Neurotrophic keratitis: inflammatory pathogenesis and novel therapies

Purpose of reviewNeurotrophic keratitis is a rare degenerative disease characterized by decrease or absence of corneal sensation. Neurotrophic keratitis varies from mild forms with mild epitheliopathy to severe manifestations such as corneal ulceration, melting and perforation that can lead to irreversible visual loss. The cause of neurotrophic keratitis comprises a long list of diseases, medications, congenital or genetic conditions as well as trauma. The mechanism of neurotrophic keratitis is complex and multifactorial and its understanding is crucial to better address the treatment strategies. We aimed to review neurotrophic keratitis pathology, mechanisms and management.Corneal nerves are critical for the homeostasis of a healthy ocular surface. The lack of nerve-derived neuromediators and corneal-released neuropeptides, neuro-trophins and neurotrophic factors in neurotrophic keratitis leads to a decrease in trophic supply to corneal cells in addition to a decrease in afferent signaling to the brain. This results in pathological tear secretion, decreased blinking rate, corneal healing along with ocular surface and corneal inflammation. Lately, nerve growth factor in special gained emphasis as a treatment strategy targeting the disease mechanism rather than its manifestations. Other therapies, including surgical interventions, are in the pipeline of neurotrophic keratitis management. However, there are still no proper therapeutic guidelines and neurotrophic keratitis treatment remains challenging.Neurotrophic keratitis may have a devastating outcome and treatment is still challenging. Understanding the disease pathology may assist in the development of new treatment strategies. Prompt disease recognition and immediate intervention are key factors to promote corneal healing and avoid further deterioration.Papers of particular interest, published within the annual period of review, have been highlighted as:The cornea is richly innervated by the ophthalmic branch of the trigeminal nerve. With a central corneal nerve density of approximately 7000 nociceptors/mm2, the cornea is 300-600 times more sensitive than skin [1,2], being the most sensitive and densely innervated tissue in the human body [1]. The sensory nerves mediate temperature, nociception and pressure sensation, being critically involved in the ocular defense mechanism of tearing, blinking and withdrawal reflex. In addition, they promote the release of trophic factors which are involved in maintaining a healthy ocular surface and promoting healing [2,3]. Moreover, corneal nerve density is negatively correlated with corneal dendritic cells density showing that corneal nerves are also directly involved in the regulation of homeostasis and immune privilege in the cornea [4].Neurotrophic keratitis is a rare degenerative disease. The exact prevalence of neurotrophic keratitis is unknown, but it is estimated between 1.6 and 4.2 cases per 10 000 [3] persons. It is characterized by decrease or absence of corneal sensation caused by impairment of corneal sensory nerves [3]. Different diseases can affect the trigeminal nerve and at different levels, including central space occupying lesions, systemic diseases, viral infections, trauma and topical drugs among others. A long list of causes can be attributed to the decrease or absence of corneal sensation, and it might be more common than described. Neurotrophic keratitis manifests initially as a corneal epithelial disease with irregularities and breakdowns that may progress with healing impairment. That, in association with decrease in blinking and tearing may lead to stromal ulceration, melting and ultimately perforation. The clinical course and prognosis are only dependent of the severity of the neurotrophic keratitis, regardless of the initial cause [3,5]. no caption availableCorneal innervation originates from the ophthalmic division (V1) of the V cranial nerve - the trigeminal nerve. Long ciliary nerves from the nasociliary branch of V1 are composed of sensory fibers, which penetrate the sclera posteriorly and course through the suprachoroidal space to the corneal limbus. These fibers then branch and radially penetrate the peripheral corneal stroma originating the stromal plexus. After stromal penetration, these fibers lose their perineurium and myelin sheaths which contributes to corneal transparency. Some fibers innervate stromal keratocytes while others continue to branch and advance anteriorly to form the sub-epithelial plexus. Finally, upon anterior branching and progression, they pierce the Bowman's layer, originating the subbasal nerve plexus and innervating the epithelium [2,3,6].From its nucleus in the pons to the corneal epithelial free endings, nerve fibers traverse a long way and are vulnerable to trauma, infections, toxicity and systemic diseases. In addition to congenital syndromes and diseases, all of those can lead to decrease or absence of corneal sensation and the development of neurotrophic keratitis [5].Ocular causes include infections such as herpes simplex and zoster virus; postsurgical [any ocular surgery can cause damage of the ciliary fibers and direct corneal surgery (laser refractive surgery, corneal transplantation, cataract, corneal incisions) can directly affect the nerves]; topic anesthetic drops abuse; chemical burns; drug toxicity (e.g. beta-blockers, NSAIDs); chronic inflammation; contact lens wear; corneal dystrophies; corneal neoplasia [5,7]; and antivascular endothelial growth factor treatment (VEGF) [8,9].Systemic diseases include diabetes, leprosy, vitamin A deficiency and auto-immune diseases such as Graves and Sjogren syndrome [10]. Systemic medications such as neuroleptics, antipsychotics and antihistamines can also cause V nerve impairment. Central nervous system causes include space occupying lesions such as neoplasia/tumors and aneurysms, stroke, trauma and iatrogenic lesions postsurgical procedures. Genetic causes include familial dysautonomia (Riley-day syndrome), Goldenhar-Gorlin syndrome, Mobius syndrome, anhidrotic ectodermal dysplasia, familial corneal hypoesthesia and congenital insensitivity to pain with anhidrosis [3,5,7]. Amyloidosis, sarcoidosis, vitamin B12 deficiency and alcoholism-related polyneuropathy may also cause neurotrophic keratitis [10].Purpose of reviewNeurotrophic keratitis is a rare degenerative disease characterized by decrease or absence of corneal sensation. Neurotrophic keratitis varies from mild forms with mild epitheliopathy to severe manifestations such as corneal ulceration, melting and perforation that can lead to irreversible visual loss. The cause of neurotrophic keratitis comprises a long list of diseases, medications, congenital or genetic conditions as well as trauma. The mechanism of neurotrophic keratitis is complex and multifactorial and its understanding is crucial to better address the treatment strategies. We aimed to review neurotrophic keratitis pathology, mechanisms and management.Corneal nerves are critical for the homeostasis of a healthy ocular surface. The lack of nerve-derived neuromediators and corneal-released neuropeptides, neuro-trophins and neurotrophic factors in neurotrophic keratitis leads to a decrease in trophic supply to corneal cells in addition to a decrease in afferent signaling to the brain. This results in pathological tear secretion, decreased blinking rate, corneal healing along with ocular surface and corneal inflammation. Lately, nerve growth factor in special gained emphasis as a treatment strategy targeting the disease mechanism rather than its manifestations. Other therapies, including surgical interventions, are in the pipeline of neurotrophic keratitis management. However, there are still no proper therapeutic guidelines and neurotrophic keratitis treatment remains challenging.Neurotrophic keratitis may have a devastating outcome and treatment is still challenging. Understanding the disease pathology may assist in the development of new treatment strategies. Prompt disease recognition and immediate intervention are key factors to promote corneal healing and avoid further deterioration.Papers of particular interest, published within the annual period of review, have been highlighted as:The cornea is richly innervated by the ophthalmic branch of the trigeminal nerve. With a central corneal nerve density of approximately 7000 nociceptors/mm2, the cornea is 300-600 times more sensitive than skin [1,2], being the most sensitive and densely innervated tissue in the human body [1]. The sensory nerves mediate temperature, nociception and pressure sensation, being