Skip to main content
Top
Published in: Graefe's Archive for Clinical and Experimental Ophthalmology 11/2012

01-11-2012 | Cornea

Morphometric analysis of postoperative corneal neovascularization after high-risk keratoplasty: herpetic versus non-herpetic disease

Authors: Amadeus E. Altenburger, Björn Bachmann, Berthold Seitz, Claus Cursiefen

Published in: Graefe's Archive for Clinical and Experimental Ophthalmology | Issue 11/2012

Login to get access

Abstract

Background

Postoperative complications after high-risk corneal grafting are decisively associated with corneal neovascularization (CNV). This study aimed to identify the incidence, extent, speed, localization, and influence of surgery-related factors on CNV after high-risk penetrating keratoplasty (PK) and to evaluate the effect of removing the angiogenic stimulus, i.e., residual components of herpes simplex virus (HSV) on postkeratoplasty CNV in patients with herpetic stromal keratitis (HSK).

Methods

All primary high-risk PK performed for HSK and non-herpetic keratitis (controls) between 1 January 1998 and 31 December 2003 at our department with available standardized corneal photographs taken preoperatively as well as 6 weeks, 3, 6 and 12 months postoperatively were evaluated (n herpes = 19, n controls = 5 patients). Maximal extension of CNV, limbus suture distance (LSD), limbus graft distance (LGD) and graft size in digitalized pictures were measured in each of the 16 sectors of the cornea at every visit.

Results

One hundred percent of the prevascularized corneas (n = 24) showed further CNV outgrowth within 1 year after keratoplasty, while 58 % of these patients featured high-grade CNV reaching the host–graft junction or invading the donor tissue. Overall, CNV outgrowth was fastest during the first 6 weeks after PK, with a mean speed of 48 μm/week. Mean CNV growth speed within 6 months post-PK was significantly lower in the herpes group (13 μm/week) than in the non-herpes group (25 μm/week, p = 0.017). Corneal location around the 12 o'clock position showed the most intense vessel outgrowth, which proved to be an independent risk factor for high-grade CNV (p = 0.025). Inverse correlation was evident between CNV growth speed and LSD (p = 0.032).

