Corneal disease

Author, Zachary Vonderach, O.D.  Edited by Abraham Zlatin, O.D., FIAOMC

Corneal disease

The first step to clear vision is a healthy cornea. Corneal diseases pose one of the biggest threats to clear vision in patients of all ages. Neurotrophic keratitis is a degenerative corneal disease that results in a breakdown of corneal clarity and structure. The cornea maintains clarity and structure using a feedback system that starts with corneal nerves. In neurotrophic keratitis, the corneal nerves become damaged which results in loss of sensation to the tissue. Nerve damage puts the cornea at risk of becoming irregular and opaque.

Causes

The causes of Neurotrophic keratitis include herpetic keratitis, diabetes, multiple sclerosis, and chemical burns. In addition to those, there are cases of LASIK induced neurotrophic keratitis. LASIK is a refractive surgery that continues to grow in popularity. There are an estimated 65,000 cases of neurotrophic keratitis in the Untied States.  Medical treatment for neurotrophic keratitis is mainly supportive therapy and does not address underlying causes. Recently, the FDA has approved a promising new treatment.
The immense number of sensory nerve endings makes the cornea the most densely innervated tissue in the human body. There are about 7,00 nerve endings per square milimeter2. The sensory nerves, which constitute the majority of corneal nerves, are mainly derived from the ophthalmic division of the trigeminal nerve3.  The autonomic nerve fibers consist of sympathetic fibers that are derived from the superior cervical ganglion and parasympathetic fibers that originate from the ciliary ganglion4.  Corneal nerves help maintain a healthy ocular surface, both by triggering protective reflexes after injury and by providing trophic factors to the corneal cells. Corneal denervation causes epithelial changes including intracellular edema, loss of microvilli, and abnormal development of the basal lamina5,6.
Any condition that damages the trigeminal nerve can cause neurotrophic keratitis. Ocular surface diseases, systemic diseases, and central or peripheral nerve damage are all examples of causes. Herpes simplex and herpes zoster eye infections are among the most common conditions leading to corneal anesthesia. Long-term systemic therapy with antipsychotics and antihistamines may also cause neurotrophic keratitis7.
Corneal surgeries like LASIK, keratoplasty, and corneal incisions for cataract may disrupt corneal innervation and cause neurotrophic keratitis8. After nerve transaction at the cornea, the distal nerves undergo Wallerian degeneration with immediate loss of sensation to the corresponding region. Nerve regeneration occurs gradually over months with variable return of corneal sensitivity.

How it presents

Presentation of neurotrophic keratitis starts with a loss of sensitivity leading to superficial punctate keratopathy and corneal edema. As the disease progresses epithelial defects become more frequent leading to corneal ulcers and stromal melt. Corneal proliferation occurs in severe cases. Patients often complain of decrease vision instead of discomfort or pain due to impaired corneal sensitivity. Treatment is often challenging in cases of neurotrophic keratitis.
The severity of the disease will dictate the treatment plan which all aim to repair corneal surface irregularities and restore clarity.  Once the underlying cause is addressed, corneal lubrication becomes the focus. Avoiding any medications associated with corneal toxicity is important. Nonpreservative artificial tears and lubricants need to are used aggressively.
While no controlled studies have been conducted to date, the use of topical Restasis is an option. Restasis has been advocated in the treatment of neurotrophic keratitis because it may enhance tear production and diminish inflammatory mediators that contribute to sensory corneal denervation.9  Substances found in Autologous serum eye drops are known to promote proliferation, migration, and differentiation of the ocular surface epithelium, and are essential in corneal homeostasis and wound healing and have been used for treatment.10 Amniotic membrane transplantation has been successfully used to treat corneal ulcers and persistent epithelial defects from different causes, including neurotrophic keratitis.11 The amniotic membrane provides mechanical protection, releases growth factors, and supports epithelial cell adhesion and proliferation. Surgical treatment is usually limited to corneal ulcers not responding to medical treatment.  Surgical approaches include tarsorrhaphy or conjunctival flap.