critically involved in the ocular defense mechanism of tearing, blinking and withdrawal reflex. In addition, they promote the release of trophic factors which are involved in maintaining a healthy ocular surface and promoting healing [2,3]. Moreover, corneal nerve density is negatively correlated with corneal dendritic cells density showing that corneal nerves are also directly involved in the regulation of homeostasis and immune privilege in the cornea [4].Neurotrophic keratitis is a rare degenerative disease. The exact prevalence of neurotrophic keratitis is unknown, but it is estimated between 1.6 and 4.2 cases per 10 000 [3] persons. It is characterized by decrease or absence of corneal sensation caused by impairment of corneal sensory nerves [3]. Different diseases can affect the trigeminal nerve and at different levels, including central space occupying lesions, systemic diseases, viral infections, trauma and topical drugs among others. A long list of causes can be attributed to the decrease or absence of corneal sensation, and it might be more common than described. Neurotrophic keratitis manifests initially as a corneal epithelial disease with irregularities and breakdowns that may progress with healing impairment. That, in association with decrease in blinking and tearing may lead to stromal ulceration, melting and ultimately perforation. The clinical course and prognosis are only dependent of the severity of the neurotrophic keratitis, regardless of the initial cause [3,5]. no caption availableCorneal innervation originates from the ophthalmic division (V1) of the V cranial nerve - the trigeminal nerve. Long ciliary nerves from the nasociliary branch of V1 are composed of sensory fibers, which penetrate the sclera posteriorly and course through the suprachoroidal space to the corneal limbus. These fibers then branch and radially penetrate the peripheral corneal stroma originating the stromal plexus. After stromal penetration, these fibers lose their perineurium and myelin sheaths which contributes to corneal transparency. Some fibers innervate stromal keratocytes while others continue to branch and advance anteriorly to form the sub-epithelial plexus. Finally, upon anterior branching and progression, they pierce the Bowman's layer, originating the subbasal nerve plexus and innervating the epithelium [2,3,6].From its nucleus in the pons to the corneal epithelial free endings, nerve fibers traverse a long way and are vulnerable to trauma, infections, toxicity and systemic diseases. In addition to congenital syndromes and diseases, all of those can lead to decrease or absence of corneal sensation and the development of neurotrophic keratitis [5].Ocular causes include infections such as herpes simplex and zoster virus; postsurgical [any ocular surgery can cause damage of the ciliary fibers and direct corneal surgery (laser refractive surgery, corneal transplantation, cataract, corneal incisions) can directly affect the nerves]; topic anesthetic drops abuse; chemical burns; drug toxicity (e.g. beta-blockers, NSAIDs); chronic inflammation; contact lens wear; corneal dystrophies; corneal neoplasia [5,7]; and antivascular endothelial growth factor treatment (VEGF) [8,9].Systemic diseases include diabetes, leprosy, vitamin A deficiency and auto-immune diseases such as Graves and Sjogren syndrome [10]. Systemic medications such as neuroleptics, antipsychotics and antihistamines can also cause V nerve impairment. Central nervous system causes include space occupying lesions such as neoplasia/tumors and aneurysms, stroke, trauma and iatrogenic lesions postsurgical procedures. Genetic causes include familial dysautonomia (Riley-day syndrome), Goldenhar-Gorlin syndrome, Mobius syndrome, anhidrotic ectodermal dysplasia, familial corneal hypoesthesia and congenital insensitivity to pain with anhidrosis [3,5,7]. Amyloidosis, sarcoidosis, vitamin B12 deficiency and alcoholism-related polyneuropathy may also cause neurotrophic keratitis [10].Purpose of reviewNeurotrophic keratitis is a rare degenerative disease characterized by decrease or absence of corneal sensation. Neurotrophic keratitis varies from mild forms with mild epitheliopathy to severe manifestations such as corneal ulceration, melting and perforation that can lead to irreversible visual loss. The cause of neurotrophic keratitis comprises a long list of diseases, medications, congenital or genetic conditions as well as trauma. The mechanism of neurotrophic keratitis is complex and multifactorial and its understanding is crucial to better address the treatment strategies. We aimed to review neurotrophic keratitis pathology, mechanisms and management.Corneal nerves are critical for the homeostasis of a healthy ocular surface. The lack of nerve-derived neuromediators and corneal-released neuropeptides, neuro-trophins and neurotrophic factors in neurotrophic keratitis leads to a decrease in trophic supply to corneal cells in addition to a decrease in afferent signaling to the brain. This results in pathological tear secretion, decreased blinking rate, corneal healing along with ocular surface and corneal inflammation. Lately, nerve growth factor in special gained emphasis as a treatment strategy targeting the disease mechanism rather than its manifestations. Other therapies, including surgical interventions, are in the pipeline of neurotrophic keratitis management. However, there are still no proper therapeutic guidelines and neurotrophic keratitis treatment remains challenging. Neurotrophic keratitis may have a devastating outcome and treatment is still challenging. Understanding the disease pathology may assist in the development of new treatment strategies. Prompt disease recognition and immediate intervention are key factors to promote corneal healing and avoid further deterioration.Papers of particular interest, published within the annual period of review, have been highlighted as:The cornea is richly innervated by the ophthalmic branch of the trigeminal nerve. With a central corneal nerve density of approximately 7000 nociceptors/mm2, the cornea is 300-600 times more sensitive than skin [1,2], being the most sensitive and densely innervated tissue in the human body [1]. The sensory nerves mediate temperature, nociception and pressure sensation, being critically involved in the ocular defense mechanism of tearing, blinking and withdrawal reflex. In addition, they promote the release of trophic factors which are involved in maintaining a healthy ocular surface and promoting healing [2,3]. Moreover, corneal nerve density is negatively correlated with corneal dendritic cells density showing that corneal nerves are also directly involved in the regulation of homeostasis and immune privilege in the cornea [4].Neurotrophic keratitis is a rare degenerative disease. The exact prevalence of neurotrophic keratitis is unknown, but it is estimated between 1.6 and 4.2 cases per 10 000 [3] persons. It is characterized by decrease or absence of corneal sensation caused by impairment of corneal sensory nerves [3]. Different diseases can affect the trigeminal nerve and at different levels, including central space occupying lesions, systemic diseases, viral infections, trauma and topical drugs among others. A long list of causes can be attributed to the decrease or absence of corneal sensation, and it might be more common than described. Neurotrophic keratitis manifests initially as a corneal epithelial disease with irregularities and breakdowns that may progress with healing impairment. That, in association with decrease in blinking and tearing may lead to stromal ulceration, melting and ultimately perforation. The clinical course and prognosis are only dependent of the severity of the neurotrophic keratitis, regardless of the initial cause [3,5]. no caption availableCorneal innervation originates from the ophthalmic division (V1) of the V cranial nerve - the trigeminal nerve. Long ciliary nerves from the nasociliary branch of V1 are composed of sensory fibers, which penetrate the sclera posteriorly and course through the suprachoroidal space to the corneal limbus. These fibers then branch and radially penetrate the peripheral corneal stroma originating the stromal plexus. After stromal penetration, these fibers lose their perineurium and myelin sheaths which contributes to corneal transparency. Some fibers innervate stromal keratocytes while others continue to branch and advance anteriorly to form the sub-epithelial plexus. Finally, upon anterior branching and progression, they pierce the Bowman's layer, originating the subbasal nerve plexus and innervating the epithelium [2,3,6].From its nucleus