Conclusions

Additional intense CNV outgrowth is a common phenomenon after high-risk keratoplasty, strongly marked in the early postoperative period. The removal of residual HSV components representing a potential angiogenic stimulus leads to a reduction in corneal angiogenesis not in the short term, but in the long term after PK in patients with HSK. In addition to preferable atraumatic operation techniques, modern antiviral prophylaxis and anti-angiogenic therapy should be applied early, possibly even prior to transplantation. Short LSD seems to be an intraoperative adjustable risk factor for CNV in high-risk setting. Attention should also be paid to the superior site around the 12 o'clock position.
Literature
1.
go back to reference Streilein JW, Dana MR, Ksander BR (1997) Immunity causing blindness: five different paths to herpes stromal keratitis. Immunol Today 18:443–449PubMedCrossRef Streilein JW, Dana MR, Ksander BR (1997) Immunity causing blindness: five different paths to herpes stromal keratitis. Immunol Today 18:443–449PubMedCrossRef
2.
3.
go back to reference Deshpande S, Banerjee K, Biswas PS, Rouse BT (2004) Herpetic eye disease: immunopathogenesis and therapeutic measures. Expert Rev Mol Med 6:1–14PubMedCrossRef Deshpande S, Banerjee K, Biswas PS, Rouse BT (2004) Herpetic eye disease: immunopathogenesis and therapeutic measures. Expert Rev Mol Med 6:1–14PubMedCrossRef
4.
go back to reference Biswas PS, Rouse BT (2005) Early events in HSV keratitis—setting the stage for a blinding disease. Microbes Infect 7:799–810PubMedCrossRef Biswas PS, Rouse BT (2005) Early events in HSV keratitis—setting the stage for a blinding disease. Microbes Infect 7:799–810PubMedCrossRef
5.
go back to reference Russell RG, Nasisse MP, Larsen HS, Rouse BT (1984) Role of T-lymphocytes in the pathogenesis of herpetic stromal keratitis. Invest Ophthalmol Vis Sci 25:938–944PubMed Russell RG, Nasisse MP, Larsen HS, Rouse BT (1984) Role of T-lymphocytes in the pathogenesis of herpetic stromal keratitis. Invest Ophthalmol Vis Sci 25:938–944PubMed
6.
7.
go back to reference Lepisto AJ, Frank GM, Hendricks RL (2007) How herpes simplex virus type 1 rescinds corneal privilege. Chem Immunol Allergy 92:203–212PubMedCrossRef Lepisto AJ, Frank GM, Hendricks RL (2007) How herpes simplex virus type 1 rescinds corneal privilege. Chem Immunol Allergy 92:203–212PubMedCrossRef
8.
go back to reference Sottile J (2004) Regulation of angiogenesis by extracellular matrix. Biochim Biophys Acta 1654:13–22PubMed Sottile J (2004) Regulation of angiogenesis by extracellular matrix. Biochim Biophys Acta 1654:13–22PubMed
10.
go back to reference Cursiefen C, Kruse FE (2006) New aspects of angiogenesis in the cornea. In: Reinhard T, Larkin F (eds) Cornea and external eye disease (Essentials in ophthalmology). Springer, Heidelberg Cursiefen C, Kruse FE (2006) New aspects of angiogenesis in the cornea. In: Reinhard T, Larkin F (eds) Cornea and external eye disease (Essentials in ophthalmology). Springer, Heidelberg
11.
go back to reference Zheng M, Deshpande S, Lee S, Ferrara N, Rouse BT (2001) Contribution of vascular endothelial growth factor in the neovascularization process during the pathogenesis of herpetic stromal keratitis. J Virol 75:9828–9835PubMedCrossRef Zheng M, Deshpande S, Lee S, Ferrara N, Rouse BT (2001) Contribution of vascular endothelial growth factor in the neovascularization process during the pathogenesis of herpetic stromal keratitis. J Virol 75:9828–9835PubMedCrossRef
12.
go back to reference Zheng M, Schwarz MA, Lee S, Kumaraguru U, Rouse BT (2001) Control of stromal keratitis by inhibition of neovascularization. Am J Pathol 159:1021–1029PubMedCrossRef Zheng M, Schwarz MA, Lee S, Kumaraguru U, Rouse BT (2001) Control of stromal keratitis by inhibition of neovascularization. Am J Pathol 159:1021–1029PubMedCrossRef
13.
go back to reference Hayashi K, Hooper LC, Chin MS, Nagineni CN, Detrick B, Hooks JJ (2006) Herpes simplex virus 1 (HSV-1) DNA and immune complex (HSV-1-human IgG) elicit vigorous interleukin 6 release from infected corneal cells via Toll-like receptors. J Gen Virol 87:2161–2169PubMedCrossRef Hayashi K, Hooper LC, Chin MS, Nagineni CN, Detrick B, Hooks JJ (2006) Herpes simplex virus 1 (HSV-1) DNA and immune complex (HSV-1-human IgG) elicit vigorous interleukin 6 release from infected corneal cells via Toll-like receptors. J Gen Virol 87:2161–2169PubMedCrossRef
