Advertisement

Der Ophthalmologe

, Volume 116, Issue 2, pp 109–119 | Cite as

Pathogenese und Epidemiologie der neurotrophen Keratopathie

  • S. MertschEmail author
  • J. Alder
  • H. S. Dua
  • G. Geerling
Leitthema

Zusammenfassung

Die neurotrophe Keratopathie (NK) ist eine degenerative Hornhauterkrankung, die auf einer Beeinträchtigung der kornealen Innervation beruht. Die Schädigung der sensiblen Innervation, die durch den 1. Ast des N. trigeminus (N. ophthalmicus) erfolgt, kann über die gesamte Länge des Nervenverlaufs erfolgen, ausgehend vom Kern im Hirnstamm z. B. durch einen Hirntumor, bis hin zu den terminalen Nervenfasern in der Kornea, z. B. verursacht durch refraktive Hornhautchirurgie (z. B. Laser-in-situ-Keratomileusis [LASIK]). Bedingt durch den Verlust der sensiblen Innervation kommt es zu einer verminderten Tränensekretion und einer Reduktion in der Ausschüttung trophischer Faktoren. Dieses wiederum inhibiert das Regenerationspotenzial des kornealen Epithels. Die Reduktion bzw. der Verlust der Tränensekretion gepaart mit dem verschlechterten Regenerationspotenzial der Epithelzellen kann in schwersten Fällen der Erkrankung zu persistierenden Epitheldefekten, Ulzera bis hin zur Perforation der Hornhaut führen. Die NK weist eine Prävalenz von 5 oder weniger Betroffenen pro 10.000 auf und wird als seltene/Orphan-Erkrankung (ORPHA137596) eingestuft. Ein grundlegendes Verständnis der Pathogenese und Epidemiologie der NK unterstützt eine frühzeitige Diagnose und damit die Einleitung einer spezifischen Therapie.

Schlüsselwörter

Kornea Innervation Nervenregeneration Degenerative Hornhauterkrankung Tränensekretion  

Pathogenesis and epidemiology of neurotrophic keratopathy

Abstract

Neurotrophic keratopathy (NK) is a degenerative corneal disease that is based on an impairment of the corneal innervation. The damage to the sensory innervation, which is delivered through the 1st branch of the trigeminal nerve (ophthalmic nerve), can occur throughout the entire length of the nerve from the nucleus in the brainstem, e.g. caused by brain tumors, to the terminal nerve fibers in the cornea, caused for example by refractive corneal surgery (e. g. LASIK). Due to the loss of the sensory innervation, a reduced lacrimation and a reduction in the secretion of trophic factors occur. This in turn inhibits the regeneration potential of the corneal epithelium. In the most severe cases of the disease, the reduction or loss of lacrimation, together with the impaired regeneration potential of the epithelial cells, can lead to persistent epithelial defects, ulcers and corneal perforation. The NK has a prevalence of 5 or fewer individuals per 10,000 and is classified as a rare, i. e. orphan disease (ORPHA137596). A fundamental understanding of the pathogenesis and epidemiology of NK supports the early diagnosis and therefore the initiation of a specific treatment.

Keywords

Cornea Innervation Nerve regeneration Degenerative corneal disease Lacrimation 

Notes

Einhaltung ethischer Richtlinien

Interessenkonflikt

S. Mertsch und J. Alder geben an, dass kein Interessenkonflikt besteht. H.S. Dua und G. Geerling geben Tätigkeiten als Berater und Vortragende für Dompé Farmaceutici an. G. Geerling hat Mittel für die Durchführung eines selbst initiierten Forschungsprojektes von Dompé Farmaceutici erhalten.

Dieser Beitrag beinhaltet keine von den Autoren durchgeführten Studien an Menschen oder Tieren.

