regimens that can safely salvage and restore corneal transparency

Proinflammatory tear cytokines are elevated bilaterally in patients with unilateral BK, and are correlated strongly with alterations in DCs and nerve density as detected by IVCM.

Monthly intraocular injections are widely used to deliver protein-based drugs that cannot cross the blood-retina barrier for the treatment of leading blinding diseases such as age-related macular degeneration (AMD). This invasive treatment carries significant risks, including bleeding, pain, infection, and retinal detachment. Further, current therapies are associated with a rate of retinal fibrosis and geographic atrophy significantly higher than that which occurs in the described natural history of AMD. A novel therapeutic strategy which improves outcomes in a less invasive manner, reduces risk, and provides long-term inhibition of angiogenesis and fibrosis is a felt medical need. Here we show that a single intravenous injection of targeted, biodegradable nanoparticles delivering a recombinant Flt23k intraceptor plasmid homes to neovascular lesions in the retina and regresses CNV in primate and murine AMD models. Moreover, this treatment suppressed subretinal fibrosis, which is currently not addressed by clinical therapies. Murine vision, as tested by OptoMotry©, significantly improved with nearly 40% restoration of visual loss induced by CNV. We found no evidence of ocular or systemic toxicity from nanoparticle treatment. These findings offer a nanoparticle-based platform for targeted, vitreous-sparing, extended-release, nonviral gene therapy.

Purpose To validate the Ocular Pain Assessment Survey (OPAS), specifically designed to measure ocular pain and quality of life for use by eye care practitioners and researchers. Design A single-center, cohort study was conducted in patients with and without corneal and ocular surface pain at initial and follow-up visits over a 6-month period. The content of the OPAS was guided by literature review, a body of experts, and incorporating conceptual frameworks from existing pain questionnaires. The Wong-Baker FACES® Pain Rating Scale served as the gold standard for measuring intensity of ocular pain. Subjects 102 patients aged 18 to 80 years completed the OPAS at the initial visit. 21 patients were followed up post-treatment. Methods and Statistical Analysis Indices of validity and internal consistency (Spearman’s rank-order, rs, or Pearson’s correlation coefficients, rp), and coefficient of reliability (Cronbach’s α) were determined in addition to equivalence testing, exploratory factor analysis (EFA) and diagnostic analysis. Main outcome measures Eye pain intensity was the primary outcome measure, while interference with quality of life (QoL), aggravating factors, associated factors, associated non-eye pain intensity and self-reported symptomatic relief were the secondary outcome measures. Results The OPAS had criterion validity at both initial (rs= 0.71, n= 102, P<0.01) and follow-up visits (rs= 0.97, n= 21, P<0.01). Equivalence tests yielded OPAS and gold standard equivalence for both the initial and follow-up visits. EFA supported 6 sub-scales (eye pain intensity 24 h and 2 weeks, non-eye pain intensity, quality of life, aggravating factors, and associated factors) confirming multi-dimensionality. Cronbach’s α >0.83 for all sub-scales established strong internal consistency, which correlated with the gold standard, including 24-hour eye pain intensity and QoL interference scores (rp = 0.81, 0.64, P< 0.001). At follow-up, reduction in pain scores was accompanied by improvement in all dimensions of the OPAS. Percent change in QoL correlated to percent change in the gold standard (rp = 0.53, P<0.05). The OPAS was sensitive (94%), specific (81%) and accurate (91%) with a diagnostic odds ratio greater than 50. Conclusions The OPAS is a valid, reliable and responsive tool with strong psychometric and diagnostic properties in the multi-dimensional quantification of corneal and ocular surface pain intensity, and quality of life.

Purpose To compare measurements of murine ocular axial lengths (AL) made with 780 nm partial coherence interferometry (PCI) and 1310 nm spectral domain–optical coherence tomography (SD-OCT). Methods AL was measured at postnatal day (P) 58 in C57BL/6J mice. Repeated AL measurements were taken using a custom-made 780 nm PCI and a commercial 1310 nm SD-OCT. Intra- and inter-user variability was assessed along the central optical axis as well as two-degree off-axes angles with the SD-OCT. Data were collected and analyzed using Cronbach’s alpha (α), Bland-Altman coefficient of repeatability (CR), agreement plots, and intra-class correlation coefficients (ICC). Results Axial length measurements agreed well between the two instruments (3.262 ± 0.042 mm for PCI; 3.264 ± 0.047 mm for SD-OCT; n= 20 eyes). The ICC for PCI compared to SD-OCT was 0.92, confirming high agreement between the two instruments. Intra-user ICC for the PCI and SD-OCT were 0.814 and 0.995, respectively. Similarly, inter-user ICC for PCI and SD-OCT were 0.970 and 0.943, respectively. Using SD-OCT, a two-degree misalignment of the eye along the horizontal meridian produced mean differences in AL of −0.002 ± 0.017 mm relative to the centrally aligned images, while similar misalignment along the vertical meridian created 0.005 ± 0.018 mm differences in AL measurements. Conclusions AL measurements from the 780 nm PCI and 1310 nm SD-OCT correlate well. Multiple statistical indices indicate that both instruments have good precision and agreement for measuring murine ocular axial length in vivo. While the vertical meridian had the greater variability in AL in the small mouse eye; two-degree off-axes differences were within the standard deviation of centrally aligned AL.

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