Neurotrophic keratitis (NK) is a degenerative disease characterized by corneal sensitivity reduction, spontaneous epithelium breakdown, and impairment of corneal healing. Several causes of NK, including herpetic keratitis, diabetes, and ophthalmic and neurosurgical procedures, share the common mechanism of trigeminal damage. Diagnosis of NK requires accurate investigation of clinical ocular and systemic history, complete eye examination, and assessment of corneal sensitivity. All diagnostic procedures to achieve correct diagnosis and classification of NK, including additional examinations such as in vivo confocal microscopy, are reviewed. NK can be classified according to severity of corneal damage, ie, epithelial alterations (stage 1), persistent epithelial defect (stage 2), and corneal ulcer (stage 3). Management of NK should be based on clinical severity, and aimed at promoting corneal healing and preventing progression of the disease to stromal melting and perforation. Concomitant ocular diseases, such as exposure keratitis, dry eye, and limbal stem cell deficiency, negatively influence the outcome of NK and should be treated. Currently, no specific medical treatment exists, and surgical approaches, such as amniotic membrane transplantation and conjunctival flap, are effective in preserving eye integrity, without ameliorating corneal sensitivity or visual function. This review describes experimental and clinical reports showing several novel and potential therapies for NK, including growth factors and metalloprotease inhibitors, as well as three ongoing Phase II clinical trials.

The ocular surface is extensively supplied by sensory and autonomic nerve fibers that play a crucial role in maintaining healthy epithelia and represent the main sources of neurogenic inflammation.^1-3 Cross-communication between the nervous and immune systems is shown by the release and binding of common neuromediators and cytokines.^4-6 Specifically, substance P (SP), calcitonin gene–related peptide (CGRP), vasoactive intestinal peptide (VIP), and neuropeptide Y (NPY) are released from ocular surface epithelial cells, lacrimal gland tissues, and nerve endings at inflammatory sites, modulating the infiltration and activation of the immune cells and triggering the reflex of tearing and ocular discomfort.^7,8

The purpose of the present review is to provide an overview on the clinical features of vernal keratoconjunctivitis on the basis of cases series presented in the literature. Furthermore, a new grading system of vernal keratoconjunctivitis based on the severity of the disease is proposed. Different treatment options are discussed based on the clinical grade of vernal keratoconjunctivitis. Recent epidemiological studies on the demographic, clinical and immunologic features of vernal keratoconjunctivitis are presented. The efficacy and complications of treatments are described. Diagnosis and treatment of patients is a challenge for ophthalmologists as no precise diagnostic criteria have been established, the pathogenesis is unclear, and antiallergic treatments are often unsuccessful. This review describes old and new concepts of vernal keratoconjunctivitis diagnosis and treatment: the clinical features, the diagnostic criteria, the common features between this and other ocular allergies and the therapeutic strategies. On the basis of this knowledge, a new grading system is introduced based on clinical signs and symptoms of ocular surface inflammation. This new grading of vernal keratoconjunctivitis may help clinicians and researchers to classify disease activity and to establish a common agreement for treatments.

The cornea has unique features that make it a useful model for regenerative medicine studies. It is an avascular, transparent, densely innervated tissue and any pathological changes can be easily detected by slit lamp examination. Corneal sensitivity is provided by the ophthalmic branch of the trigeminal nerve that elicits protective reflexes such as blinking and tearing and exerts trophic support by releasing neuromediators and growth factors. Corneal nerves are easily evaluated for both function and morphology using standard instruments such as corneal esthesiometer and in vivo confocal microscope. All local and systemic conditions that are associated with damage of the trigeminal nerve cause the development of neurotrophic keratitis, a rare degenerative disease. Neurotrophic keratitis is characterized by impairment of corneal sensitivity associated with development of persistent epithelial defects that may progress to corneal ulcer, melting and perforation. Current neurotrophic keratitis treatments aim at supporting corneal healing and preventing progression of corneal damage. Novel compounds able to stimulate corneal nerve recovery are in advanced development stage. Among them, nerve growth factor eye drops showed to be safe and effective in stimulating corneal healing and improving corneal sensitivity in patients with neurotrophic keratitis. Neurotrophic keratitis represents an useful model to evaluate in clinical practice novel neuro-regenerative drugs.