14.
go back to reference Shimomura Y, Deai T, Fukuda M, Higaki S, Hooper LC, Hayashi K (2007) Corneal buttons obtained from patients with HSK harbor high copy numbers of the HSV genome. Cornea 26:190–193PubMedCrossRef Shimomura Y, Deai T, Fukuda M, Higaki S, Hooper LC, Hayashi K (2007) Corneal buttons obtained from patients with HSK harbor high copy numbers of the HSV genome. Cornea 26:190–193PubMedCrossRef
15.
go back to reference Hayashi K, Hooper LC, Detrick B, Hooks JJ (2009) HSV immune complex (HSV-IgG: IC) and HSV-DNA elicit the production of angiogenic factor VEGF and MMP-9. Arch Virol 154:219–226PubMedCrossRef Hayashi K, Hooper LC, Detrick B, Hooks JJ (2009) HSV immune complex (HSV-IgG: IC) and HSV-DNA elicit the production of angiogenic factor VEGF and MMP-9. Arch Virol 154:219–226PubMedCrossRef
16.
go back to reference Cursiefen C, Chen L, Dana MR, Streilein JW (2003) Corneal lymphangiogenesis: evidence, mechanisms, and implications for corneal transplant immunology. Cornea 22:273–281PubMedCrossRef Cursiefen C, Chen L, Dana MR, Streilein JW (2003) Corneal lymphangiogenesis: evidence, mechanisms, and implications for corneal transplant immunology. Cornea 22:273–281PubMedCrossRef
17.
go back to reference Shtein RM, Elner VM (2010) Herpes simplex virus keratitis: histopathology and corneal allograft outcomes. Expert Rev Ophthalmol 5:129–134PubMedCrossRef Shtein RM, Elner VM (2010) Herpes simplex virus keratitis: histopathology and corneal allograft outcomes. Expert Rev Ophthalmol 5:129–134PubMedCrossRef
18.
go back to reference Maguire MG, Stark WJ, Gottsch JD, Stulting RD, Sugar A, Fink NE, Schwartz A (1994) Risk factors for corneal graft failure and rejection in the collaborative corneal transplantation studies. Collaborative Corneal Transplantation Studies Research Group. Ophthalmology 101:1536–1547PubMed Maguire MG, Stark WJ, Gottsch JD, Stulting RD, Sugar A, Fink NE, Schwartz A (1994) Risk factors for corneal graft failure and rejection in the collaborative corneal transplantation studies. Collaborative Corneal Transplantation Studies Research Group. Ophthalmology 101:1536–1547PubMed
19.
go back to reference Shtein RMGD, Mush DC, Elner VM (2008) HSV keratitis: histopathologic predictors of corneal allograft complications. Trans Am Ophthalmol Soc 106:161–170PubMed Shtein RMGD, Mush DC, Elner VM (2008) HSV keratitis: histopathologic predictors of corneal allograft complications. Trans Am Ophthalmol Soc 106:161–170PubMed
20.
go back to reference Dana MR, Streilein JW (1996) Loss and restoration of immune privilege in eyes with corneal neovascularization. Invest Ophthalmol Vis Sci 37:2485–2494PubMed Dana MR, Streilein JW (1996) Loss and restoration of immune privilege in eyes with corneal neovascularization. Invest Ophthalmol Vis Sci 37:2485–2494PubMed
21.
go back to reference Bachmann BO, Bock F, Wiegand SJ, Maruyama K, Dana MR, Kruse FE, Luetjen-Drecoll E, Cursiefen C (2008) Promotion of graft survival by vascular endothelial growth factor a neutralization after high-risk corneal transplantation. Arch Ophthalmol 126:71–77PubMedCrossRef Bachmann BO, Bock F, Wiegand SJ, Maruyama K, Dana MR, Kruse FE, Luetjen-Drecoll E, Cursiefen C (2008) Promotion of graft survival by vascular endothelial growth factor a neutralization after high-risk corneal transplantation. Arch Ophthalmol 126:71–77PubMedCrossRef
22.
go back to reference Foster CS, Duncan J (1981) Penetrating keratoplasty for herpes simplex keratitis. Am J Ophthalmol 92:336–343PubMed Foster CS, Duncan J (1981) Penetrating keratoplasty for herpes simplex keratitis. Am J Ophthalmol 92:336–343PubMed
23.
go back to reference Nicholls SM, Shimeld C, Easty DL, Hill TJ (1996) Recurrent herpes simplex after corneal transplantation in rats. Invest Ophthalmol Vis Sci 37:425–435PubMed Nicholls SM, Shimeld C, Easty DL, Hill TJ (1996) Recurrent herpes simplex after corneal transplantation in rats. Invest Ophthalmol Vis Sci 37:425–435PubMed
25.