Other treatments

The FDA has recently approved Oxervate (cenegermin, Dompé farmaceutici SpA), a topical eye drop that is the first drug for the treatment of neurotrophic keratitis. Oxervate is a topical solution of 0.002%  cenegermin-bkbj (20 mcg/mL) administered six times per day for eight weeks to treat neurotrophic keratitis.  Its active ingredient is a recombinant form of human nerve growth factor, a protein made by the human body. Nerve growth factor (NGF) acts through specific high-affinity and low-affinity nerve growth factor receptors in the anterior segment of the eye to support corneal innervation and integrity. In one study, after eight weeks, 72.0 percent of patients in the treatment group were completely healed vs. 33.3 percent in the vehicle group.12 Management of neurotrophic keratopathy requires decisive action. Early treatment intervention is important to help avoid severe complications.

Corneal disease References:

1 Sacchetti M, Lambiase A. Diagnosis and Management of Neurotrophic Keratitis. Clinical Ophthalmology. 2014;8:571-9.
2. Rozsa AJ, Beuerman RW. Density and organization of free nerve endings in the corneal epithelium of the rabbit. Pain. 1982;14(2):105–120. [PubMed] [Google Scholar]
3. Bonini S, Lambiase A, Rama P, Caprioglio G, Aloe L. Topical treatment with nerve growth factor for neurotrophic keratitis. Ophthalmology. 2000;107(7):1347–1351. [PubMed] [Google Scholar]
4. Bonini S, Aloe L, Bonini S, Rama P, Lamagna A, Lambiase A. Nerve growth factor (NGF): an important molecule for trophism and healing of the ocular surface. Adv Exp Med Biol. 2002;506(Pt A):531–537. [PubMed] [Google Scholar]
5. Sigelman S, Friedenwald JS. Mitotic and wound-healing activities of the corneal epithelium: effect of sensory denervation. AMA Arch Ophthalmol. 1954;52(1):46–57. [PubMed] [Google Scholar]
6. Alper MG. The anesthetic eye: an investigation of changes in the anterior ocular segment of the monkey caused by interrupting the trigeminal nerve at various levels along its course. Trans Am Ophthalmol Soc. 1975;73:323–365. [PMC free article] [PubMed] [Google Scholar]
7. Sacchetti M, Lambiase A. Diagnosis and management of neurotrophic keratitis. Clin Ophthalmol. 2014;8:571–579. [PMC free article] [PubMed] [Google Scholar]
8.  Lee BH, McLaren JW, Erie JC, Hodge DO, Bourne WM. Reinnervation in the cornea after LASIK. Invest Ophthalmol Vis Sci. 2002;43(12):3660–3664. [PubMed] [Google Scholar]
9. Kabat AG, Reynolds SA. The role of topical cyclosporine in managing HSV-related neurotrophic keratopathy. Paper presented at the American Academy of Optometry meeting. December 12, 2004; Tampa, Fla.
10. Matsumoto Y, Dogru M, Goto E, et al. Autologous serum application in the treatment of neurotrophic keratopathy. Ophthalmology. 2004;111(6):1115–1120. [PubMed] [Google Scholar]
11. Chen HJ, Pires RT, Tseng SC. Amniotic membrane transplantation for severe neurotrophic corneal ulcers. Br J Ophthalmol. 2000;84(8):826–833.
12.Chao W, Benitez Del Castillo JM, Dana R, Geerling G, Mantelli F, Massaro-Giordano G, Rama P. Healing of Persistent Epithelial Defects or Corneal Ulcer by Recombinant Human Nerve Growth Factor Eye Drops in Patients with Stage 2 or 3 Neurotrophic Keratitis. Presented at the Congress of the European Society of Ophthalmology (SOE), Barcelona, Spain, June, 10–13, 2017.
13.Versura, Piera et al. “Neurotrophic keratitis: current challenges and future prospects.” Eye and brain vol. 10 37-45. 28 Jun. 2018, doi:10.2147/EB.S117261
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