in the pons to the corneal epithelial free endings, nerve fibers traverse a long way and are vulnerable to trauma, infections, toxicity and systemic diseases. In addition to congenital syndromes and diseases, all of those can lead to decrease or absence of corneal sensation and the development of neurotrophic keratitis [5]. Ocular causes include infections such as herpes simplex and zoster virus; postsurgical [any ocular surgery can cause damage of the ciliary fibers and direct corneal surgery (laser refractive surgery, corneal transplantation, cataract, corneal incisions) can directly affect the nerves]; topic anesthetic drops abuse; chemical burns; drug toxicity (e.g. beta-blockers, NSAIDs); chronic inflammation; contact lens wear; corneal dystrophies; corneal neoplasia [5,7]; and antivascular endothelial growth factor treatment (VEGF) [8,9].Systemic diseases include diabetes, leprosy, vitamin A deficiency and auto-immune diseases such as Graves and Sjogren syndrome [10]. Systemic medications such as neuroleptics, antipsychotics and antihistamines can also cause V nerve impairment. Central nervous system causes include space occupying lesions such as neoplasia/tumors and aneurysms, stroke, trauma and iatrogenic lesions postsurgical procedures. Genetic causes include familial dysautonomia (Riley-day syndrome), Goldenhar-Gorlin syndrome, Mobius syndrome, anhidrotic ectodermal dysplasia, familial corneal hypoesthesia and congenital insensitivity to pain with anhidrosis [3,5,7]. Amyloidosis, sarcoidosis, vitamin B12 deficiency and alcoholism-related polyneuropathy may also cause neurotrophic keratitis [10].Purpose of reviewNeurotrophic keratitis is a rare degenerative disease characterized by decrease or absence of corneal sensation. Neurotrophic keratitis varies from mild forms with mild epitheliopathy to severe manifestations such as corneal ulceration, melting and perforation that can lead to irreversible visual loss. The cause of neurotrophic keratitis comprises a long list of diseases, medications, congenital or genetic conditions as well as trauma. The mechanism of neurotrophic keratitis is complex and multifactorial and its understanding is crucial to better address the treatment strategies. We aimed to review neurotrophic keratitis pathology, mechanisms and management.Corneal nerves are critical for the homeostasis of a healthy ocular surface. The lack of nerve-derived neuromediators and corneal-released neuropeptides, neuro-trophins and neurotrophic factors in neurotrophic keratitis leads to a decrease in trophic supply to corneal cells in addition to a decrease in afferent signaling to the brain. This results in pathological tear secretion, decreased blinking rate, corneal healing along with ocular surface and corneal inflammation. Lately, nerve growth factor in special gained emphasis as a treatment strategy targeting the disease mechanism rather than its manifestations. Other therapies, including surgical interventions, are in the pipeline of neurotrophic keratitis management. However, there are still no proper therapeutic guidelines and neurotrophic keratitis treatment remains challenging.Neurotrophic keratitis may have a devastating outcome and treatment is still challenging. Understanding the disease pathology may assist in the development of new treatment strategies. Prompt disease recognition and immediate intervention are key factors to promote corneal healing and avoid further deterioration.Papers of particular interest, published within the annual period of review, have been highlighted as:The cornea is richly innervated by the ophthalmic branch of the trigeminal nerve. With a central corneal nerve density of approximately 7000 nociceptors/mm2, the cornea is 300-600 times more sensitive than skin [1,2], being the most sensitive and densely innervated tissue in the human body [1]. The sensory nerves mediate temperature, nociception and pressure sensation, being critically involved in the ocular defense mechanism of tearing, blinking and withdrawal reflex. In addition, they promote the release of trophic factors which are involved in maintaining a healthy ocular surface and promoting healing [2,3]. Moreover, corneal nerve density is negatively correlated with corneal dendritic cells density showing that corneal nerves are also directly involved in the regulation of homeostasis and immune privilege in the cornea [4].Neurotrophic keratitis is a rare degenerative disease. The exact prevalence of neurotrophic keratitis is unknown, but it is estimated between 1.6 and 4.2 cases per 10 000 [3] persons. It is characterized by decrease or absence of corneal sensation caused by impairment of corneal sensory nerves [3]. Different diseases can affect the trigeminal nerve and at different levels, including central space occupying lesions, systemic diseases, viral infections, trauma and topical drugs among others. A long list of causes can be attributed to the decrease or absence of corneal sensation, and it might be more common than described. Neurotrophic keratitis manifests initially as a corneal epithelial disease with irregularities and breakdowns that may progress with healing impairment. That, in association with decrease in blinking and tearing may lead to stromal ulceration, melting and ultimately perforation. The clinical course and prognosis are only dependent of the severity of the neurotrophic keratitis, regardless of the initial cause [3,5]. no caption availableCorneal innervation originates from the ophthalmic division (V1) of the V cranial nerve - the trigeminal nerve. Long ciliary nerves from the nasociliary branch of V1 are composed of sensory fibers, which penetrate the sclera posteriorly and course through the suprachoroidal space to the corneal limbus. These fibers then branch and radially penetrate the peripheral corneal stroma originating the stromal plexus. After stromal penetration, these fibers lose their perineurium and myelin sheaths which contributes to corneal transparency. Some fibers innervate stromal keratocytes while others continue to branch and advance anteriorly to form the sub-epithelial plexus. Finally, upon anterior branching and progression, they pierce the Bowman's layer, originating the subbasal nerve plexus and innervating the epithelium [2,3,6].From its nucleus in the pons to the corneal epithelial free endings, nerve fibers traverse a long way and are vulnerable to trauma, infections, toxicity and systemic diseases. In addition to congenital syndromes and diseases, all of those can lead to decrease or absence of corneal sensation and the development of neurotrophic keratitis [5].Ocular causes include infections such as herpes simplex and zoster virus; postsurgical [any ocular surgery can cause damage of the ciliary fibers and direct corneal surgery (laser refractive surgery, corneal transplantation, cataract, corneal incisions) can directly affect the nerves]; topic anesthetic drops abuse; chemical burns; drug toxicity (e.g. beta-blockers, NSAIDs); chronic inflammation; contact lens wear; corneal dystrophies; corneal neoplasia [5,7]; and antivascular endothelial growth factor treatment (VEGF) [8,9].Systemic diseases include diabetes, leprosy, vitamin A deficiency and auto-immune diseases such as Graves and Sjogren syndrome [10]. Systemic medications such as neuroleptics, antipsychotics and antihistamines can also cause V nerve impairment. Central nervous system causes include space occupying lesions such as neoplasia/tumors and aneurysms, stroke, trauma and iatrogenic lesions postsurgical procedures. Genetic causes include familial dysautonomia (Riley-day syndrome), Goldenhar-Gorlin syndrome, Mobius syndrome, anhidrotic ectodermal dysplasia, familial corneal hypoesthesia and congenital insensitivity to pain with anhidrosis [3,5,7]. Amyloidosis, sarcoidosis, vitamin B12 deficiency and alcoholism-related polyneuropathy may also cause neurotrophic keratitis [10].Purpose of reviewNeurotrophic keratitis is a rare degenerative disease characterized by decrease or absence of corneal sensation. Neurotrophic keratitis varies from mild forms with mild epitheliopathy to severe manifestations such as corneal ulceration, melting and perforation that can lead to irreversible visual loss. The cause of neurotrophic keratitis comprises a long list of diseases, medications, congenital or genetic conditions as well as trauma. The mechanism of neurotrophic keratitis is complex and multifactorial and its understanding is crucial to better address the treatment strategies. We aimed to review neurotrophic keratitis pathology, mechanisms and management.Corneal nerves are critical for the homeostasis of a healthy