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Neurotrophic Keratitis


Key Concepts

  • Corneal sensation should be assessed in any poorly healing cornea.

  • Topical anesthetic abuse should be considered if no other cause is found.

  • Careful and close follow-up is essential.

  • Lid defects should be corrected early.

  • Removal of toxins such as preservatives followed by aggressive lubrication is the best first step.

  • Escalation to autologous serum tears and/or preservative-free, antibiotic/steroid combination drops may be necessary.

  • Consider topical cenegermin-bkbj (recombinant human nerve growth factor [rhNGF]/Oxervate-Dompe) or surgical neurotization for permanent cure.

  • Timely lateral tarsorrhaphy is necessary when medical therapy fails.

  • Prevention of melting or scarring will avoid the need for transplant.

  • Transplantation is very high-risk but is possible with aggressive medical therapy.

Neurotrophic keratitis is a degenerative disease of corneal epithelium characterized by impaired healing. Absence of corneal sensitivity is the hallmark of the condition, which may end in corneal stromal melting and perforation. The causes of decreased corneal sensation are myriad and may affect sensory nerve supply from the trigeminal nucleus to the corneal nerve endings. Reduced corneal sensation renders the corneal surface prone to occult injury and decreases reflex tearing; it also appears to decrease healing rates of corneal epithelial injuries. Vulnerability and poor healing, secondary to corneal sensory denervation, favor the formation of nonhealing epithelial defects. These defects tend to ulcerate and ultimately perforate if not appropriately treated in a timely fashion.

The initial clinical appearance of an anesthetic cornea may include loss of the usual corneal epithelial sheen with mild disruptions in the tear surface. Even in the absence of injury, the condition may progress to punctate keratitis, epithelial loss, and ultimately stromal ulceration. Evaluation of a patient found to have impaired or absent corneal sensation should include careful review of previous surgical procedures, concomitant systemic diseases, and topical and systemic medications. A careful ocular examination should follow to elucidate clues to local disease processes causing corneal anesthesia and to identify defects in other external ocular structures that may contribute to poor corneal epithelial healing. Management should emphasize the prevention of epithelial defects because of profoundly impaired epithelial healing. Recent surgical and medical therapies promise possible resolution of corneal anesthesia. An epithelial defect in the setting of corneal anesthesia is a serious ocular condition requiring prompt and aggressive therapy to prevent ulceration and possible perforation.

Clinical Causes

Both local ocular and distant neurologic conditions may impair corneal sensation. The most common causes of corneal anesthesia are herpes simplex (HSV) and zoster (HZV) virus infections of the ocular surface. Next in frequency are tumors and surgical procedures that damage the ophthalmic branch of the trigeminal nerve. Other causes include congenital syndromes, corneal dystrophies, local trauma to the corneal nerves, infections such as leprosy, systemic disease, topical medications, and exposure to toxins. Also, chronic corneal epithelial injury or severe stromal inflammation may cause corneal hypesthesia ( Box 88.1 ). Although any cornea with decreased sensation may develop neurotrophic keratitis, conditions that result in more profound corneal anesthesia are more likely to develop neurotrophic changes.

BOX 88.1
Causes of Corneal Hypesthesia

  • Infection

    • Herpes simplex ,

    • Herpes zoster ,

    • Leprosy

  • Fifth nerve palsy

    • Surgery (as for trigeminal neuralgia) , ,

    • Neoplasia (such as acoustic neuroma) ,

    • Aneurysms

    • Facial trauma

    • Congenital ,

    • Familial dysautonomia (Riley-Day syndrome)

    • Goldenhar-Gorlin syndrome

    • Möbius syndrome

    • Familial corneal hypesthesia

    • Congenital insensitivity to pain with anhidrosis

  • Topical medications

    • Anesthetics ,

    • Timolol

    • Betaxolol

    • Sulfacetamide 30%

    • Diclofenac sodium

  • Corneal dystrophies

    • Lattice

    • Granular (rare)

