Neurotrophic Keratopathy

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Classification according to ICD-10
H16.2 Keratoconjunctivitis neuroparalytica
ICD-10 online (WHO version 2019)

The neurotrophic keratopathy (including neurotrophic keratitis , keratopathy neuroparalytica or keratitis neuroparalytica ) NK, abbreviated, is a degenerative disease of the cornea of the eye due to damage of the trigeminal nerve caused the spontaneous to loss of corneal sensitivity and develop injury of the corneal epithelium as well as impaired healing properties, which can lead to the development of ulcers, aseptic necrosis and perforations of the cornea.

Neurotrophic keratopathy is classified as a rare disease that is estimated to affect less than 5 in 10,000 people in Europe. According to records, an average of 6 percent of cases can develop herpetic keratopathy and up to 12.8 percent of cases can develop keratopathy due to herpes zoster.

The diagnosis and, in particular, the treatment of neurotrophic keratopathy are the most complex aspects of this disease as there is currently no satisfactory therapeutic approach.

causes

The cornea is an avascular tissue and is one of the most densely innervated structures in the human body . The nerves of the cornea are responsible for maintaining the anatomical and functional integrity of the cornea as well as for the transmission of tactile, temperature and pain sensations and play a role in the blink reflex and the tear reflex.

Most of the nerve fibers are of sensory origin and come from the eye area of ​​the trigeminal nerve. Congenital or acquired and systemic eye diseases can lead to injury at different levels of the trigeminal nerve, which in turn can lead to a reduction ( hypoesthesia ) or a loss ( anesthesia ) of the sensitivity of the cornea.

The most common causes of corneal loss of sensitivity are viral infections ( herpes simplex and ocular herpes zoster ), chemical burns, physical injuries, some results of surgery or neurosurgery on the cornea, chronic use of topical drugs, and abuse of contact lenses.

Possible causes also include systemic diseases such as diabetes , multiple sclerosis or leprosy .

There are other potential causes of the disease, although less common: Injuries that spread to the intercranial space, such as a neuroma , meningioma, or aneurysms that can compress the trigeminal nerve and make the cornea less sensitive.

Congenital diseases that can trigger neurotrophic keratopathy are very rare.

Classification

According to the Mackie classification, neurotrophic keratopathy can be divided into three stages, depending on its severity:

  1. Stage I: characterized by changes in the corneal epithelium, which becomes cloudy and has superficial keratopathy and corneal edema. Long-term neurotrophic keratopathy can also be associated with hyperplasia of the epithelium, opacity in the stroma, and neovascularization of the cornea.
  2. Stage II: characterized by developing epithelial damage, often in the area near the center of the cornea.
  3. Stage III: characterized by ulcers of the cornea associated with stroma edema and aseptic necrosis, which could lead to perforations of the cornea.

diagnosis

The diagnosis can be made based on a patient's medical history and careful examination of the eye and surrounding area.

Given the patient's clinical history, particular attention should be paid to any herpes virus infection and possible corneal surgery, trauma, abuse of anesthetics or chronic topical therapies, chemical burns and, in some cases, the abuse of contact lenses. Likewise, it is necessary to examine the patient for a possible diabetes disease or for other systemic diseases such as multiple sclerosis.

The clinical examination is generally carried out using a number of assessments and tools:

  • General examination of the cranial nerves to assess the presence of damage to the nervous system.
  • Eye exams:
  1. Full eye examination: examination of the eyelids, blinking, presence of inflammatory reactions and secretions, changes in the corneal epithelium.
  2. Corneal sensitivity test: this is carried out by contacting a cotton swab on the surface of the cornea, which makes it possible to determine whether the sensitivity of the cornea is normal, limited or absent, or with the aid of an esthesiometer, which measures the corneal sensitivity can be made.
  3. Functional test of the tear film, such as the Schirmer test or test of the tear film break up time .
  4. Eye color tests with fluorescein, which can be used to check for any damage to the corneal epithelium and conjunctiva.

Treatment and therapeutic perspectives

Early diagnosis, treatment according to the severity of the disease, and regular examination of the patient with neurotrophic keratopathy are essential to avoid the progression of damage and the appearance of corneal ulcers, especially given the fact that it deteriorates of the clinical picture often run without clear symptoms.

The purpose of therapy is to prevent the damage to the cornea from progressing and to encourage the corneal epithelium to heal. The treatment must always be designed individually, depending on the severity of the disease. In general, conservative treatment is resorted to.

In the less severe stage I, by administering eye preparations with a lubricating effect without preservatives several times a day, the aim is to lubricate and protect the surface of the eye, thereby improving the quality of the epithelium and preventing a possible loss of corneal transparency.

In stage II, however, the development of corneal ulcers must be prevented and the healing of any injuries to the epithelium promoted. In addition to eye preparations with a smear effect, antibiotics can also be used to prevent possible infections, and the patient must undergo special treatment: since the disease is without clear symptoms, therapeutic contact lenses can also be used at this stage, which have a protective effect Have an effect and aid in the healing of corneal injuries.