ocular surface. The lack of nerve-derived neuromediators and corneal-released neuropeptides, neuro-trophins and neurotrophic factors in neurotrophic keratitis leads to a decrease in trophic supply to corneal cells in addition to a decrease in afferent signaling to the brain. This results in pathological tear secretion, decreased blinking rate, corneal healing along with ocular surface and corneal inflammation. Lately, nerve growth factor in special gained emphasis as a treatment strategy targeting the disease mechanism rather than its manifestations. Other therapies, including surgical interventions, are in the pipeline of neurotrophic keratitis management. However, there are still no proper therapeutic guidelines and neurotrophic keratitis treatment remains challenging.Neurotrophic keratitis may have a devastating outcome and treatment is still challenging. Understanding the disease pathology may assist in the development of new treatment strategies. Prompt disease recognition and immediate intervention are key factors to promote corneal healing and avoid further deterioration.Papers of particular interest, published within the annual period of review, have been highlighted as:The cornea is richly innervated by the ophthalmic branch of the trigeminal nerve. With a central corneal nerve density of approximately 7000 nociceptors/mm2, the cornea is 300-600 times more sensitive than skin [1,2], being the most sensitive and densely innervated tissue in the human body [1]. The sensory nerves mediate temperature, nociception and pressure sensation, being critically involved in the ocular defense mechanism of tearing, blinking and withdrawal reflex. In addition, they promote the release of trophic factors which are involved in maintaining a healthy ocular surface and promoting healing [2,3]. Moreover, corneal nerve density is negatively correlated with corneal dendritic cells density showing that corneal nerves are also directly involved in the regulation of homeostasis and immune privilege in the cornea [4].Neurotrophic keratitis is a rare degenerative disease. The exact prevalence of neurotrophic keratitis is unknown, but it is estimated between 1.6 and 4.2 cases per 10 000 [3] persons. It is characterized by decrease or absence of corneal sensation caused by impairment of corneal sensory nerves [3]. Different diseases can affect the trigeminal nerve and at different levels, including central space occupying lesions, systemic diseases, viral infections, trauma and topical drugs among others. A long list of causes can be attributed to the decrease or absence of corneal sensation, and it might be more common than described. Neurotrophic keratitis manifests initially as a corneal epithelial disease with irregularities and breakdowns that may progress with healing impairment. That, in association with decrease in blinking and tearing may lead to stromal ulceration, melting and ultimately perforation. The clinical course and prognosis are only dependent of the severity of the neurotrophic keratitis, regardless of the initial cause [3,5]. no caption availableCorneal innervation originates from the ophthalmic division (V1) of the V cranial nerve - the trigeminal nerve. Long ciliary nerves from the nasociliary branch of V1 are composed of sensory fibers, which penetrate the sclera posteriorly and course through the suprachoroidal space to the corneal limbus. These fibers then branch and radially penetrate the peripheral corneal stroma originating the stromal plexus. After stromal penetration, these fibers lose their perineurium and myelin sheaths which contributes to corneal transparency. Some fibers innervate stromal keratocytes while others continue to branch and advance anteriorly to form the sub-epithelial plexus. Finally, upon anterior branching and progression, they pierce the Bowman's layer, originating the subbasal nerve plexus and innervating the epithelium [2,3,6].From its nucleus in the pons to the corneal epithelial free endings, nerve fibers traverse a long way and are vulnerable to trauma, infections, toxicity and systemic diseases. In addition to congenital syndromes and diseases, all of those can lead to decrease or absence of corneal sensation and the development of neurotrophic keratitis [5].Ocular causes include infections such as herpes simplex and zoster virus; postsurgical [any ocular surgery can cause damage of the ciliary fibers and direct corneal surgery (laser refractive surgery, corneal transplantation, cataract, corneal incisions) can directly affect the nerves]; topic anesthetic drops abuse; chemical burns; drug toxicity (e.g. beta-blockers, NSAIDs); chronic inflammation; contact lens wear; corneal dystrophies; corneal neoplasia [5,7]; and antivascular endothelial growth factor treatment (VEGF) [8,9].Systemic diseases include diabetes, leprosy, vitamin A deficiency and auto-immune diseases such as Graves and Sjogren syndrome [10]. Systemic medications such as neuroleptics, antipsychotics and antihistamines can also cause V nerve impairment. Central nervous system causes include space occupying lesions such as neoplasia/tumors and aneurysms, stroke, trauma and iatrogenic lesions postsurgical procedures. Genetic causes include familial dysautonomia (Riley-day syndrome), Goldenhar-Gorlin syndrome, Mobius syndrome, anhidrotic ectodermal dysplasia, familial corneal hypoesthesia and congenital insensitivity to pain with anhidrosis [3,5,7]. Amyloidosis, sarcoidosis, vitamin B12 deficiency and alcoholism-related polyneuropathy may also cause neurotrophic keratitis [10].Purpose of reviewNeurotrophic keratitis is a rare degenerative disease characterized by decrease or absence of corneal sensation. Neurotrophic keratitis varies from mild forms with mild epitheliopathy to severe manifestations such as corneal ulceration, melting and perforation that can lead to irreversible visual loss. The cause of neurotrophic keratitis comprises a long list of diseases, medications, congenital or genetic conditions as well as trauma. The mechanism of neurotrophic keratitis is complex and multifactorial and its understanding is crucial to better address the treatment strategies. We aimed to review neurotrophic keratitis pathology, mechanisms and management.Corneal nerves are critical for the homeostasis of a healthy ocular surface. The lack of nerve-derived neuromediators and corneal-released neuropeptides, neuro-trophins and neurotrophic factors in neurotrophic keratitis leads to a decrease in trophic supply to corneal cells in addition to a decrease in afferent signaling to the brain. This results in pathological tear secretion, decreased blinking rate, corneal healing along with ocular surface and corneal inflammation. Lately, nerve growth factor in special gained emphasis as a treatment strategy targeting the disease mechanism rather than its manifestations. Other therapies, including surgical interventions, are in the pipeline of neurotrophic keratitis management. However, there are still no proper therapeutic guidelines and neurotrophic keratitis treatment remains challenging.Neurotrophic keratitis may have a devastating outcome and treatment is still challenging. Understanding the disease pathology may assist in the development of new treatment strategies. Prompt disease recognition and immediate intervention are key factors to promote corneal healing and avoid further deterioration.Papers of particular interest, published within the annual period of review, have been highlighted as:The cornea is richly innervated by the ophthalmic branch of the trigeminal nerve. With a central corneal nerve density of approximately 7000 nociceptors/mm2, the cornea is 300-600 times more sensitive than skin [1,2], being the most sensitive and densely innervated tissue in the human body [1]. The sensory nerves mediate temperature, nociception and pressure sensation, being critically involved in the ocular defense mechanism of tearing, blinking and withdrawal reflex. In addition, they promote the release of trophic factors which are involved in maintaining a healthy ocular surface and promoting healing [2,3]. Moreover, corneal nerve density is negatively correlated with corneal dendritic cells density showing that corneal nerves are also directly involved in the regulation of homeostasis and immune privilege in the cornea [4].Neurotrophic keratitis is a rare degenerative disease. The exact prevalence of neurotrophic keratitis is unknown, but it is estimated between 1.6 and 4.2 cases per 10 000 [3] persons. It is characterized by decrease or absence of corneal sensation caused by impairment of corneal sensory nerves [3]. Different diseases can affect the trigeminal