  • Systemic disease

    • Diabetes mellitus

    • Vitamin A deficiency

  • Iatrogenic

    • Contact lens wear

    • Trauma to ciliary nerves by laser and surgery (primarily for retinal conditions) ,

    • Corneal incisions

    • LASIK

  • Toxic

    • Chemical burns

    • Carbon disulfide exposure ,

    • Hydrogen sulfide exposure ,

  • Miscellaneous

    • Increasing age

    • Dark eye color

    • Adie syndrome

    • Dihydroxypyrimidine dehydrogenase (DHPD) deficiency

    • Any condition causing chronic corneal epithelial injury or inflammation

HSV and HZV infections of the cornea have characteristic clinical appearances that are described in detail in other chapters. The extent of corneal anesthesia in both entities is well known, with HZV causing more segmental hypesthesia than herpes simplex. Although the lack of corneal sensation plays a central role in the development of persistent epithelial defects and corneal ulceration in HSV corneal disease, HZV keratitis promotes more classic neurotrophic lesions, which often occur without viral epithelial infection. Twenty-one percent of patients with herpes zoster ophthalmicus will demonstrate decreased central corneal sensitivity. Forty-nine percent will develop corneal hypesthesia to some degree within 1 year, and one-third of that total will have persistent decreased sensation beyond 1 year. Despite improving methods for treatment, both conditions can lead to ulceration and perforation of the cornea, significantly affecting vision.

Pure neuroparalytic keratitis secondary to fifth nerve palsy is second to herpetic infection in terms of the incidence of persistent corneal epithelial defects and subsequent perforations. The condition may occur secondary to intentional or inadvertent damage to the trigeminal nucleus, root, ganglion, or any segment of the ophthalmic branch of this cranial nerve. Most frequently, the nerve is damaged during attempted ablative procedures for trigeminal neuralgia. Surgical procedures to repair maxillary fractures may also damage the fifth cranial nerves, resulting in neurotrophic keratitis. A fertile setting for neurotrophic keratitis occurs after resection of an acoustic neuroma, particularly when both the fifth and seventh cranial nerves are affected. With concomitant facial nerve paralysis the anesthetic cornea suffers chronic exposure, a combination that, despite aggressive therapy, favors recurrent or persistent epithelial defects, stromal lysis, and ultimately perforation.

Another cause of corneal anesthesia that may predispose to neurotrophic keratitis is diabetes mellitus. , Diabetics have decreased corneal sensation that increases in severity and prevalence in proportion to the duration of their diabetes. Corneal sensory loss is another manifestation of the generalized peripheral neuropathy often found with long-standing diabetes. Peripheral panretinal photocoagulation for neovascular retinal disease often deepens the hypesthesia already present. Because these patients are at risk for developing proliferative vitreoretinopathy and vitreous hemorrhage requiring surgical intervention, they are also at risk for developing persistent nonhealing corneal epithelial defects in the immediate postoperative period. Some diabetics, however, may develop neurotrophic keratitis without previous surgical injury.

The chronic use of various topical medications will cause corneal sensory loss. These medications include timolol, betaxolol, 30% sulfacetamide, and diclofenac sodium. When used after keratorefractive surgery, this effect of diclofenac sodium aids pain control but may aggravate epithelial integrity in an environment of temporary corneal hypesthesia seen with laser in situ keratomileusis (LASIK) and photorefractive keratectomy (PRK). , Moreover, the illicit use of topical anesthetics produces a profound and predictable course of corneal ulceration ( Fig. 88.1 ). , The most frequent cases appear in the setting of cocaine abuse or the use of a diagnostic topical anesthetic, usually by a healthcare professional, as an analgesic for the relief of eye pain after an ocular injury. In the latter situation, topical anesthetics are used more frequently and with increasingly inadequate results until the cornea is severely damaged. The epithelium will not heal with continued use of the topical anesthetic, promoting frequent infectious keratitis and occasional corneal perforation in these patients.

Fig. 88.1, Complete corneal necrosis secondary to topical anesthetic abuse.

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