Neurotrophic Keratopathy (NK) refers to a condition where corneal epitheliopathy leading to frank epithelial defect with or without stromal ulceration (melting) is associated with reduced or absent corneal sensations. Sensory nerves serve nociceptor and trophic functions, which can be affected independently or simultaneously. Loss of trophic function and consequent epithelial breakdown exposes the stroma making it susceptible to enzymatic degradation. Nerve pathology can range from attrition to aberrant re-generation with corresponding symptoms from anaesthesia to hyperaesthesia/allodynia. Many systemic and ocular conditions, including surgery and preserved medications can lead to NK. NK can be mild (epithelium and tear film changes), moderate (non-healing epithelial defect) or severe (stromal melting and perforation). Moderate and severe NK can profoundly affect vision and adversely impact on the quality of life. Medical management with lubricating agents from artificial tears to serum/plasma drops, anti-inflammatory agents, antibiotics and anti-proteases all provide non-specific relief, which may be temporary. Contact lenses, punctal plugs, lid closure with botulinum toxin and surgical interventions like tarsorrhaphy, conjunctival flaps and amniotic membrane provide greater success but often at the cost of obscuring sight. Corneal surgery in a dry ocular surface with reduced sensation is at high risk of failure. The recent advent of biologicals such as biopolymers mimicking heparan sulfate; coenzyme Q10 and antisense oligonucleotide that suppress connexin 43 expression, all offer promise. Recombinant nerve growth factor (cenegermin), recently approved for human use targets the nerve pathology and has the potential of addressing the underlying deficit and becoming a specific therapy for NK.

Corneal opacity is the 5th leading cause of blindness and visual impairment globally, affecting ~6 million of the world population. In addition, it is responsible for 1.5–2.0 million new cases of monocular blindness per year, highlighting an ongoing uncurbed burden on human health. Among all aetiologies such as infection, trauma, inflammation, degeneration and nutritional deficiency, infectious keratitis (IK) represents the leading cause of corneal blindness in both developed and developing countries, with an estimated incidence ranging from 2.5 to 799 per 100,000 population-year. IK can be caused by a wide range of microorganisms, including bacteria, fungi, virus, parasites and polymicrobial infection. Subject to the geographical and temporal variations, bacteria and fungi have been shown to be the most common causative microorganisms for corneal infection. Although viral and Acanthamoeba keratitis are less common, they represent important causes for corneal blindness in the developed countries. Contact lens wear, trauma, ocular surface diseases, lid diseases, and post-ocular surgery have been shown to be the major risk factors for IK. Broad-spectrum topical antimicrobial treatment is the current mainstay of treatment for IK, though its effectiveness is being challenged by the emergence of antimicrobial resistance, including multidrug resistance, in some parts of the world. In this review, we aim to provide an updated review on IK, encompassing the epidemiology, causative microorganisms, major risk factors and the impact of antimicrobial resistance.

Contents: 1. Introduction 2. Neuroanatomy of the corneal nerves 2.1. Embryology and development of corneal innervation 2.2. Origin of corneal nerves 2.3. Corneal nerve architecture 3. Neurochemistry of the cornea (Neurotrophins, Neurotransmitters and Neuropeptides) 4. The role of corneal nerves 4.1. Sensory and reflex function 4.2. Axonal reflex and neurogenic inflammation 4.3. Trophic function 5. Manifestations of corneal nerve dysfunction 5.1. Definitions 5.2. Corneal pain in the absence of ocular surface disease "Pain without stain" 5.3. Anaesthetic cornea with intact corneal nerves (pre-ganglionic damage) 5.4. Anaesthetic/hypoesthetic cornea with absent nerves and abnormal ocular surface "neurotrophic keratopathy, stain without pain" 6. Visualisation of corneal nerves 6.1. In vitro/ex vivo techniques 6.2. In vivo techniques: In vivo confocal microscopy (IVCM) 7. Nerve affection in corneal pathology 7.1. Post-surgical conditions 7.2. Diabetic Keratopathy 7.3. Herpetic corneal disease 7.4. Dry eyes 7.5. Keratoconus 7.6. Contact lens wear 7.7. Bullous keratopathy 7.8. Neurotrophic keratopathy (NK) 7.9. Glaucoma 7.10. Corneal dystrophies 7.11. Limbal stem cell deficiency 7.12 Small-fibre sensory neuropathy (SFSN) 79 8. Future directions 9. Funding support 10. Acknowledgement 11. References 12. Figure legends