nerve and at different levels, including central space occupying lesions, systemic diseases, viral infections, trauma and topical drugs among others. A long list of causes can be attributed to the decrease or absence of corneal sensation, and it might be more common than described. Neurotrophic keratitis manifests initially as a corneal epithelial disease with irregularities and breakdowns that may progress with healing impairment. That, in association with decrease in blinking and tearing may lead to stromal ulceration, melting and ultimately perforation. The clinical course and prognosis are only dependent of the severity of the neurotrophic keratitis, regardless of the initial cause [3,5]. no caption availableCorneal innervation originates from the ophthalmic division (V1) of the V cranial nerve - the trigeminal nerve. Long ciliary nerves from the nasociliary branch of V1 are composed of sensory fibers, which penetrate the sclera posteriorly and course through the suprachoroidal space to the corneal limbus. These fibers then branch and radially penetrate the peripheral corneal stroma originating the stromal plexus. After stromal penetration, these fibers lose their perineurium and myelin sheaths which contributes to corneal transparency. Some fibers innervate stromal keratocytes while others continue to branch and advance anteriorly to form the sub-epithelial plexus. Finally, upon anterior branching and progression, they pierce the Bowman's layer, originating the subbasal nerve plexus and innervating the epithelium [2,3,6].From its nucleus in the pons to the corneal epithelial free endings, nerve fibers traverse a long way and are vulnerable to trauma, infections, toxicity and systemic diseases. In addition to congenital syndromes and diseases, all of those can lead to decrease or absence of corneal sensation and the development of neurotrophic keratitis [5].Ocular causes include infections such as herpes simplex and zoster virus; postsurgical [any ocular surgery can cause damage of the ciliary fibers and direct corneal surgery (laser refractive surgery, corneal transplantation, cataract, corneal incisions) can directly affect the nerves]; topic anesthetic drops abuse; chemical burns; drug toxicity (e.g. beta-blockers, NSAIDs); chronic inflammation; contact lens wear; corneal dystrophies; corneal neoplasia [5,7]; and antivascular endothelial growth factor treatment (VEGF) [8,9].Systemic diseases include diabetes, leprosy, vitamin A deficiency and auto-immune diseases such as Graves and Sjogren syndrome [10]. Systemic medications such as neuroleptics, antipsychotics and antihistamines can also cause V nerve impairment. Central nervous system causes include space occupying lesions such as neoplasia/tumors and aneurysms, stroke, trauma and iatrogenic lesions postsurgical procedures. Genetic causes include familial dysautonomia (Riley-day syndrome), Goldenhar-Gorlin syndrome, Mobius syndrome, anhidrotic ectodermal dysplasia, familial corneal hypoesthesia and congenital insensitivity to pain with anhidrosis [3,5,7]. Amyloidosis, sarcoidosis, vitamin B12 deficiency and alcoholism-related polyneuropathy may also cause neurotrophic keratitis [10].Purpose of reviewNeurotrophic keratitis is a rare degenerative disease characterized by decrease or absence of corneal sensation. Neurotrophic keratitis varies from mild forms with mild epitheliopathy to severe manifestations such as corneal ulceration, melting and perforation that can lead to irreversible visual loss. The cause of neurotrophic keratitis comprises a long list of diseases, medications, congenital or genetic conditions as well as trauma. The mechanism of neurotrophic keratitis is complex and multifactorial and its understanding is crucial to better address the treatment strategies. We aimed to review neurotrophic keratitis pathology, mechanisms and management.Corneal nerves are critical for the homeostasis of a healthy ocular surface. The lack of nerve-derived neuromediators and corneal-released neuropeptides, neuro-trophins and neurotrophic factors in neurotrophic keratitis leads to a decrease in trophic supply to corneal cells in addition to a decrease in afferent signaling to the brain. This results in pathological tear secretion, decreased blinking rate, corneal healing along with ocular surface and corneal inflammation. Lately, nerve growth factor in special gained emphasis as a treatment strategy targeting the disease mechanism rather than its manifestations. Other therapies, including surgical interventions, are in the pipeline of neurotrophic keratitis management. However, there are still no proper therapeutic guidelines and neurotrophic keratitis treatment remains challenging.Neurotrophic keratitis may have a devastating outcome and treatment is still challenging. Understanding the disease pathology may assist in the development of new treatment strategies. Prompt disease recognition and immediate intervention are key factors to promote corneal healing and avoid further deterioration.Papers of particular interest, published within the annual period of review, have been highlighted as:The cornea is richly innervated by the ophthalmic branch of the trigeminal nerve. With a central corneal nerve density of approximately 7000 nociceptors/mm2, the cornea is 300-600 times more sensitive than skin [1,2], being the most sensitive and densely innervated tissue in the human body [1]. The sensory nerves mediate temperature, nociception and pressure sensation, being critically involved in the ocular defense mechanism of tearing, blinking and withdrawal reflex. In addition, they promote the release of trophic factors which are involved in maintaining a healthy ocular surface and promoting healing [2,3]. Moreover, corneal nerve density is negatively correlated with corneal dendritic cells density showing that corneal nerves are also directly involved in the regulation of homeostasis and immune privilege in the cornea [4].Neurotrophic keratitis is a rare degenerative disease. The exact prevalence of neurotrophic keratitis is unknown, but it is estimated between 1.6 and 4.2 cases per 10 000 [3] persons. It is characterized by decrease or absence of corneal sensation caused by impairment of corneal sensory nerves [3]. Different diseases can affect the trigeminal nerve and at different levels, including central space occupying lesions, systemic diseases, viral infections, trauma and topical drugs among others. A long list of causes can be attributed to the decrease or absence of corneal sensation, and it might be more common than described. Neurotrophic keratitis manifests initially as a corneal epithelial disease with irregularities and breakdowns that may progress with healing impairment. That, in association with decrease in blinking and tearing may lead to stromal ulceration, melting and ultimately perforation. The clinical course and prognosis are only dependent of the severity of the neurotrophic keratitis, regardless of the initial cause [3,5]. no caption availableCorneal innervation originates from the ophthalmic division (V1) of the V cranial nerve - the trigeminal nerve. Long ciliary nerves from the nasociliary branch of V1 are composed of sensory fibers, which penetrate the sclera posteriorly and course through the suprachoroidal space to the corneal limbus. These fibers then branch and radially penetrate the peripheral corneal stroma originating the stromal plexus. After stromal penetration, these fibers lose their perineurium and myelin sheaths which contributes to corneal transparency. Some fibers innervate stromal keratocytes while others continue to branch and advance anteriorly to form the sub-epithelial plexus. Finally, upon anterior branching and progression, they pierce the Bowman's layer, originating the subbasal nerve plexus and innervating the epithelium [2,3,6].From its nucleus in the pons to the corneal epithelial free endings, nerve fibers traverse a long way and are vulnerable to trauma, infections, toxicity and systemic diseases. In addition to congenital syndromes and diseases, all of those can lead to decrease or absence of corneal sensation and the development of neurotrophic keratitis [5].Ocular causes include infections such as herpes simplex and zoster virus; postsurgical [any ocular surgery can cause damage of the ciliary fibers and direct corneal surgery (laser refractive surgery, corneal transplantation, cataract, corneal incisions) can directly affect the nerves]; topic anesthetic drops abuse; chemical burns; drug toxicity (e.g. beta-blockers, NSAIDs); chronic inflammation; contact lens wear; corneal dystrophies; corneal neoplasia [5,7]; and antivascular endothelial