Literatur

  1. 1.
    Beuerman RW, Schimmelpfennig B (1980) Sensory denervation of the rabbit cornea affects epithelial properties. Exp Neurol 69(1):196–201PubMedGoogle Scholar
  2. 2.
    Heigle TJ, Pflugfelder SC (1996) Aqueous tear production in patients with neurotrophic keratitis. Cornea 15(2):135–138PubMedGoogle Scholar
  3. 3.
    Nishida T et al (2012) Differential contributions of impaired corneal sensitivity and reduced tear secretion to corneal epithelial disorders. Jpn J Ophthalmol 56(1):20–25PubMedGoogle Scholar
  4. 4.
    Hovanesian JA, Shah SS, Maloney RK (2001) Symptoms of dry eye and recurrent erosion syndrome after refractive surgery. J Cataract Refract Surg 27(4):577–584PubMedGoogle Scholar
  5. 5.
    Lee BH et al (2002) Reinnervation in the cornea after LASIK. Invest Ophthalmol Vis Sci 43(12):3660–3664PubMedGoogle Scholar
  6. 6.
    Hamrah P et al (2010) Corneal sensation and subbasal nerve alterations in patients with herpes simplex keratitis: an in vivo confocal microscopy study. Ophthalmology 117(10):1930–1936PubMedPubMedCentralGoogle Scholar
  7. 7.
    Cocho L et al (2015) Gene Expression-Based Predictive Models of Graft Versus Host Disease-Associated Dry Eye. Invest Ophthalmol Vis Sci 56(8):4570–4581PubMedGoogle Scholar
  8. 8.
    Steger B et al (2015) In vivo confocal microscopic characterisation of the cornea in chronic graft-versus-host disease related severe dry eye disease. Br J Ophthalmol 99(2):160–165PubMedGoogle Scholar
  9. 9.
    Bonini S et al (2003) Neurotrophic keratitis. Eye (Lond) 17(8):989–995Google Scholar
  10. 10.
    Rozsa AJ, Beuerman RW (1982) Density and organization of free nerve endings in the corneal epithelium of the rabbit. Pain 14(2):105–120PubMedGoogle Scholar
  11. 11.
    Wells JR, Michelson MA, (2008) Diagnosing and Treating Neurotrophic Keratopathy. EyeNet Magazine. American Academy of Ophthalmology. https://www.aao.org/eyenet/article/diagnosing-treating-neurotrophic-keratopathy Accessed date: 13 September 2018
  12. 12.
    Mannis MJ, Holland EJ (2016) Cornea E‑Book. Elsevier, AmsterdamGoogle Scholar
  13. 13.
    Mantelli F et al (2015) Congenital corneal anesthesia and neurotrophic keratitis: diagnosis and management. Biomed Res Int 2015:805876PubMedPubMedCentralGoogle Scholar
  14. 14.
    Semeraro F et al (2014) Neurotrophic keratitis. Ophthalmologica 231(4):191–197PubMedGoogle Scholar
  15. 15.
    Ruskell GL (1974) Ocular fibres of the maxillary nerve in monkeys. J Anat 118(2):195–203PubMedPubMedCentralGoogle Scholar
  16. 16.
    Gray H (1918) [1825–1861] Anatomy of the Human Body. Lea & Febiger, PhiladelphiaGoogle Scholar
  17. 17.
    Launay PS et al (2015) Combined 3DISCO clearing method, retrograde tracer and ultramicroscopy to map corneal neurons in a whole adult mouse trigeminal ganglion. Exp Eye Res 139:136–143PubMedGoogle Scholar
  18. 18.
    Muller LJ et al (2003) Corneal nerves: structure, contents and function. Exp Eye Res 76(5):521–542PubMedGoogle Scholar
  19. 19.
    Marfurt CF et al (2010) Anatomy of the human corneal innervation. Exp Eye Res 90(4):478–492PubMedGoogle Scholar
  20. 20.
    Muller LJ, Pels E, Vrensen GF (2001) The specific architecture of the anterior stroma accounts for maintenance of corneal curvature. Br J Ophthalmol 85(4):437–443PubMedPubMedCentralGoogle Scholar
  21. 21.
    Muller LJ, Pels L, Vrensen GF (1996) Ultrastructural organization of human corneal nerves. Invest Ophthalmol Vis Sci 37(4):476–488PubMedGoogle Scholar
  22. 22.
    ten Tusscher MP, Klooster J, Vrensen GF (1988) The innervation of the rabbit’s anterior eye segment: a retrograde tracing study. Exp Eye Res 46(5):717–730PubMedGoogle Scholar