In more severe forms (stage III), in addition to treatment with contact lenses and antibiotics, the progression towards corneal perforation must also be prevented; In these cases, a possible surgical treatment is tarsorrhaphy, in which the eyelids are temporarily or permanently closed with sutures or botulinum toxin injections. This procedure enables the cornea to be protected, even if the aesthetic result of such procedures may hardly be acceptable to the patient. Similarly, a procedure involving the erection of a conjunctival valve has been shown to be effective in treating chronic corneal ulcers with or without perforation of the cornea. Aside from these surgical procedures, amniotic membrane grafting is another option. It has recently been shown to play a role in stimulating corneal epithelium healing, reducing corneal neovascularization, and reducing inflammation of the ocular surface. Other treatment options used for severe forms include the administration of autologous serum eye drops.

Research studies have focused on developing novel treatments for NK, and various polypeptides, growth factors, and neurotransmitters have been suggested. Studies of topical treatments with substance P and IGF-1 (insulin-like growth factor-1) have been conducted and have shown an effect on epithelial healing. The nerve growth factor (NGF) plays a role in epithelial proliferation and differentiation and survival of corneal sensory nerves. Topical treatment with murine NGF has been shown to promote the recovery of epithelial integrity and corneal sensitivity in NK patients. Recently, an eye drop formulation containing recombinant human nerve growth factor was developed for clinical use. Cenegermin, a recombinant form of human NGF (nerve growth factor), was recently approved in Europe in an eye drop formulation for neurotrophic keratopathy.

Individual evidence

  1. ↑ a b c d e S. Bonini, P. Rama, D. Olzi, A. Lambiase: Neurotrophic Keratopathie. In: Eye. 17, 2003, pp. 989-995.
  2. ↑ a b c d e f g h M. Sacchetti, A. Lambiase: Diagnosis and management of neurotrophic keratopathy. In: Clin Ophthalmol. 8, 2014, pp. 571-579.
  3. ^ BS Shaheen, M. Bakir, S. Jain: Corneal nerves in health and disease. In: Surv Ophthalmol. 59, 2014, pp. 263-285.
  4. ^ LJ Müller, CF Marfurt, F. Kruse, TM Tervo: Corneal nerves: structure, contents and function. In: Experimental Eye Research. 76, 2003, pp. 521-542.
  5. ↑ a b L. Mastropasqua, G. Massaro-Giordano, M. Nubile, M. Sacchetti: Understanding the Pathogenesis of Neurotrophic Keratopathie: The Role of Corneal Nerves. In: J Cell Physiol. 232 (4), Apr 2017, pp. 717-724.
  6. ↑ J. Gallar, TM Tervo, W. Neira, JM Holopainen, ME Lamberg, F. Miñana, MC Acosta, C. Belmonte: Selective changes in human corneal sensation associated with herpes simplex virus keratopathy. In: Invest Ophthalmol Vis Sci. 51, 2010, pp. 4516-4522.
  7. ^ TJ Liesegang: Corneal complications from herpes zoster ophthalmicus. In: Ophthalmology. 92, 1985, pp. 316-324.
  8. ↑ RA Hyndiuk, EL Kazarian, RO Schultz, P. Seideman: neurotrophic corneal ulcers in diabetes mellitus. In: Arch Ophthalmol. 95, 1977, pp. 2193-2196.
  9. ↑ D. John, M. Thomas, P. Jacob: Neurotrophic Keratopathie and congenital insensitivity to pain with anhidrosis - a case report with 10-year follow-up. In: Cornea. 30, 2011, pp. 100-102.
  10. ↑ F. Semeraro, E. Forbice, V. Romano, M. Angi, MR Romano, ME Filippelli, R. Di Iorio, C. Costagliola: Neurotrophic keratopathy. In: Ophthalmologica. 231, 2014, pp. 191-197.
  11. ^ HL Gould: Treatment of neurotrophic keratopathy with scleral contact lenses. In: Eye Ear Nose Throat Mon. 46, 1967, pp. 1406-1414.
  12. ↑ E. Turkoglu, E. Celik, G. Alagoz: A comparison of the efficacy of autologous serum eye drops with amniotic membrane transplantation in neurotrophic keratopathy. In: Semin Ophthalmol. 29, 2014, pp. 119–126.
  13. ^ R. Yanai, R. Nishida, T. Chikama, N. Morishige, N. Yamada, KH Sonoda: Potential New Modes of Treatment of Neurotrophic Keratopathy. In: Cornea. 34, Suppl 11, 2015, pp. S121-S127.
  14. ↑ A. Lambiase, P. Rama, S. Bonini, G. Caprioglio: Aloe L. Topical treatment with nerve growth factor for corneal neurotrophic ulcers. In: N Engl J Med. 338 (17), 1998, pp. 1174-1180.
  15. ^ [1] European Medicines Agency, New medicine for rare eye disease