growth factor treatment (VEGF) [8,9].Systemic diseases include diabetes, leprosy, vitamin A deficiency and auto-immune diseases such as Graves and Sjogren syndrome [10]. Systemic medications such as neuroleptics, antipsychotics and antihistamines can also cause V nerve impairment. Central nervous system causes include space occupying lesions such as neoplasia/tumors and aneurysms, stroke, trauma and iatrogenic lesions postsurgical procedures. Genetic causes include familial dysautonomia (Riley-day syndrome), Goldenhar-Gorlin syndrome, Mobius syndrome, anhidrotic ectodermal dysplasia, familial corneal hypoesthesia and congenital insensitivity to pain with anhidrosis [3,5,7]. Amyloidosis, sarcoidosis, vitamin B12 deficiency and alcoholism-related polyneuropathy may also cause neurotrophic keratitis [10].Purpose of reviewNeurotrophic keratitis is a rare degenerative disease characterized by decrease or absence of corneal sensation. Neurotrophic keratitis varies from mild forms with mild epitheliopathy to severe manifestations such as corneal ulceration, melting and perforation that can lead to irreversible visual loss. The cause of neurotrophic keratitis comprises a long list of diseases, medications, congenital or genetic conditions as well as trauma. The mechanism of neurotrophic keratitis is complex and multifactorial and its understanding is crucial to better address the treatment strategies. We aimed to review neurotrophic keratitis pathology, mechanisms and management.Corneal nerves are critical for the homeostasis of a healthy ocular surface. The lack of nerve-derived neuromediators and corneal-released neuropeptides, neuro-trophins and neurotrophic factors in neurotrophic keratitis leads to a decrease in trophic supply to corneal cells in addition to a decrease in afferent signaling to the brain. This results in pathological tear secretion, decreased blinking rate, corneal healing along with ocular surface and corneal inflammation. Lately, nerve growth factor in special gained emphasis as a treatment strategy targeting the disease mechanism rather than its manifestations. Other therapies, including surgical interventions, are in the pipeline of neurotrophic keratitis management. However, there are still no proper therapeutic guidelines and neurotrophic keratitis treatment remains challenging. Neurotrophic keratitis may have a devastating outcome and treatment is still challenging. Understanding the disease pathology may assist in the development of new treatment strategies. Prompt disease recognition and immediate intervention are key factors to promote corneal healing and avoid further deterioration.Papers of particular interest, published within the annual period of review, have been highlighted as:The cornea is richly innervated by the ophthalmic branch of the trigeminal nerve. With a central corneal nerve density of approximately 7000 nociceptors/mm2, the cornea is 300-600 times more sensitive than skin [1,2], being the most sensitive and densely innervated tissue in the human body [1]. The sensory nerves mediate temperature, nociception and pressure sensation, being critically involved in the ocular defense mechanism of tearing, blinking and withdrawal reflex. In addition, they promote the release of trophic factors which are involved in maintaining a healthy ocular surface and promoting healing [2,3]. Moreover, corneal nerve density is negatively correlated with corneal dendritic cells density showing that corneal nerves are also directly involved in the regulation of homeostasis and immune privilege in the cornea [4].Neurotrophic keratitis is a rare degenerative disease. The exact prevalence of neurotrophic keratitis is unknown, but it is estimated between 1.6 and 4.2 cases per 10 000 [3] persons. It is characterized by decrease or absence of corneal sensation caused by impairment of corneal sensory nerves [3]. Different diseases can affect the trigeminal nerve and at different levels, including central space occupying lesions, systemic diseases, viral infections, trauma and topical drugs among others. A long list of causes can be attributed to the decrease or absence of corneal sensation, and it might be more common than described. Neurotrophic keratitis manifests initially as a corneal epithelial disease with irregularities and breakdowns that may progress with healing impairment. That, in association with decrease in blinking and tearing may lead to stromal ulceration, melting and ultimately perforation. The clinical course and prognosis are only dependent of the severity of the neurotrophic keratitis, regardless of the initial cause [3,5]. no caption availableCorneal innervation originates from the ophthalmic division (V1) of the V cranial nerve - the trigeminal nerve. Long ciliary nerves from the nasociliary branch of V1 are composed of sensory fibers, which penetrate the sclera posteriorly and course through the suprachoroidal space to the corneal limbus. These fibers then branch and radially penetrate the peripheral corneal stroma originating the stromal plexus. After stromal penetration, these fibers lose their perineurium and myelin sheaths which contributes to corneal transparency. Some fibers innervate stromal keratocytes while others continue to branch and advance anteriorly to form the sub-epithelial plexus. Finally, upon anterior branching and progression, they pierce the Bowman's layer, originating the subbasal nerve plexus and innervating the epithelium [2,3,6].From its nucleus in the pons to the corneal epithelial free endings, nerve fibers traverse a long way and are vulnerable to trauma, infections, toxicity and systemic diseases. In addition to congenital syndromes and diseases, all of those can lead to decrease or absence of corneal sensation and the development of neurotrophic keratitis [5]. Ocular causes include infections such as herpes simplex and zoster virus; postsurgical [any ocular surgery can cause damage of the ciliary fibers and direct corneal surgery (laser refractive surgery, corneal transplantation, cataract, corneal incisions) can directly affect the nerves]; topic anesthetic drops abuse; chemical burns; drug toxicity (e.g. beta-blockers, NSAIDs); chronic inflammation; contact lens wear; corneal dystrophies; corneal neoplasia [5,7]; and antivascular endothelial growth factor treatment (VEGF) [8,9].Systemic diseases include diabetes, leprosy, vitamin A deficiency and auto-immune diseases such as Graves and Sjogren syndrome [10]. Systemic medications such as neuroleptics, antipsychotics and antihistamines can also cause V nerve impairment. Central nervous system causes include space occupying lesions such as neoplasia/tumors and aneurysms, stroke, trauma and iatrogenic lesions postsurgical procedures. Genetic causes include familial dysautonomia (Riley-day syndrome), Goldenhar-Gorlin syndrome, Mobius syndrome, anhidrotic ectodermal dysplasia, familial corneal hypoesthesia and congenital insensitivity to pain with anhidrosis [3,5,7]. Amyloidosis, sarcoidosis, vitamin B12 deficiency and alcoholism-related polyneuropathy may also cause neurotrophic keratitis [10].Purpose of reviewNeurotrophic keratitis is a rare degenerative disease characterized by decrease or absence of corneal sensation. Neurotrophic keratitis varies from mild forms with mild epitheliopathy to severe manifestations such as corneal ulceration, melting and perforation that can lead to irreversible visual loss. The cause of neurotrophic keratitis comprises a long list of diseases, medications, congenital or genetic conditions as well as trauma. The mechanism of neurotrophic keratitis is complex and multifactorial and its understanding is crucial to better address the treatment strategies. We aimed to review neurotrophic keratitis pathology, mechanisms and management.Corneal nerves are critical for the homeostasis of a healthy ocular surface. The lack of nerve-derived neuromediators and corneal-released neuropeptides, neuro-trophins and neurotrophic factors in neurotrophic keratitis leads to a decrease in trophic supply to corneal cells in addition to a decrease in afferent signaling to the brain. This results in pathological tear secretion, decreased blinking rate, corneal healing along with ocular surface and corneal inflammation. Lately, nerve growth factor in special gained emphasis as a treatment strategy targeting the disease mechanism rather than its manifestations. Other therapies, including surgical interventions, are in the pipeline of neurotrophic keratitis management. However, there are still no proper therapeutic guidelines and neurotrophic keratitis treatment remains challenging.Neurotrophic keratitis may have a