Diagnosis and management of neurotrophic keratitis

Marta Sacchetti, Alessandro Lambiase, Marta Sacchetti, Alessandro Lambiase

Abstract

Neurotrophic keratitis (NK) is a degenerative disease characterized by corneal sensitivity reduction, spontaneous epithelium breakdown, and impairment of corneal healing. Several causes of NK, including herpetic keratitis, diabetes, and ophthalmic and neurosurgical procedures, share the common mechanism of trigeminal damage. Diagnosis of NK requires accurate investigation of clinical ocular and systemic history, complete eye examination, and assessment of corneal sensitivity. All diagnostic procedures to achieve correct diagnosis and classification of NK, including additional examinations such as in vivo confocal microscopy, are reviewed. NK can be classified according to severity of corneal damage, ie, epithelial alterations (stage 1), persistent epithelial defect (stage 2), and corneal ulcer (stage 3). Management of NK should be based on clinical severity, and aimed at promoting corneal healing and preventing progression of the disease to stromal melting and perforation. Concomitant ocular diseases, such as exposure keratitis, dry eye, and limbal stem cell deficiency, negatively influence the outcome of NK and should be treated. Currently, no specific medical treatment exists, and surgical approaches, such as amniotic membrane transplantation and conjunctival flap, are effective in preserving eye integrity, without ameliorating corneal sensitivity or visual function. This review describes experimental and clinical reports showing several novel and potential therapies for NK, including growth factors and metalloprotease inhibitors, as well as three ongoing Phase II clinical trials.

Keywords: cornea innervation; cornea sensitivity; neurotrophic keratitis; persistent epithelial defect.

Figures

Figure 1
Figure 1
Stage 1 neurotrophic keratitis (A) showing cloudy and irregular corneal epithelium associated with mild stromal scarring. Stage 2 neurotrophic keratitis (B) with a large persistent epithelial defect characterized by smooth, rolled edges. No signs of ocular inflammation are present. Stage 3 neurotrophic keratitis (C) characterized by deep corneal ulcer, stromal melting, and sterile hypopyon.
Figure 2
Figure 2
Stepwise approach to the diagnosis and treatment of neurotrophic keratitis (NK).