go back to reference Garcia DD, Shtein RM, Musch DC, Elner VM (2009) Herpes simplex virus keratitis: histopathologic neovascularization and corneal allograft failure. Cornea 28:963–965PubMedCrossRef Garcia DD, Shtein RM, Musch DC, Elner VM (2009) Herpes simplex virus keratitis: histopathologic neovascularization and corneal allograft failure. Cornea 28:963–965PubMedCrossRef
26.
go back to reference Cursiefen C, Cao J, Chen L, Liu Y, Maruyama K, Jackson D, Kruse FE, Wiegand SJ, Dana MR, Streilein JW (2004) Inhibition of hemangiogenesis and lymphangiogenesis after normal-risk corneal transplantation by neutralizing VEGF promotes graft survival. Invest Ophthalmol Vis Sci 45:2666–2673PubMedCrossRef Cursiefen C, Cao J, Chen L, Liu Y, Maruyama K, Jackson D, Kruse FE, Wiegand SJ, Dana MR, Streilein JW (2004) Inhibition of hemangiogenesis and lymphangiogenesis after normal-risk corneal transplantation by neutralizing VEGF promotes graft survival. Invest Ophthalmol Vis Sci 45:2666–2673PubMedCrossRef
27.
go back to reference Cursiefen C, Martus P, Nguyen NX, Langenbucher A, Seitz B, Kuchle M (2002) Corneal neovascularization after nonmechanical versus mechanical corneal trephination for non-high-risk keratoplasty. Cornea 21:648–652PubMedCrossRef Cursiefen C, Martus P, Nguyen NX, Langenbucher A, Seitz B, Kuchle M (2002) Corneal neovascularization after nonmechanical versus mechanical corneal trephination for non-high-risk keratoplasty. Cornea 21:648–652PubMedCrossRef
28.
go back to reference Lam VM, Nguyen NX, Martus P, Seitz B, Kruse FE, Cursiefen C (2006) Surgery-related factors influencing corneal neovascularization after low-risk keratoplasty. Am J Ophthalmol 141:260–266PubMedCrossRef Lam VM, Nguyen NX, Martus P, Seitz B, Kruse FE, Cursiefen C (2006) Surgery-related factors influencing corneal neovascularization after low-risk keratoplasty. Am J Ophthalmol 141:260–266PubMedCrossRef
29.
go back to reference Cursiefen C, Wenkel H, Martus P, Langenbucher A, Nguyen NX, Seitz B, Kuchle M, Naumann GO (2001) Impact of short-term versus long-term topical steroids on corneal neovascularization after non-high-risk keratoplasty. Graefes Arch Clin Exp Ophthalmol 239:514–521PubMedCrossRef Cursiefen C, Wenkel H, Martus P, Langenbucher A, Nguyen NX, Seitz B, Kuchle M, Naumann GO (2001) Impact of short-term versus long-term topical steroids on corneal neovascularization after non-high-risk keratoplasty. Graefes Arch Clin Exp Ophthalmol 239:514–521PubMedCrossRef
30.
go back to reference Cursiefen C, Wenkel H, Martus P, Langenbucher A, Seitz B, Kuchle M (2001) Standardized semiquantitative analysis of corneal neovascularization using projected corneal photographs–pilot study after perforating corneal keratoplasty before immune reaction. Klin Monatsbl Augenheilkd 218:484–491PubMedCrossRef Cursiefen C, Wenkel H, Martus P, Langenbucher A, Seitz B, Kuchle M (2001) Standardized semiquantitative analysis of corneal neovascularization using projected corneal photographs–pilot study after perforating corneal keratoplasty before immune reaction. Klin Monatsbl Augenheilkd 218:484–491PubMedCrossRef
31.
go back to reference Streilein JW (2003) Ocular immune privilege: therapeutic opportunities from an experiment of nature. Nat Rev Immunol 3:879–889PubMedCrossRef Streilein JW (2003) Ocular immune privilege: therapeutic opportunities from an experiment of nature. Nat Rev Immunol 3:879–889PubMedCrossRef
32.
go back to reference Gerten G (2008) Bevacizumab (avastin) and argon laser to treat neovascularization in corneal transplant surgery. Cornea 27:1195–1199PubMedCrossRef Gerten G (2008) Bevacizumab (avastin) and argon laser to treat neovascularization in corneal transplant surgery. Cornea 27:1195–1199PubMedCrossRef
33.
go back to reference Bachmann B, Taylor RS, Cursiefen C (2010) Corneal neovascularization as a risk factor for graft failure and rejection after keratoplasty: an evidence-based meta-analysis. Ophthalmology 117:1300–1305PubMedCrossRef Bachmann B, Taylor RS, Cursiefen C (2010) Corneal neovascularization as a risk factor for graft failure and rejection after keratoplasty: an evidence-based meta-analysis. Ophthalmology 117:1300–1305PubMedCrossRef
34.
