Corneal nerves in health and disease

The cornea is the most sensitive structure in the human body. Corneal nerves adapt to maintain transparency and contribute to corneal health by mediating tear secretion and protective reflexes and provide trophic support to epithelial and stromal cells. The nerves destined for the cornea travel from the trigeminal ganglion in a complex and coordinated manner to terminate between and within corneal epithelial cells with which they are intricately integrated in a relationship of mutual support involving neurotrophins and neuromediators. The nerve terminals/receptors carry sensory impulses generated by mechanical, pain, cold and chemical stimuli. Modern imaging modalities have revealed a range of structural abnormalities such as attrition of nerves in neurotrophic keratopathy and post-penetrating keratoplasty; hyper-regeneration in keratoconus; decrease of sub-basal plexus with increased stromal nerves in bullous keratopathy and changes such as thickening, tortuosity, coiling and looping in a host of conditions including post corneal surgery. Functionally, symptoms of hyperaesthesia, pain, hypoaesthesia and anaesthesia dominate. Morphology and function do not always correlate. Symptoms can dominate in the absence of any visible nerve pathology and vice-versa. Sensory and trophic functions too can be dissociated with pre-ganglionic lesions causing sensory loss despite preservation of the sub-basal nerve plexus and minimal neurotrophic keratopathy. Structural and/or functional nerve anomalies can be induced by corneal pathology and conversely, nerve pathology can drive inflammation and corneal pathology. Improvements in accuracy of assessing sensory function and imaging nerves in vivo will reveal more information on the cause and effect relationship between corneal nerves and corneal diseases

In vivo confocal microscopy features and clinicohistological correlation of limbal nerve corpuscles

Aims To describe the in vivo confocal microscopy (IVCM) features of human limbal nerve corpuscles (LNCs) and correlate these with the histological features.Methods We examined 40 eyes of 29 healthy living subjects (17 female, 12 male; mean age=47.6) by IVCM. Four limbal quadrants were scanned through all epithelial layers and stroma to identify the LNCs and associated nerves. Ten fresh normal human corneoscleral discs from five deceased patients with a mean age of 67 years and 17 eye-bank corneoscleral rims with a mean age of 57.6 years were stained as whole mounts by the acetylcholinesterase (AChE) method to demonstrate LNCs and corneal nerves. Stained tissue was scanned in multiple layers with the NanoZoomer digital pathology microscope. The in vivo results were correlated to the histological findings.Results On IVCM, LNCs were identified in 65% of the eyes studied and were mainly (84%) located in the inferior or superior limbal regions. They appeared either as bright (hyper-reflective) round or oval single structures within the hyporeflective, relatively acellular fibrous core of the palisades or were clustered in groups, often located anterior to the palisades of Vogt. They measured 36 µm in largest diameter (range 20–56 µm). The in vivo features were consistent with the histology, which showed LNCs as strongly AChE positive round or oval structures.Conclusion The strong correlation with histology will enable use of IVCM to study LNCs in normal and disease conditions

12-year analysis of incidence, microbiological profiles and in vitro antimicrobial susceptibility of infectious keratitis: the Nottingham Infectious Keratitis Study

Background/aims: To examine the incidence, causative microorganisms and in vitro antimicrobial susceptibility and resistance profiles of infectious keratitis (IK) in Nottingham, UK.Methods: A retrospective study of all patients who were diagnosed with IK and underwent corneal scraping between July 2007 and October 2019 (a 12-year period) at a UK tertiary referral centre. Relevant data, including demographic factors, microbiological profiles and in vitro antibiotic susceptibility of IK, were analysed.Results: The estimated incidence of IK was 34.7 per 100 000 people/year. Of the 1333 corneal scrapes, 502 (37.7%) were culture-positive and 572 causative microorganisms were identified. Sixty (4.5%) cases were of polymicrobial origin (caused by ≥2 different microorganisms). Gram-positive bacteria (308, 53.8%) were most commonly isolated, followed by Gram-negative bacteria (223, 39.0%), acanthamoeba (24, 4.2%) and fungi (17, 3.0%). Pseudomonas aeruginosa (135, 23.6%) was the single most common organism isolated. There was a significant increase in Moraxella spp (