References

    1. Bonini S, Rama P, Olzi D, Lambiase A. Neurotrophic keratitis. Eye (Lond) 2003;17:989–995.
    1. Groos EB., Jr . Neurotrophic keratitis. In: Krachmer JH, Mannis MJ, Holland EJ, editors. Cornea: Clinical Diagnosis and Management. St Louis, MO, USA: Mosby; 1997.
    1. Magendie F. De l’influence de la cinquieme paire de nerfs sur la nutrition et les fonctions de l’oeil. [The influence of the fifth pair of nerves on nutrition and function of the eye] J Physiol Exp Pathol. 1824;4:176–182. French.
    1. Müller LJ, Marfurt CF, Kruse F, Tervo TM. Corneal nerves: structure, contents and function. Exp Eye Res. 2003;76:521–542.
    1. Labetoulle M, Auquier P, Conrad H, et al. Incidence of herpes simplex virus keratitis in France. Ophthalmology. 2005;112:888–895.
    1. Dworkin RH, Johnson RW, Breuer J, et al. Recommendations for the management of herpes zoster. Clin Infect Dis. 2007;44( Suppl 1):S1–S26.
    1. Bhatti MT, Patel R. Neuro-ophthalmic considerations in trigeminal neuralgia and its surgical treatment. Curr Opin Ophthalmol. 2005;16:334–340.
    1. Mackie IA. Neuroparalytic keratitis. In: Fraunfelder F, Roy FH, Meyer SM, editors. Current Ocular Therapy. Philadelphia, PA, USA: WB Saunders; 1995.
    1. Faulkner WJ, Varley GA. Corneal diagnostic technique. In: Krachmer JH, Mannis MJ, Holland EJ, editors. Cornea: Fundamentals of Corneal and External Disease. St Louis, MO, USA: Mosby; 1997.
    1. Norn MS. Measurement of sensitivity. In: Norn MS, editor. External Eye Diseases Methods of Examination. Copenhagen, Denmark: Munksgaard International Publisher Ltd; 1974.
    1. Belmonte C, Acosta MC, Schmelz M, Gallar J. Measurement of corneal sensitivity to mechanical and chemical stimulation with a CO2 esthesiometer. Invest Ophthalmol Vis Sci. 1999;40:513–519.
    1. Mandahl A. Hypertonic saline test for ophthalmic nerve impairment. Acta Ophthalmol (Copenh) 1993;71:556–559.
    1. Heigle TJ, Pflugfelder SC. Aqueous tear production in patients with neurotrophic keratitis. Cornea. 1996;15:135–138.
    1. Patel DV, McGhee CN. In vivo confocal microscopy of human corneal nerves in health, in ocular and systemic disease, and following corneal surgery: a review. Br J Ophthalmol. 2009;93:853–860.
    1. Hamrah P, Cruzat A, Dastjerdi MH, et al. Unilateral herpes zoster ophthalmicus results in bilateral corneal nerve alteration: an in vivo confocal microscopy study. Ophthalmology. 2013;120:40–47.
    1. Hamrah P, Cruzat A, Dastjerdi MH, et al. Corneal sensation and subbasal nerve alterations in patients with herpes simplex keratitis: an in vivo confocal microscopy study. Ophthalmology. 2010;117:1930–1936.
    1. Linna TU, Vesaluoma MH, Pérez-Santonja JJ, Petroll WM, Alió JL, Tervo TM. Effect of myopic LASIK on corneal sensitivity and morphology of subbasal nerves. Invest Ophthalmol Vis Sci. 2000;41:393–397.
    1. Rosenberg ME, Tervo TM, Immonen IJ, et al. Corneal structure and sensitivity in type 1 diabetes mellitus. Invest Ophthalmol Vis Sci. 2000;41:2915–2921.
    1. Cruzat A, Pavan-Langston D, Hamrah P. In vivo confocal microscopy of corneal nerves: analysis and clinical correlation. Semin Ophthalmol. 2010;25:171–177.
    1. Lambiase A, Sacchetti M, Mastropasqua A, Bonini S. Corneal changes in neurosurgically induced neurotrophic keratitis. JAMA Ophthalmol. 2013;131:1547–1553.
    1. Scarpa F, Zheng X, Ohashi Y, Ruggeri A. Automatic evaluation of corneal nerve tortuosity in images from in vivo confocal microscopy. Invest Ophthalmol Vis Sci. 2011;16(52):6404–6408.
    1. Rao K, Leveque C, Pflugfelder SC. Corneal nerve regeneration in neurotrophic keratopathy following autologous plasma therapy. Br J Ophthalmol. 2010;94:584–591.
    1. Parissi M, Karanis G, Randjelovic S, et al. Standardized baseline human corneal subbasal nerve density for clinical investigations with laser-scanning in vivo confocal microscopy. Invest Ophthalmol Vis Sci. 2013;54:7091–7102.
    1. Sacchetti M, Lambiase A, Cortes M, et al. Clinical and cytological findings in limbal stem cell deficiency. Graefes Arch Clin Exp Ophthalmol. 2005;243:870–876.
    1. Lambiase A, Rama P, Aloe L, Bonini S. Management of neurotrophic keratopathy. Curr Opin Ophthalmol. 1999;10:270–276.
    1. Sacchetti M, Lambiase A, Coassin M, Bonini S, Bonini S. Toxic corneal ulcer: a frequent and sight-threatening disease. Eur J Ophthalmol. 2009;19:916–922.
    1. Nishida T, Yanai R. Advances in treatment for neurotrophic keratopathy. Curr Opin Ophthalmol. 2009;20:276–281.
    1. Petroutsos G, Guimaraes R, Giraud JP, Pouliquen Y. Corticosteroids and corneal epithelial wound healing. Br J Ophthalmol. 1982;66:705–708.
    1. Hersh PS, Rice BA, Baer JC, et al. Topical nonsteroidal agents and corneal wound healing. Arch Ophthalmol. 1990;108:577–583.
    1. Hossain P. The corneal melting point. Eye (Lond) 2012;26:1029–1030.
    1. Perry HD, Golub LM. Systemic tetracyclines in the treatment of non-infected corneal ulcers: a case report and proposed new mechanism of action. Ann Ophthalmol. 1985;17:742–744.
    1. Hicks CR, Crawford GJ. Melting after keratoprosthesis implantation: the effects of medroxyprogesterone. Cornea. 2003;22:497–500.
    1. Grey F, Carley F, Biswas S, Tromans C. Scleral contact lens management of bilateral exposure and neurotrophic keratopathy. Cont Lens Anterior Eye. 2012;35:288–291.