  23. 23.
    Wolter JR (1957) Innervation of the corneal endothelium of the eye of the rabbit. AMA Arch Ophthalmol 58(2):246–250PubMedGoogle Scholar
  24. 24.
    Yamaguchi TZA, Menelau Cavalcanti B, Harris DL, von Andrian U, Jurkunas U, Hamrah P (2014) Neurogenic homeostasis of corneal endothelial cells: peripheral innervation maintains endothelial cell survival through vasoactive intestinal peptide. Invest Ophthalmol Vis Sci 55(13):2077Google Scholar
  25. 25.
    Al-Aqaba MA et al (2010) Architecture and distribution of human corneal nerves. Br J Ophthalmol 94(6):784–789PubMedGoogle Scholar
  26. 26.
    Schimmelpfennig B (1982) Nerve structures in human central corneal epithelium. Graefes Arch Clin Exp Ophthalmol 218(1):14–20PubMedGoogle Scholar
  27. 27.
    Stepp MA et al (2017) Corneal epithelial cells function as surrogate Schwann cells for their sensory nerves. Glia 65(6):851–863PubMedGoogle Scholar
  28. 28.
    Muller LJ et al (1997) Architecture of human corneal nerves. Invest Ophthalmol Vis Sci 38(5):985–994PubMedGoogle Scholar
  29. 29.
    Belmonte C, Acosta MC, Gallar J (2004) Neural basis of sensation in intact and injured corneas. Exp Eye Res 78(3):513–525PubMedGoogle Scholar
  30. 30.
    Acosta MC et al (2004) Tear secretion induced by selective stimulation of corneal and conjunctival sensory nerve fibers. Invest Ophthalmol Vis Sci 45(7):2333–2336PubMedGoogle Scholar
  31. 31.
    Parra A et al (2010) Ocular surface wetness is regulated by TRPM8-dependent cold thermoreceptors of the cornea. Nat Med 16(12):1396–1399PubMedGoogle Scholar
  32. 32.
    Belmonte C et al (2015) What causes eye pain? Curr Ophthalmol Rep 3(2):111–121PubMedPubMedCentralGoogle Scholar
  33. 33.
    Kovacs I et al (2016) Abnormal activity of corneal cold thermoreceptors underlies the unpleasant sensations in dry eye disease. Pain 157(2):399–417PubMedGoogle Scholar
  34. 34.
    Di G et al (2017) Corneal epithelium-derived neurotrophic factors promote nerve regeneration. Invest Ophthalmol Vis Sci 58(11):4695–4702PubMedGoogle Scholar
  35. 35.
    You L, Kruse FE, Volcker HE (2000) Neurotrophic factors in the human cornea. Invest Ophthalmol Vis Sci 41(3):692–702PubMedGoogle Scholar
  36. 36.
    Qi H et al (2008) Expression of glial cell-derived neurotrophic factor and its receptor in the stem-cell-containing human limbal epithelium. Br J Ophthalmol 92(9):1269–1274PubMedPubMedCentralGoogle Scholar
  37. 37.
    Mastropasqua L et al (2017) Understanding the pathogenesis of neurotrophic keratitis: the role of corneal nerves. J Cell Physiol 232(4):717–724PubMedGoogle Scholar
  38. 38.
    Kruse FE, Tseng SC (1993) Growth factors modulate clonal growth and differentiation of cultured rabbit limbal and corneal epithelium. Invest Ophthalmol Vis Sci 34(6):1963–1976PubMedGoogle Scholar
  39. 39.
    Levi-Montalcini R (1987) The nerve growth factor 35 years later. Science 237(4819):1154–1162PubMedGoogle Scholar
  40. 40.
    Lambiase A et al (2000) Nerve growth factor promotes corneal healing: structural, biochemical, and molecular analyses of rat and human corneas. Invest Ophthalmol Vis Sci 41(5):1063–1069PubMedGoogle Scholar
  41. 41.
    Sarkar J et al (2013) CD11b+GR1+ myeloid cells secrete NGF and promote trigeminal ganglion neurite growth: implications for corneal nerve regeneration. Invest Ophthalmol Vis Sci 54(9):5920–5936PubMedPubMedCentralGoogle Scholar
  42. 42.
    Matsuyama A et al (2017) Effect of nerve growth factor on innervation of perivascular nerves in neovasculatures of mouse cornea. Biol Pharm Bull 40(4):396–401PubMedGoogle Scholar
  43. 43.