Seasonal patterns of incidence, demographic factors and microbiological profiles of infectious keratitis: the Nottingham Infectious Keratitis Study

PurposeThe purpose of this study is to examine the seasonal patterns of incidence, demographic factors and microbiological profiles of infectious keratitis (IK) in Nottingham, UK.MethodsA retrospective study of all patients who were diagnosed with IK and underwent corneal scraping during 2008–2019 at a UK tertiary referral centre. Seasonal patterns of incidence (in per 100,000 population-year), demographic factors, culture positivity rate and microbiological profiles of IK were analysed.ResultsA total of 1272 IK cases were included. The overall incidence of IK was highest during summer (37.7, 95% confidence interval (CI): 31.3–44.1), followed by autumn (36.7, 95% CI: 31.0–42.4), winter (36.4, 95% CI: 32.1–40.8) and spring (30.6, 95% CI: 26.8–34.3), though not statistically significant (p = 0.14). The incidence of IK during summer increased significantly over the 12 years of study (r = 0.58, p = 0.049), but the incidence of IK in other seasons remained relatively stable throughout the study period. Significant seasonal variations were observed in patients’ age (younger age in summer) and causative organisms, including Pseudomonas aeruginosa (32.9% in summer vs. 14.8% in winter; p [less than] 0.001) and gram-positive bacilli (16.1% in summer vs. 4.7% in winter; p = 0.014).ConclusionThe incidence of IK in Nottingham was similar among four seasons. No temporal trend in the annual incidence of IK was observed, as reported previously, but there was a significant yearly increase in the incidence of IK during summer in Nottingham over the past decade. The association of younger age, P. aeruginosa and gram-positive bacilli infection with summer was likely attributed to contact lens wear, increased outdoor/water activity and warmer temperature conducive for microbial growth

Corneal Nerve Aberrations in Bullous Keratopathy

PurposeTo study the corneal nerves in patients with chronic bullous keratopathy.DesignProspective observational case series with histologic evaluation.MethodsWe studied 25 eyes of 25 bullous keratopathy patients of different etiologies (17 female, 8 male; mean age, 76.3 years) as well as 6 eyes of 6 normal control subjects (5 male, 1 female; mean age, 38 years). All subjects were scanned by laser scanning confocal microscope. Five corneal buttons obtained following penetrating keratoplasty from 5 of the above patients and 6 normal control corneal buttons were stained as whole mounts with acetylcholinesterase (AChE) method for corneal nerve demonstration and scanned in multiple layers with digital pathology scanning microscope.ResultsThe density, branching pattern, and diameter of sub-basal nerves were significantly lower in corneas with bullous keratopathy compared with normal corneas (density: 4.42 ± 1.91 mm/mm2 vs 20.05 ± 4.24 mm/mm2; branching pattern: 36.02% ± 26.57% vs 70.79% ± 10.53%; diameter: 3.07 ± 0.64 μm vs 4.57 ± 1.12 μm). Aberrations such as localized thickenings or excrescences, abnormal twisting, coiling, and looping of the (mid) stromal nerves were observed in the study group both by in vivo confocal microscopy and on histology.ConclusionsStriking alterations in corneal innervation are present in corneas with bullous keratopathy that are unrelated to any specific etiology of bullous keratopathy. This study provides histologic confirmation of novel in vivo confocal microscopy findings related to corneal nerves in bullous keratopathy

