Surgical management of infectious keratitis.

The successful management of infectious keratitis is usually achieved with a combination of tools for accurate diagnosis and targeted timely antimicrobial therapy. An armamentarium of surgical interventions is available in the acute stage which can be resorted to in a step wise manner or in combination guided by the response to treatment. Simple surgical modalities can facilitate accurate diagnosis e.g. corneal biopsy and alcohol delamination. Surgery to promote epithelial healing can vary from tarsorrhaphy, amniotic membrane transplantation or conjunctival flaps depending on the extent of infection, visual prognosis, availability of tissue and surgeon's experience. Collagen crosslinking has been increasingly utilized with successful results to strengthen the cornea and reduce the infective load consequently the need for further elaborate surgical interventions. It has shown encouraging results specially in superficial bacterial and fungal keratitis but for deeper infections, viral and acanthamoeba keratitis, its use remains questionable. When globe integrity is compromised, corneal gluing is the most commonly used procedure to seal small perforations. In larger perforations/fulminant infections a tectonic/therapeutic graft is advisable. Partial thickness grafts are increasingly popular to treat superficial infection or internally tamponade perforations. Peripheral therapeutic grafts face challenges with potential requirement for a manually fashioned graft, and increased risk of rejection due to proximity to the limbal vessels. Late stage visual rehabilitation is likely to require further surgical interventions after complete resolution of infection and inflammation. A preliminary assessment of corneal sensation and integrity of the ocular surface are key for any successful surgical intervention to restore vision.

Manifestation of Herpetic Eye Disease after COVID-19 Vaccine: A UK Case Series.

PURPOSE: To highlight the potential risk of herpetic eye disease (HED) reactivation following COVID-19 vaccine. METHODS: Retrospective analysis of all patients who presented with HED within 28 days post-first dose COVID-19 vaccination. RESULTS: Eleven eyes (n = 10 patients) were included. The mean interval between COVID-19 vaccination and ocular symptoms/signs was 12.3 ± 10.3 days. Four (40%) patients presented with HSV keratitis, and six (60%) patients presented with VZV keratitis (five had concurrent other signs of herpes zoster ophthalmicus). Common ocular signs included multiple scattered dendritic/pseudodendritic corneal epitheliopathy (90.9%), anterior uveitis (63.6%), and endothelitis (27.3%). All cases were successfully treated with topical and systemic antiviral treatment and/or topical corticosteroids (mean healing time = 3.9 ± 1.6 weeks). CONCLUSIONS: Our case series highlights the potential temporal association between HED and COVID-19 vaccine. Prophylactic antiviral treatment is recommended in patients with a history of HED prior to COVID-19 vaccination.

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.

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.

Profile of sight-threatening infectious keratitis: a prospective study.

PURPOSE: To prospectively study patients presenting with sight-threatening corneal ulcers with a view to identify the predisposing factors, causative organisms, clinical signs and treatment outcomes. METHODS: Prospectively, over 3-year period, all cases with serious infective keratitis presenting to Queens Medical Hospital in Nottingham, UK, were recruited. Detailed information on the aetiology, culture results, signs & symptoms, the treatment given and the patient's response was collected and statistically analysed. RESULTS: One hundred and forty-three eyes of 129 patients were enrolled. Thirty-one patients were managed as out-patients, and 98 were treated as in-patients. The mean duration of admission was 9 ± 13 days but was significantly higher in older patients and in Acanthamoeba keratitis cases. The important risk factors were ocular surface disease (32%), contact lens wear (26%) and previous ocular surgery (20%). Old age, deep infiltration, steroid use and poor initial vision were risk factors for prolonged course of treatment in bacterial keratitis. Corneal scrapings were done in 89% of the cases, but positive results were obtained only in 41.7%. Staphylococcus aureus was the most common isolated bacteria (18.8%). Acanthamoeba and Pseudomonas aeruginosa were the second and third common causative organisms (16.6% and 15%, respectively). Overall, 8.3% needed corneal grafting, which survived in 83.3% and eradicated infection in 100%. CONCLUSION: Microbial keratitis is an important cause of ocular morbidity. Previous ocular disease is an important predisposing factor. Old age, steroid use and poor presenting visual acuity are important prognostic indicators. Corneal grafting is an effective option for managing recalcitrant corneal infections.

Variable expression of human Beta defensins 3 and 9 at the human ocular surface in infectious keratitis.

PURPOSE: The authors have previously reported the presence of the antimicrobial peptides human beta defensin (hBD) 3 and hBD9 on the ocular surface (OS). These play an important role in infection and inflammation. In the present study, the authors studied the gene expression levels of hBD3 and hBD9 in healthy subjects and during and after healing of infectious keratitis. METHODS: Human OS specimens were obtained by impression cytology from healthy controls and patients with Acanthamoeba and Gram-negative and -positive bacterial keratitis (BK), both during active infection and after healing. The gene expression levels of hBD3 and hBD9 were determined using quantitative real-time polymerase chain reaction (RT-PCR). RESULTS: hBD3 and hBD9 were constitutively expressed in all healthy controls. During acute Acanthamoeba keratitis (AK), hBD3 levels were markedly increased and then returned close to normal levels after healing. In BK, hBD3 gene expression was moderately increased and then decreased after healing. In contrast to hBD3, hBD9 was significantly downregulated in both AK and Gram-positive BK, whereas it showed an insignificant decrease in Gram-negative BK. After healing, the expression showed upregulation except in Gram-positive BK, where it continued to decline. CONCLUSIONS: This is the first study that demonstrates the gene expression of hBD3 and hBD9 in response to infection. It illustrates that not all antimicrobial peptides (AMPs) behave in a similar manner. Some are upregulated and some are downregulated, suggesting a diverse role of AMP in infection and inflammation. The results point to a role of AMP-mediated host defense in Acanthamoeba keratitis as well.

