October 10, 2014
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Clinical findings and management of neurotrophic keratopathy

Management depends on the clinical stage of the condition.

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Neurotrophic keratopathy is a degenerative disease characterized by impaired corneal epithelium healing and absence of corneal sensitivity. Corneal sensory denervation makes the cornea vulnerable to occult injury and poor healing that triggers a nonhealing epithelial defect. Epithelial breakdown can lead to ulceration, infection, melting and perforation.

Ladan Espandar, MD

Ladan Espandar

Clinical causes

Herpes simplex and herpes zoster keratitis are the most common causes of corneal anesthesia. Fifth nerve palsy secondary to surgery (as for trigeminal neuralgia), neoplasia (acoustic neuroma), aneurysms and facial trauma are in second place. Other causes include congenital syndromes such as Riley-Day, Goldenhar-Gorlin or Möbius syndrome; corneal dystrophies such as lattice or granular dystrophy; local trauma to the corneal nerves; infections such as leprosy; systemic disease such as diabetes and vitamin A deficiency; topical medications such as anesthetics, glaucoma medications or diclofenac sodium; exposure to toxins such as chemical burns; and chronic corneal inflammation.

Clinical findings

Corneal anesthesia triggers a cascade of ocular surface abnormalities that promote the development of ulceration. Decrease in reflex tearing, lower blink rate and increase in viscosity of tear film result in tear film abnormalities. An anesthetic cornea produces fewer neurotrophic factors that result in decreased cell metabolism, increased permeability, decreased cell mitosis and progressive corneal epithelial microvilli abnormalities. These changes make the cornea vulnerable to injury and incapable of regeneration. The earliest sign of sensory denervation is rose bengal staining of the inferior palpebral conjunctival surface. Decreased tear breakup time forms geographic dry spots on the corneal epithelium. Small patches of drying epithelium, also known as Gaule spots, may be seen in retroillumination. These findings may become chronic, resulting in superficial vascularization, stromal scarring, and epithelial hyperplasia and irregularity. Rarely, a hyperplastic precorneal membrane will grow centrally from the limbus to cover intact corneal epithelium.

Clinical stages of neurotrophic keratopathy (Mackie classification)

Stage 1

  • Rose bengal staining of the palpebral conjunctivae
  • Decreased tear breakup time
  • Increased mucus viscosity of tears
  • Punctate epithelial fluorescein staining
  • Scattered small patches of dried epithelium (Gaule spots)

Stage 2

  • Epithelial defect, usually oval and in the superior cornea
  • Edges of the epithelial defect become smooth and rolled with time
  • Stromal edema with Descemet’s membrane folds
  • Sometimes associated with aqueous cell and flare

Stage 3

  • Stromal lysis, sometimes resulting in corneal perforation

Prognosis

Prognostic indicators include the degree of sensory loss, the duration of the condition and the presence of other ocular surface disease. The incidence of neurotrophic keratopathy increases with age.

Management

Neurotrophic keratopathy management depends on the condition of the ocular surface and the degree of sensory denervation. Stage 1 can be treated by topical lubrication such as preservative-free artificial tears, gels and ointments. Eyelid abnormalities must be carefully assessed and treated to prevent exposure keratopathy and progression to stage 2. If there is severe or total loss of corneal sensation, a lateral tarsorrhaphy often prevents epithelial defects. Punctal occlusion may need to be considered.

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The presence of an epithelial defect requires immediate and proper treatment. An epithelial defect in the mild form of corneal denervation may respond well to lubricants and topical prophylactic antibiotics, whereas the presence of severe or complete loss of sensation requires a more aggressive approach, such as oral doxycycline or minocycline, which improves tear stability and prevents corneal stromal lysis. Also, a tarsorrhaphy that covers most of the defect will often help close an epithelial defect, even without eyelid malfunctions.

Recent studies have shown that substance P and insulin-like growth factor 1 (IGF-1) together and nerve growth factor (NGF) alone accelerate epithelial healing in neurotrophic corneas. Currently, the safety and effectiveness of recombinant human NGF (rhNGF, Dompe) are being evaluated through the REPARO study, which is taking place across 39 centers in nine European countries. Recently, the U.S. Food and Drug Administration granted orphan drug designation for this drug, and a second phase 2 trial is planned at nine U.S. sites. Published studies have shown a role for umbilical cord serum and platelet-rich autologous serum eye drops.

Stage 3 of neurotrophic keratopathy involves stromal ulceration and lysis with thinning of the cornea. Corneas that show progressive thinning despite previously mentioned treatments require immediate attention to halt stromal lysis and subsequent progression to corneal perforation.

Cyanoacrylate glue, tectonic lamellar keratoplasty, conjunctival flaps and multilayer amniotic membrane transplantation may all assist to stop progression of stromal lysis to perforation. Use of amniotic membrane such as ProKera (Bio-Tissue) shows additional promise not only for arresting progressive melting but also for eliminating the surrounding stromal infiltrate.

In case of perforation, glue may be applied if the perforation is smaller than 2 mm. Larger defects require lamellar or penetrating keratoplasty. The lamellar graft, because of its lower rejection rate and more rapid healing, is the procedure of choice for small to intermediate-size perforations.

Visit UPMCPhysicianResources.com/Ocular to learn more about neurotrophic keratopathy. You can also submit clinical questions or read the most recent questions asked of the UPMC Eye Center’s ophthalmology experts.

References:

Alio JL, et al. Ophthalmology. 2007;doi:10.1016/j.ophtha.2006.10.044.
Bonini S, et al. Ophthalmology. 2000;doi:10.1016/S0161-6420(00)00163-9.
Chang BH, Groos Jr EB. Neurotrophic keratopathy. In: Krachmer JH, Mannis MJ, Holland EJ, eds. Cornea. 3rd ed. Elsevier; 2011:1101-1108.
Gilbard JP, et al. Ophthalmology. 1990;doi:10.1016/S0161-6420(90)32587-3.
Nishida T, et al. Jpn J Ophthalmol. 2007;doi:10.1007/s10384-007-0480-z.
Poon AC, et al. Br J Ophthalmol. 2001;doi:10.1136/bjo.85.10.1188.
Tan MH, et al. Cornea. 2006;doi:10.1097/01.ico.0000176609.42838.df.
Yoon KC, et al. Ophthalmology. 2007;doi:10.1016/j.ophtha.2006.12.014.

For more information:

Ladan Espandar, MD, is an assistant professor of ophthalmology at UPMC and the University of Pittsburgh. She can be reached at UPMC Eye Center, 203 Lothrop St., Floor 7, Pittsburgh, PA 15213; 412-647-2200.

Disclosure: Espandar has no relevant financial disclosures.