Nerve terminals at the human corneoscleral limbus

Aims: To demonstrate and characterise distinct subepithelial compact nerve endings (CNE) at the human corneoscleral limbus.Methods: Ten fresh human donor corneoscleral discs (mean age, 67 years) and 26 organ-cultured corneoscleral rims (mean age, 59 years) were studied. All samples were subjected to enzyme histochemical staining related to endogenous acetylcholinesterase present in nerve tissue and H&E staining. Whole-mount en face imaging with NanoZoomer digital pathology microscope and serial cross-section imaging with light microscope were undertaken.Results: Nerves entering the corneoscleral limbus and peripheral cornea terminate under the epithelium as enlarged multiloculated and multinucleated ovoid structures within a 2 mm zone. They are closely associated with the rete pegs of the limbal palisades and the limbal epithelial crypts, often located within characteristic stromal invaginations of these structures. Their numbers ranged from 70 to 300 per corneoscleral rim. The size ranged from 20 to 100 µm. They had one or more nerve connections and were interconnected to other similar endings and to the limbal nerve plexus.Conclusion: Human corneoscleral limbus demonstrates a population of nerve terminals resembling CNE with distinct morphological features. They are closely associated with the limbal stem cell niches, suggesting a potential contribution to the niche environment

Correlation of central and peripheral corneal thickness in healthy corneas

PurposeTo study the thickness profile of the normal cornea in order to establish any correlation between central and peripheral points.MethodsSixty-seven eyes of 40 patients were subjected to central corneal thickness measurement (CCT) with an ultrasound pachymeter (UP) and corneal thickness mapping with the Oculus Pentacam. The corneal apex thickness (CAT), pupil centre thickness (recorded as CCT and corresponded to CCT of UP) and thickness at the thinnest location (CTL) were obtained and compared with each other. Corneal thickness data at 3 mm and 7 mm temporally, nasally, superiorly and inferiorly from the corneal apex were obtained. The mean corneal thickness values along the 2, 4, 6, 8 and 10 mm diameter concentric circles, with the CTL as the centre, were also obtained. The above data at different points were statistically correlated.ResultsThere was no significant difference between CCT readings measured by UP and Pentacam (P = 0.721). There was high positive correlation between the CAT values and the thickness at 3 mm (R ≥ 0.845, P

Corneal Densitometry as an Indicator of Corneal Health

PurposeTo establish prospectively the normal values of corneal density of healthy subjects using the Pentacam Scheimpflug system (Oculus, Inc., Wetzlar, Germany) and to investigate alteration in corneal density during active and healed stages of bacterial keratitis.DesignProspective, comparative case series.Participants and ControlsSixty-four eyes of 40 healthy controls and 36 eyes of 35 patients with bacterial keratitis were studied.MethodsThis study was conducted at the Queen's Medical Centre, Nottingham, United Kingdom. A Pentacam system was used to study corneal density. Corneal densitometry readings in subjects with bacterial keratitis were recorded during the active stage and 4 to 6 weeks after complete healing. Densitometry was recorded at the site of infection and at a point in clear cornea furthest away from the infectious infiltrate. Corneal thickness also was measured.Main Outcome MeasuresDensitometry values of normal cornea, at the site of corneal ulcer or abscess, and at a distant point of clear cornea during active and healed keratitis.ResultsThe mean densitometry value of normal corneas was 12.3±2.4. In infectious keratitis, the densitometry values were greatest at the site of the active infection and significantly more than in controls. The densitometry values at the points of clear cornea furthest away from the site of infection also were significantly higher than in controls during active disease, but failed to return to normal values, despite complete resolution of infection. The density of the infiltrates was much higher than that of residual scars after healing of ulcers. No correlation was found between the pachymetry and the densitometry values.ConclusionsDensitometry of active infectious corneal infiltrates is more than that resulting from the corneal scarring after healing. Persistent increase in density of clear cornea furthest away from the focus of corneal infection suggests that the host response extends beyond the immediate area of infection and indeed may occur through the entire cornea. These changes persist beyond 4 weeks of healing, which was the duration of follow-up of this study. Densitometry can be used as an objective measure of the corneal response to infection and to monitor response to therapy