    Rabiolo AWM (2017) Neurotrophic keratitis. American Academy of Ophthalmology, Eye Wiki. http://eyewiki.aao.org/Neurotrophic_Keratitis Google Scholar
  44. 44.
    DEWS Definition and Classification Subcommittee (2007) The definition and classification of dry eye disease: report of the definition and classification subcommittee of the international dry eye workshop. Ocul Surf 5(2):75–92Google Scholar
  45. 45.
    Gabison EES, Doan S, Cochereau I (2018) Epidemiology of neurotrophic keratitis: prevalence, etiologies, outcomes and clinical management. Invest Ophthalmol Vis Sci 59(9):1800Google Scholar
  46. 46.
    Alder JS, Geerling G (2018) Incidence of neurotrophic keratopathy in a German cohort of persistent epithelial defects. Invest Ophthalmol Vis Sci 59(9):1801Google Scholar
  47. 47.
    Sacchetti M, Lambiase A (2014) Diagnosis and management of neurotrophic keratitis. Clin Ophthalmol 8:571–579PubMedPubMedCentralGoogle Scholar
  48. 48.
    Labetoulle M et al (2005) Incidence of herpes simplex virus keratitis in France. Ophthalmology 112(5):888–895PubMedGoogle Scholar
  49. 49.
    Dworkin RH et al (2007) Recommendations for the management of herpes zoster. Clin Infect Dis 44(Suppl 1):S1–S26PubMedGoogle Scholar
  50. 50.
    Bhatti MT, Patel R (2005) Neuro-ophthalmic considerations in trigeminal neuralgia and its surgical treatment. Curr Opin Ophthalmol 16(6):334–340PubMedGoogle Scholar
  51. 51.
    Albietz JM, Lenton LM, McLennan SG (2005) Dry eye after LASIK: comparison of outcomes for Asian and Caucasian eyes. Clin Exp Optom 88(2):89–96PubMedGoogle Scholar
  52. 52.
    Azuma M et al (2014) Dry eye in LASIK patients. Bmc Res Notes 7:420PubMedPubMedCentralGoogle Scholar
  53. 53.
    Belmonte C, Gallar J (2011) Cold thermoreceptors, unexpected players in tear production and ocular dryness sensations. Invest Ophthalmol Vis Sci 52(6):3888–3892PubMedGoogle Scholar
  54. 54.
    Alper MG (1975) 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 73:323–365PubMedGoogle Scholar
  55. 55.
    Araki K et al (1994) Epithelial wound healing in the denervated cornea. Curr Eye Res 13(3):203–211PubMedGoogle Scholar
  56. 56.
    Dhillon VK et al (2016) Corneal hypoesthesia with normal sub-basal nerve density following surgery for trigeminal neuralgia. Acta Ophthalmol 94(1):e6–10PubMedGoogle Scholar
  57. 57.
    Sacchetti M, Lambiase A (2017) Neurotrophic factors and corneal nerve regeneration. Neural Regen Res 12(8):1220–1224PubMedPubMedCentralGoogle Scholar
  58. 58.
    Chen L et al (2014) Nerve growth factor expression and nerve regeneration in monkey corneas after LASIK. J Refract Surg 30(2):134–139PubMedGoogle Scholar
  59. 59.
    Park JH et al (2016) Nerve growth factor attenuates apoptosis and inflammation in the diabetic cornea. Invest Ophthalmol Vis Sci 57(15):6767–6775PubMedGoogle Scholar
  60. 60.
    Hodges RR, Dartt DA (2013) Tear film mucins: front line defenders of the ocular surface; comparison with airway and gastrointestinal tract mucins. Exp Eye Res 117:62–78PubMedPubMedCentralGoogle Scholar
  61. 61.
    Wilson SE, Ambrosio R (2001) Laser in situ keratomileusis-induced neurotrophic epitheliopathy. Am J Ophthalmol 132(3):405–406PubMedGoogle Scholar
  62. 62.
    Lin X et al (2014) Comparison of deep anterior lamellar keratoplasty and penetrating keratoplasty with respect to postoperative corneal sensitivity and tear film function. Graefes Arch Clin Exp Ophthalmol 252(11):1779–1787PubMedGoogle Scholar
  63. 63.
    Wasilewski D, Mello GH, Moreira H (2013) Impact of collagen crosslinking on corneal sensitivity in keratoconus patients. Cornea 32(7):899–902PubMedGoogle Scholar
  64. 64.
    Tinley CG, Gray RH (2009) Routine, single session, indirect laser for proliferative diabetic retinopathy. Eye (Lond) 23(9):1819–1823Google Scholar