go back to reference Hayashi K, Hooper LC, Hooks JJ (2008) Who (what) pays toll for the development of herpetic stromal keratitis (HSK). Semin Ophthalmol 23:229–234PubMedCrossRef Hayashi K, Hooper LC, Hooks JJ (2008) Who (what) pays toll for the development of herpetic stromal keratitis (HSK). Semin Ophthalmol 23:229–234PubMedCrossRef
35.
go back to reference Remeijer L, Duan R, van Dun JM, Wefers Bettink MA, Osterhaus AD, Verjans GM (2009) Prevalence and clinical consequences of herpes simplex virus type 1 DNA in human cornea tissues. J Infect Dis 200:11–19PubMedCrossRef Remeijer L, Duan R, van Dun JM, Wefers Bettink MA, Osterhaus AD, Verjans GM (2009) Prevalence and clinical consequences of herpes simplex virus type 1 DNA in human cornea tissues. J Infect Dis 200:11–19PubMedCrossRef
36.
go back to reference Remeijer L, Doornenbal P, Geerards AJ, Rijneveld WA, Beekhuis WH (1997) Newly acquired herpes simplex virus keratitis after penetrating keratoplasty. Ophthalmology 104:648–652PubMed Remeijer L, Doornenbal P, Geerards AJ, Rijneveld WA, Beekhuis WH (1997) Newly acquired herpes simplex virus keratitis after penetrating keratoplasty. Ophthalmology 104:648–652PubMed
37.
go back to reference Rezende RA, Uchoa UB, Raber IM, Rapuano CJ, Laibson PR, Cohen EJ (2004) New onset of herpes simplex virus epithelial keratitis after penetrating keratoplasty. Am J Ophthalmol 137:415–419PubMedCrossRef Rezende RA, Uchoa UB, Raber IM, Rapuano CJ, Laibson PR, Cohen EJ (2004) New onset of herpes simplex virus epithelial keratitis after penetrating keratoplasty. Am J Ophthalmol 137:415–419PubMedCrossRef
38.
go back to reference Kaye SB, Lynas C, Patterson A, Risk JM, McCarthy K, Hart CA (1991) Evidence for herpes simplex viral latency in the human cornea. Br J Ophthalmol 75:195–200PubMedCrossRef Kaye SB, Lynas C, Patterson A, Risk JM, McCarthy K, Hart CA (1991) Evidence for herpes simplex viral latency in the human cornea. Br J Ophthalmol 75:195–200PubMedCrossRef
39.
go back to reference Biswas S, Suresh P, Bonshek RE, Corbitt G, Tullo AB, Ridgway AE (2000) Graft failure in human donor corneas due to transmission of herpes simplex virus. Br J Ophthalmol 84:701–705PubMedCrossRef Biswas S, Suresh P, Bonshek RE, Corbitt G, Tullo AB, Ridgway AE (2000) Graft failure in human donor corneas due to transmission of herpes simplex virus. Br J Ophthalmol 84:701–705PubMedCrossRef
40.
go back to reference Cleator GM, Klapper PE, Dennett C, Sullivan AL, Bonshek RE, Marcyniuk B, Tullo AB (1994) Corneal donor infection by herpes simplex virus: herpes simplex virus DNA in donor corneas. Cornea 13:294–304PubMedCrossRef Cleator GM, Klapper PE, Dennett C, Sullivan AL, Bonshek RE, Marcyniuk B, Tullo AB (1994) Corneal donor infection by herpes simplex virus: herpes simplex virus DNA in donor corneas. Cornea 13:294–304PubMedCrossRef
41.
go back to reference Garweg JG, Russ CE, Schellhorn M, Bohnke M, Halberstadt M (2003) HSV-1 antigens and DNA in the corneal explant buttons of patients with non-herpetic or clinically atypical herpetic stromal keratitis. Graefes Arch Clin Exp Ophthalmol 241:734–739PubMedCrossRef Garweg JG, Russ CE, Schellhorn M, Bohnke M, Halberstadt M (2003) HSV-1 antigens and DNA in the corneal explant buttons of patients with non-herpetic or clinically atypical herpetic stromal keratitis. Graefes Arch Clin Exp Ophthalmol 241:734–739PubMedCrossRef
42.
go back to reference Dana MR, Schaumberg DA, Kowal VO, Goren MB, Rapuano CJ, Laibson PR, Cohen EJ (1995) Corneal neovascularization after penetrating keratoplasty. Cornea 14:604–609PubMed Dana MR, Schaumberg DA, Kowal VO, Goren MB, Rapuano CJ, Laibson PR, Cohen EJ (1995) Corneal neovascularization after penetrating keratoplasty. Cornea 14:604–609PubMed
Metadata
Title
Morphometric analysis of postoperative corneal neovascularization after high-risk keratoplasty: herpetic versus non-herpetic disease
Authors
Amadeus E. Altenburger
Björn Bachmann
Berthold Seitz
Claus Cursiefen
Publication date
01-11-2012
Publisher
Springer-Verlag
Published in
Graefe's Archive for Clinical and Experimental Ophthalmology / Issue 11/2012
Print ISSN: 0721-832X
Electronic ISSN: 1435-702X
DOI
https://doi.org/10.1007/s00417-012-1988-6

Other articles of this Issue 11/2012

Graefe's Archive for Clinical and Experimental Ophthalmology 11/2012 Go to the issue