Corneal densitometry as an indicator of corneal health.

PURPOSE: To 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. DESIGN: Prospective, comparative case series. PARTICIPANTS AND CONTROLS: Sixty-four eyes of 40 healthy controls and 36 eyes of 35 patients with bacterial keratitis were studied. METHODS: This 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 MEASURES: Densitometry 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. RESULTS: The 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. CONCLUSIONS: Densitometry 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.

Ex vivo confocal microscopy of human corneal nerves.

AIMS: To evaluate the distribution, morphometry and the postmortem changes of the central and peripheral human corneal nerves by exvivo laser-scanning confocal microscopy (EVCM). METHODS: 24 eyes from 14 cadavers were retrieved at different time intervals after death and examined by EVCM. Five regions were examined in each eye: central, superior, inferior, temporal and nasal. In each region, corneal nerve images were categorised according to their anatomical location in the cornea into sub-basal, stromal and limbal nerves. Five nerve parameters were measured: density, orientation, diameter, numbers and branching pattern. RESULTS: Exvivo confocal scanning of a motionless eye allows high quality imaging and tracking of corneal and limbal nerves. Stromal nerves from the sub-Bowman's plexus perforate the Bowman's zone and terminate in bulb-like structures, from each of which a leash of sub-basal nerves arises. Following death, sub-basal nerve parameters showed significant changes. The density decreased from 9.23+/-4.48 to 0.45+/-0.07 mm/mm(2), the diameter from 4.01+/-0.81 to 2.08+/-0.20 microm, the numbers from 8.3 to 1.0 and branching pattern from 39.38% to 0% (p<0.05) from day 1 to day 5 postmortem. Stromal and limbal nerves showed no significant changes in their density and diameter. CONCLUSIONS: This study establishes a direct link between sub-basal nerves and the sub-Bowman's nerves via distinct terminal bulbs. Limbal nerves are the thickest, are seen in all quadrants and can be traced to the corneal centre. The sub-basal nerve plexus rapidly degenerates after death but stromal and limbal nerves survive during the first five days after death.

Architecture and distribution of human corneal nerves.

AIMS: To comprehensively study the gross anatomy of human corneal innervation. METHODS: Twenty-one specimens, including 12 normal human corneas from seven deceased patients, two eye-bank corneo-scleral buttons, two eye-bank corneo-scleral rims and five post-surgical specimens from three patients with keratoconus were studied. Corneal whole mounts were stained for cholinesterase enzyme using the Karnovsky & Roots direct colouring thiocholine modification of acetylcholinesterase (AchE) technique. RESULTS: Approximately 44 thick nerve bundles were found to enter the human cornea in a relatively equal distribution round the limbus and move randomly towards the central cornea. At the mid-peripheral zone, anterior stromal nerves showed a characteristic budding and branching pattern. After passing through Bowman's zone they were noted to terminate into bulb-like thickenings from which multiple sub-basal nerves arose. The perforation sites were predominantly located in the mid-peripheral cornea. The orientation of sub-basal nerves was mainly vertical at their origin from the perforation sites. Nerves from all directions converged towards the infero-central cornea to form a characteristic clockwise whorl pattern. CONCLUSIONS: This study provides a comprehensive account of the architecture and distribution of nerves in the human cornea. It reconciles some of the existing information obtained from other modalities of investigation and identifies some novel features that provide a more complete picture of corneal innervation.

Correlation between the pattern of myopic fundal changes and the axis of astigmatism of the eye.

AIMS: Myopic fundal changes have been studied in great detail, clinically and pathologically. To our knowledge correlation between these changes and the axis of astigmatism has not been studied before. This study was conducted to assess the correlation, if any, between the pattern of myopic fundal changes and the axis of astigmatism. METHODS: Sixty-nine eyes (42 patients) with one or more characteristic myopic fundal change were studied prospectively. The patterns of myopic change were recorded by fundus photography. The deep/longest axis of the crescent and peripapillary atrophy was determined and ascribed a value in degrees in a manner similar to the axis of astigmatism in refraction. Refraction was then carried out. The axis of peripapillary atrophy and that of the crescent was correlated with the axis of myopic astigmatism and the coefficient of correlation determined (Spearman's rank correlation coefficient). RESULTS: A statistically significant correlation was found between the axis of compound myopic astigmatism and the long axis of myopic retinal degeneration (r=0.89, p<0.001) and with the deep axis of disc crescents (r=0.80, p <0.001). CONCLUSION: Astigmatism is likely to have an aetiopathogenic association with myopic fundal changes.