  65. 65.
    Geerling G, Lisch W, Finis D (2018) Rezidivierende Hornhauterosion bei epithelialen Hornhautdystrophien. Klin Monatsbl Augenheilkd 06(235):697–701Google Scholar
  66. 66.
    Hamrah P et al (2013) Unilateral herpes zoster ophthalmicus results in bilateral corneal nerve alteration: an in vivo confocal microscopy study. Ophthalmology 120(1):40–47PubMedGoogle Scholar
  67. 67.
    Moein HR et al (2018) Corneal nerve regeneration after herpes simplex keratitis: a longitudinal in vivo confocal microscopy study. Ocul Surf 16(2):218–225PubMedGoogle Scholar
  68. 68.
    Rousseau A et al (2015) Diffusion tensor magnetic resonance imaging of trigeminal nerves in relapsing herpetic keratouveitis. PLoS ONE 10(4):e122186PubMedPubMedCentralGoogle Scholar
  69. 69.
    M’Garrech M et al (2013) Impairment of lacrimal secretion in the unaffected fellow eye of patients with recurrent unilateral herpetic keratitis. Ophthalmology 120(10):1959–1967PubMedGoogle Scholar
  70. 70.
    Jabbarvand M et al (2015) Do unilateral herpetic stromal keratitis and neurotrophic ulcers cause bilateral dry eye? Cornea 34(7):768–772PubMedGoogle Scholar
  71. 71.
    Yamaguchi T et al (2013) Bilateral nerve alterations in a unilateral experimental neurotrophic keratopathy model: a lateral conjunctival approach for trigeminal axotomy. PLoS ONE 8(8).  https://doi.org/10.1371/journal.pone.0070908 CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Yamaguchi T, Hamrah P, Shimazaki J (2016) Bilateral alterations in corneal nerves, dendritic cells, and tear cytokine levels in ocular surface disease. Cornea 35:S65–S70PubMedPubMedCentralGoogle Scholar
  73. 73.
    Dua HS et al (2018) Neurotrophic keratopathy. Prog Retin Eye Res 66:107–131.  https://doi.org/10.1016/j.preteyeres.2018.04.003 CrossRefPubMedGoogle Scholar
  74. 74.
    Bucher F et al (2014) Corneal nerve alterations in different stages of Fuchs’ endothelial corneal dystrophy: an in vivo confocal microscopy study. Graefes Arch Clin Exp Ophthalmol 252(7):1119–1126PubMedGoogle Scholar
  75. 75.
    Ahuja Y et al (2012) Decreased corneal sensitivity and abnormal corneal nerves in Fuchs endothelial dystrophy. Cornea 31(11):1257–1263PubMedPubMedCentralGoogle Scholar
  76. 76.
    Schrems-Hoesl LM et al (2013) Cellular and subbasal nerve alterations in early stage Fuchs’ endothelial corneal dystrophy: an in vivo confocal microscopy study. Eye (Lond) 27(1):42–49Google Scholar
  77. 77.
    Bonzano C et al (2018) A case of neurotrophic keratopathy concomitant to brain metastasis. Cureus 10(e2309):3Google Scholar
  78. 78.
    Puca A et al (1995) Evaluation of fifth nerve dysfunction in 136 patients with middle and posterior cranial fossae tumors. Eur Neurol 35(1):33–37PubMedGoogle Scholar
  79. 79.
    Lockwood A, Hope-Ross M, Chell P (2006) Neurotrophic keratopathy and diabetes mellitus. Eye (Lond) 20(7):837–839Google Scholar
  80. 80.
    O’Connor AB et al (2008) Pain associated with multiple sclerosis: systematic review and proposed classification. Pain 137(1):96–111PubMedGoogle Scholar
  81. 81.
    Messmer EM et al (2010) In vivo confocal microscopy of corneal small fiber damage in diabetes mellitus. Graefes Arch Clin Exp Ophthalmol 248(9):1307–1312PubMedGoogle Scholar
  82. 82.
    Sekhar GC et al (1994) Ocular manifestations of Hansen’s disease. Doc Ophthalmol 87(3):211–221PubMedGoogle Scholar
  83. 83.
    Ambrosio R Jr., Tervo T, Wilson SE (2008) LASIK-associated dry eye and neurotrophic epitheliopathy: pathophysiology and strategies for prevention and treatment. J Refract Surg 24(4):396–407PubMedGoogle Scholar