devastating outcome and treatment is still challenging. Understanding the disease pathology may assist in the development of new treatment strategies. Prompt disease recognition and immediate intervention are key factors to promote corneal healing and avoid further deterioration.Papers of particular interest, published within the annual period of review, have been highlighted as:The cornea is richly innervated by the ophthalmic branch of the trigeminal nerve. With a central corneal nerve density of approximately 7000 nociceptors/mm2, the cornea is 300-600 times more sensitive than skin [1,2], being the most sensitive and densely innervated tissue in the human body [1]. The sensory nerves mediate temperature, nociception and pressure sensation, being critically involved in the ocular defense mechanism of tearing, blinking and withdrawal reflex. In addition, they promote the release of trophic factors which are involved in maintaining a healthy ocular surface and promoting healing [2,3]. Moreover, corneal nerve density is negatively correlated with corneal dendritic cells density showing that corneal nerves are also directly involved in the regulation of homeostasis and immune privilege in the cornea [4].Neurotrophic keratitis is a rare degenerative disease. The exact prevalence of neurotrophic keratitis is unknown, but it is estimated between 1.6 and 4.2 cases per 10 000 [3] persons. It is characterized by decrease or absence of corneal sensation caused by impairment of corneal sensory nerves [3]. Different diseases can affect the trigeminal nerve and at different levels, including central space occupying lesions, systemic diseases, viral infections, trauma and topical drugs among others. A long list of causes can be attributed to the decrease or absence of corneal sensation, and it might be more common than described. Neurotrophic keratitis manifests initially as a corneal epithelial disease with irregularities and breakdowns that may progress with healing impairment. That, in association with decrease in blinking and tearing may lead to stromal ulceration, melting and ultimately perforation. The clinical course and prognosis are only dependent of the severity of the neurotrophic keratitis, regardless of the initial cause [3,5]. no caption availableCorneal innervation originates from the ophthalmic division (V1) of the V cranial nerve - the trigeminal nerve. Long ciliary nerves from the nasociliary branch of V1 are composed of sensory fibers, which penetrate the sclera posteriorly and course through the suprachoroidal space to the corneal limbus. These fibers then branch and radially penetrate the peripheral corneal stroma originating the stromal plexus. After stromal penetration, these fibers lose their perineurium and myelin sheaths which contributes to corneal transparency. Some fibers innervate stromal keratocytes while others continue to branch and advance anteriorly to form the sub-epithelial plexus. Finally, upon anterior branching and progression, they pierce the Bowman's layer, originating the subbasal nerve plexus and innervating the epithelium [2,3,6].From its nucleus in the pons to the corneal epithelial free endings, nerve fibers traverse a long way and are vulnerable to trauma, infections, toxicity and systemic diseases. In addition to congenital syndromes and diseases, all of those can lead to decrease or absence of corneal sensation and the development of neurotrophic keratitis [5].Ocular causes include infections such as herpes simplex and zoster virus; postsurgical [any ocular surgery can cause damage of the ciliary fibers and direct corneal surgery (laser refractive surgery, corneal transplantation, cataract, corneal incisions) can directly affect the nerves]; topic anesthetic drops abuse; chemical burns; drug toxicity (e.g. beta-blockers, NSAIDs); chronic inflammation; contact lens wear; corneal dystrophies; corneal neoplasia [5,7]; and antivascular endothelial growth factor treatment (VEGF) [8,9].Systemic diseases include diabetes, leprosy, vitamin A deficiency and auto-immune diseases such as Graves and Sjogren syndrome [10]. Systemic medications such as neuroleptics, antipsychotics and antihistamines can also cause V nerve impairment. Central nervous system causes include space occupying lesions such as neoplasia/tumors and aneurysms, stroke, trauma and iatrogenic lesions postsurgical procedures. Genetic causes include familial dysautonomia (Riley-day syndrome), Goldenhar-Gorlin syndrome, Mobius syndrome, anhidrotic ectodermal dysplasia, familial corneal hypoesthesia and congenital insensitivity to pain with anhidrosis [3,5,7]. Amyloidosis, sarcoidosis, vitamin B12 deficiency and alcoholism-related polyneuropathy may also cause neurotrophic keratitis [10].Purpose of reviewNeurotrophic keratitis is a rare degenerative disease characterized by decrease or absence of corneal sensation. Neurotrophic keratitis varies from mild forms with mild epitheliopathy to severe manifestations such as corneal ulceration, melting and perforation that can lead to irreversible visual loss. The cause of neurotrophic keratitis comprises a long list of diseases, medications, congenital or genetic conditions as well as trauma. The mechanism of neurotrophic keratitis is complex and multifactorial and its understanding is crucial to better address the treatment strategies. We aimed to review neurotrophic keratitis pathology, mechanisms and management.Corneal nerves are critical for the homeostasis of a healthy ocular surface. The lack of nerve-derived neuromediators and corneal-released neuropeptides, neuro-trophins and neurotrophic factors in neurotrophic keratitis leads to a decrease in trophic supply to corneal cells in addition to a decrease in afferent signaling to the brain. This results in pathological tear secretion, decreased blinking rate, corneal healing along with ocular surface and corneal inflammation. Lately, nerve growth factor in special gained emphasis as a treatment strategy targeting the disease mechanism rather than its manifestations. Other therapies, including surgical interventions, are in the pipeline of neurotrophic keratitis management. However, there are still no proper therapeutic guidelines and neurotrophic keratitis treatment remains challenging.Neurotrophic keratitis may have a devastating outcome and treatment is still challenging. Understanding the disease pathology may assist in the development of new treatment strategies. Prompt disease recognition and immediate intervention are key factors to promote corneal healing and avoid further deterioration.Papers of particular interest, published within the annual period of review, have been highlighted as:The cornea is richly innervated by the ophthalmic branch of the trigeminal nerve. With a central corneal nerve density of approximately 7000 nociceptors/mm2, the cornea is 300-600 times more sensitive than skin [1,2], being the most sensitive and densely innervated tissue in the human body [1]. The sensory nerves mediate temperature, nociception and pressure sensation, being critically involved in the ocular defense mechanism of tearing, blinking and withdrawal reflex. In addition, they promote the release of trophic factors which are involved in maintaining a healthy ocular surface and promoting healing [2,3]. Moreover, corneal nerve density is negatively correlated with corneal dendritic cells density showing that corneal nerves are also directly involved in the regulation of homeostasis and immune privilege in the cornea [4].Neurotrophic keratitis is a rare degenerative disease. The exact prevalence of neurotrophic keratitis is unknown, but it is estimated between 1.6 and 4.2 cases per 10 000 [3] persons. It is characterized by decrease or absence of corneal sensation caused by impairment of corneal sensory nerves [3]. Different diseases can affect the trigeminal nerve and at different levels, including central space occupying lesions, systemic diseases, viral infections, trauma and topical drugs among others. A long list of causes can be attributed to the decrease or absence of corneal sensation, and it might be more common than described. Neurotrophic keratitis manifests initially as a corneal epithelial disease with irregularities and breakdowns that may progress with healing impairment. That, in association with decrease in blinking and tearing may lead to stromal ulceration, melting and ultimately perforation. The clinical course and prognosis are only dependent of the severity of the neurotrophic keratitis, regardless of the initial cause [3,5]. no caption availableCorneal innervation originates from the ophthalmic division (V1) of the V cranial nerve - the