    1. Portnoy SL, Insler MS, Kaufman HE. Surgical management of corneal ulceration and perforation. Surv Ophthalmol. 1989;34:47–58.
    1. Khokhar S, Natung T, Sony P, et al. Amniotic membrane transplantation in refractory neurotrophic corneal ulcers: a randomized, controlled clinical trial. Cornea. 2005;24:654–660.
    1. Kruse FE, Rohrschneider K, Völcker HE. Multilayer amniotic membrane transplantation for reconstruction of deep corneal ulcers. Ophthalmology. 1999;106:1504–1510.
    1. Hurtado-Sarrió M, Duch-Samper A, Cisneros-Lanuza A, Díaz-Llopis M. Tachosil: a new alternative for the treatment of non-traumatic corneal perforations. Br J Ophthalmol. 2009;93:1410–1411.
    1. Grau AE, Durán JA. Treatment of a large corneal perforation with a multilayer of amniotic membrane and Tachosil. Cornea. 2012;31:98–100.
    1. Gundersen T, Pearlson HR. Conjunctival flaps for corneal diseases: their usefulness and complications. Trans Am Ophthalmol Soc. 1969;67:78–95.
    1. Lugo M, Arentsen JJ. Treatment of neurotrophic ulcers with conjunctival flaps. Am J Ophthalmol. 1987;103:711–712.
    1. Khodadoust A, Quinter AP. Microsurgical approach to the conjunctival flap. Arch Ophthalmol. 2003;121:1189–1193.
    1. Golubović S, Parunović A. Cyanoacrylate glue in the treatment of corneal ulcerations. Fortschr Ophthalmol. 1990;87:378–381. German.
    1. Hirst LW, Smiddy WE, Stark WJ. Corneal perforations: changing methods of treatment, 1960–1980. Ophthalmology. 1982;89:630–634.
    1. Jhanji V, Young AL, Mehta JS, Sharma N, Agarwal T, Vajpayee RB. Management of corneal perforation. Surv Ophthalmol. 2011;56:522–538.
    1. Semeraro F, Forbice E, Romano V, et al. Neurotrophic keratitis. Ophthalmologica. 2013 Oct 2; [Epub ahead of print.]
    1. Terzis JK, Dryer MM, Bodner BI. Corneal neurotization: a novel solution to neurotrophic keratopathy. Plast Reconstr Surg. 2009;123:112–120.
    1. Pavan-Langston D, Dohlman CH. Boston keratoprosthesis treatment of herpes zoster neurotrophic keratopathy. Ophthalmology. 2008;115(Suppl 2):S21–S23.
    1. Aifa A, Gueudry J, Portmann A, Delcampe A, Muraine M. Topical treatment with a new matrix therapy agent (RGTA) for the treatment of corneal neurotrophic ulcers. Invest Ophthalmol Vis Sci. 2012;53:8181–8185.
    1. Dunn SP, Heidemann DG, Chow CY, et al. Treatment of chronic nonhealing neurotrophic corneal epithelial defects with thymosin beta4. Ann N Y Acad Sci. 2010;1194:199–206.
    1. Jeng BH, Dupps WJ., Jr Autologous serum 50% eye drops in the treatment of persistent corneal epithelial defects. Cornea. 2009;28:1104–1108.
    1. Turkoglu E, Celik E, Alagoz G. A comparison of the efficacy of autologous serum eye drops with amniotic membrane transplantation in neurotrophic keratitis. Semin Ophthalmol. 2013 Jun 12; [Epub ahead of print.]
    1. Geremicca W, Fonte C, Vecchio S. Blood components for topical use in tissue regeneration: evaluation of corneal lesions treated with platelet lysate and considerations on repair mechanisms. Blood Transfus. 2010;8:107–112.
    1. Yoon KC, You IC, Im SK, Jeong TS, Park YG, Choi J. Application of umbilical cord serum eyedrops for the treatment of neurotrophic keratitis. Ophthalmology. 2007;114:1637–1642.
    1. Daniele S, Gilbard JP, Schepens CL. Treatment of persistent epithelial defects in neurotrophic keratitis with epidermal growth factor: a preliminary open study. Graefes Arch Clin Exp Ophthalmol. 1992;230:314–317.
    1. Yamada N, Matsuda R, Morishige N, et al. Open clinical study of eye-drops containing tetrapeptides derived from substance P and insulin-like growth factor-1 for treatment of persistent corneal epithelial defects associated with neurotrophic keratopathy. Br J Ophthalmol. 2008;92:896–900.
    1. Nishida T, Chikama T, Morishige N, Yanai R, Yamada N, Saito J. Persistent epithelial defects due to neurotrophic keratopathy treated with a substance P-derived peptide and insulin-like growth factor 1. Jpn J Ophthalmol. 2007;51:442–447.
    1. Lambiase A, Rama P, Bonini S, Caprioglio G, Aloe L. Topical treatment with nerve growth factor for corneal neurotrophic ulcers. N Engl J Med. 1998;338:1174–1180.
    1. Bonini S, Lambiase A, Rama P, Caprioglio G, Aloe L. Topical treatment with nerve growth factor for neurotrophic keratitis. Ophthalmology. 2000;107:1347–1351.
    1. Lambiase A, Sacchetti M, Bonini S. Nerve growth factor therapy for corneal disease. Curr Opin Ophthalmol. 2012;23:296–302.
    1. Ferrari MP, Mantelli F, Sacchetti M, et al. Safety and pharmacokinetics of escalating doses of human recombinant nerve growth factor eye drops in a double-masked, randomized clinical trial. BioDrugs. 2013 Dec 11; [Epub ahead of print.]
    1. Dompé s.p.a Evaluation of Safety and Efficacy of rhNGF in Patients With Stage 2 and 3 Neurotrophic Keratitis. REPARO. [Accessed February 18, 2014]. Available from: . NLM identifier: NCT01756456.
    1. Laboratoires Thea Efficacy and Safety Assessment of T4020 Versus Vehicule in Patients With Chronic Neurotrophic Keratitis or Corneal Ulcer. [Accessed February 18, 2014]. Available from: . NLM identifier: NCT01794312.
    1. University of California, San Francisco Efficacy and Safety Study of Nexagon for Persistent Corneal Epithelial Defects (NTX-PED-001) [Accessed February 18, 2014]. Available from: . NLM identifier: NCT01165450.

Source: PubMed

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