  84. 84.
    Calvillo MP et al (2004) Corneal reinnervation after LASIK: prospective 3‑year longitudinal study. Invest Ophthalmol Vis Sci 45(11):3991–3996PubMedGoogle Scholar
  85. 85.
    Chao C et al (2015) Structural and functional changes in corneal innervation after laser in situ keratomileusis and their relationship with dry eye. Graefes Arch Clin Exp Ophthalmol 253(11):2029–2039PubMedGoogle Scholar
  86. 86.
    Mohamed-Noriega K et al (2014) Early corneal nerve damage and recovery following small incision lenticule extraction (SMILE) and laser in situ keratomileusis (LASIK). Invest Ophthalmol Vis Sci 55(3):1823–1834PubMedGoogle Scholar
  87. 87.
    Tervo T et al (1985) Histochemical evidence of limited reinnervation of human corneal grafts. Acta Ophthalmol (copenh) 63(2):207–214Google Scholar
  88. 88.
    Richter A et al (1996) Corneal reinnervation following penetrating keratoplasty—correlation of esthesiometry and confocal microscopy. Ger J Ophthalmol 5(6):513–517PubMedGoogle Scholar
  89. 89.
    Patel SV et al (2007) Keratocyte and subbasal nerve density after penetrating keratoplasty. Trans Am Ophthalmol Soc 105:180–189 (discussion 189–90.)PubMedPubMedCentralGoogle Scholar
  90. 90.
    Patel SV et al (2007) Keratocyte density and recovery of subbasal nerves after penetrating keratoplasty and in late endothelial failure. Arch Ophthalmol 125(12):1693–1698PubMedGoogle Scholar
  91. 91.
    Baudouin C et al (2013) Role of hyperosmolarity in the pathogenesis and management of dry eye disease: proceedings of the OCEAN group meeting. Ocul Surf 11(4):246–258PubMedGoogle Scholar
  92. 92.
    Geerling G et al (2001) Toxicity of natural tear substitutes in a fully defined culture model of human corneal epithelial cells. Invest Ophthalmol Vis Sci 42(5):948–956PubMedGoogle Scholar
  93. 93.
    Sarkar J et al (2012) Corneal neurotoxicity due to topical benzalkonium chloride. Invest Ophthalmol Vis Sci 53(4):1792–1802PubMedPubMedCentralGoogle Scholar
  94. 94.
    Martone G et al (2009) An in vivo confocal microscopy analysis of effects of topical antiglaucoma therapy with preservative on corneal innervation and morphology. Am J Ophthalmol 147(4):725–735 (e1)PubMedGoogle Scholar
  95. 95.
    Nagai N et al (2010) Comparison of corneal wound healing rates after instillation of commercially available latanoprost and travoprost in rat debrided corneal epithelium. J Oleo Sci 59(3):135–141PubMedGoogle Scholar
  96. 96.
    Sharma C et al (2011) Effect of fluoroquinolones on the expression of matrix metalloproteinase in debrided cornea of rats. Toxicol Mech Methods 21(1):6–12PubMedGoogle Scholar
  97. 97.
    Baratz KH et al (2006) Effects of glaucoma medications on corneal endothelium, keratocytes, and subbasal nerves among participants in the ocular hypertension treatment study. Cornea 25(9):1046–1052PubMedGoogle Scholar
  98. 98.
    Pflugfelder SC et al (2005) Matrix metalloproteinase-9 knockout confers resistance to corneal epithelial barrier disruption in experimental dry eye. Am J Pathol 166(1):61–71PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Medizin Verlag GmbH, ein Teil von Springer Nature 2018

Authors and Affiliations

  • S. Mertsch
    • 1
    • 2
    Email author
  • J. Alder
    • 1
  • H. S. Dua
    • 3
  • G. Geerling
    • 1
  1. 1.Univ.-Klinik für AugenheilkundeHeinrich-Heine-Universität DüsseldorfDüsseldorfDeutschland
  2. 2.Univ.-Klinik für AugenheilkundePius-Hospital Oldenburg, Medizinischer Campus Universität OldenburgOldenburgDeutschland
  3. 3.Academic Section of Ophthalmology, Division of Clinical NeuroscienceUniversity of NottinghamNottinghamGroßbritannien

Personalised recommendations