trigeminal nerve. Long ciliary nerves from the nasociliary branch of V1 are composed of sensory fibers, which penetrate the sclera posteriorly and course through the suprachoroidal space to the corneal limbus. These fibers then branch and radially penetrate the peripheral corneal stroma originating the stromal plexus. After stromal penetration, these fibers lose their perineurium and myelin sheaths which contributes to corneal transparency. Some fibers innervate stromal keratocytes while others continue to branch and advance anteriorly to form the sub-epithelial plexus. Finally, upon anterior branching and progression, they pierce the Bowman's layer, originating the subbasal nerve plexus and innervating the epithelium [2,3,6].From its nucleus in the pons to the corneal epithelial free endings, nerve fibers traverse a long way and are vulnerable to trauma, infections, toxicity and systemic diseases. In addition to congenital syndromes and diseases, all of those can lead to decrease or absence of corneal sensation and the development of neurotrophic keratitis [5].Ocular causes include infections such as herpes simplex and zoster virus; postsurgical [any ocular surgery can cause damage of the ciliary fibers and direct corneal surgery (laser refractive surgery, corneal transplantation, cataract, corneal incisions) can directly affect the nerves]; topic anesthetic drops abuse; chemical burns; drug toxicity (e.g. beta-blockers, NSAIDs); chronic inflammation; contact lens wear; corneal dystrophies; corneal neoplasia [5,7]; and antivascular endothelial growth factor treatment (VEGF) [8,9].Systemic diseases include diabetes, leprosy, vitamin A deficiency and auto-immune diseases such as Graves and Sjogren syndrome [10]. Systemic medications such as neuroleptics, antipsychotics and antihistamines can also cause V nerve impairment. Central nervous system causes include space occupying lesions such as neoplasia/tumors and aneurysms, stroke, trauma and iatrogenic lesions postsurgical procedures. Genetic causes include familial dysautonomia (Riley-day syndrome), Goldenhar-Gorlin syndrome, Mobius syndrome, anhidrotic ectodermal dysplasia, familial corneal hypoesthesia and congenital insensitivity to pain with anhidrosis [3,5,7]. Amyloidosis, sarcoidosis, vitamin B12 deficiency and alcoholism-related polyneuropathy may also cause neurotrophic keratitis [10].Purpose of reviewNeurotrophic keratitis is a rare degenerative disease characterized by decrease or absence of corneal sensation. Neurotrophic keratitis varies from mild forms with mild epitheliopathy to severe manifestations such as corneal ulceration, melting and perforation that can lead to irreversible visual loss. The cause of neurotrophic keratitis comprises a long list of diseases, medications, congenital or genetic conditions as well as trauma. The mechanism of neurotrophic keratitis is complex and multifactorial and its understanding is crucial to better address the treatment strategies. We aimed to review neurotrophic keratitis pathology, mechanisms and management.Corneal nerves are critical for the homeostasis of a healthy ocular surface. The lack of nerve-derived neuromediators and corneal-released neuropeptides, neuro-trophins and neurotrophic factors in neurotrophic keratitis leads to a decrease in trophic supply to corneal cells in addition to a decrease in afferent signaling to the brain. This results in pathological tear secretion, decreased blinking rate, corneal healing along with ocular surface and corneal inflammation. Lately, nerve growth factor in special gained emphasis as a treatment strategy targeting the disease mechanism rather than its manifestations. Other therapies, including surgical interventions, are in the pipeline of neurotrophic keratitis management. However, there are still no proper therapeutic guidelines and neurotrophic keratitis treatment remains challenging.Neurotrophic keratitis may have a devastating outcome and treatment is still challenging. Understanding the disease pathology may assist in the development of new treatment strategies. Prompt disease recognition and immediate intervention are key factors to promote corneal healing and avoid further deterioration.Papers of particular interest, published within the annual period of review, have been highlighted as:The cornea is richly innervated by the ophthalmic branch of the trigeminal nerve. With a central corneal nerve density of approximately 7000 nociceptors/mm2, the cornea is 300-600 times more sensitive than skin [1,2], being the most sensitive and densely innervated tissue in the human body [1]. The sensory nerves mediate temperature, nociception and pressure sensation, being critically involved in the ocular defense mechanism of tearing, blinking and withdrawal reflex. In addition, they promote the release of trophic factors which are involved in maintaining a healthy ocular surface and promoting healing [2,3]. Moreover, corneal nerve density is negatively correlated with corneal dendritic cells density showing that corneal nerves are also directly involved in the regulation of homeostasis and immune privilege in the cornea [4].Neurotrophic keratitis is a rare degenerative disease. The exact prevalence of neurotrophic keratitis is unknown, but it is estimated between 1.6 and 4.2 cases per 10 000 [3] persons. It is characterized by decrease or absence of corneal sensation caused by impairment of corneal sensory nerves [3]. Different diseases can affect the trigeminal nerve and at different levels, including central space occupying lesions, systemic diseases, viral infections, trauma and topical drugs among others. A long list of causes can be attributed to the decrease or absence of corneal sensation, and it might be more common than described. Neurotrophic keratitis manifests initially as a corneal epithelial disease with irregularities and breakdowns that may progress with healing impairment. That, in association with decrease in blinking and tearing may lead to stromal ulceration, melting and ultimately perforation. The clinical course and prognosis are only dependent of the severity of the neurotrophic keratitis, regardless of the initial cause [3,5]. no caption availableCorneal innervation originates from the ophthalmic division (V1) of the V cranial nerve - the trigeminal nerve. Long ciliary nerves from the nasociliary branch of V1 are composed of sensory fibers, which penetrate the sclera posteriorly and course through the suprachoroidal space to the corneal limbus. These fibers then branch and radially penetrate the peripheral corneal stroma originating the stromal plexus. After stromal penetration, these fibers lose their perineurium and myelin sheaths which contributes to corneal transparency. Some fibers innervate stromal keratocytes while others continue to branch and advance anteriorly to form the sub-epithelial plexus. Finally, upon anterior branching and progression, they pierce the Bowman's layer, originating the subbasal nerve plexus and innervating the epithelium [2,3,6].From its nucleus in the pons to the corneal epithelial free endings, nerve fibers traverse a long way and are vulnerable to trauma, infections, toxicity and systemic diseases. In addition to congenital syndromes and diseases, all of those can lead to decrease or absence of corneal sensation and the development of neurotrophic keratitis [5].Ocular causes include infections such as herpes simplex and zoster virus; postsurgical [any ocular surgery can cause damage of the ciliary fibers and direct corneal surgery (laser refractive surgery, corneal transplantation, cataract, corneal incisions) can directly affect the nerves]; topic anesthetic drops abuse; chemical burns; drug toxicity (e.g. beta-blockers, NSAIDs); chronic inflammation; contact lens wear; corneal dystrophies; corneal neoplasia [5,7]; and antivascular endothelial growth factor treatment (VEGF) [8,9].Systemic diseases include diabetes, leprosy, vitamin A deficiency and auto-immune diseases such as Graves and Sjogren syndrome [10]. Systemic medications such as neuroleptics, antipsychotics and antihistamines can also cause V nerve impairment. Central nervous system causes include space occupying lesions such as neoplasia/tumors and aneurysms, stroke, trauma and iatrogenic lesions postsurgical procedures. Genetic causes include familial dysautonomia (Riley-day syndrome), Goldenhar-Gorlin syndrome, Mobius syndrome, anhidrotic ectodermal dysplasia, familial corneal hypoesthesia and congenital insensitivity to pain with anhidrosis [3,5,7]. Amyloidosis, sarcoidosis, vitamin B12 deficiency and alcoholism-related polyneuropathy may also cause neurotrophic keratitis [10].