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Corneal neovascularization is a major risk factor for graft failure after corneal transplantation. The purpose of this study was to investigate the effect of subconjunctival, perilimbal, and/or intrastromal bevacizumab (Avastin®) on corneal neovascularization in patients with penetrating keratoplasty (PKP).
Fourteen eyes of 14 patients with high risk corneal transplantation and corneal neovascularization after PKP (nine men and five women with a mean age of 63 years) were included in this non-comparative interventional case series. Indications for PKP were: vascularized leucomas after herpetic keratitis and chemical burn, advanced pseudophakic bullous keratopathy with superficial and deep corneal vascularization, keratoconus, severe infection in hereditary corneal dystrophy, and failed corneal grafts. Subconjunctival, perilimbal, and/or intrastromal bevacizumab of dose of 2.5 mg/ 0.1 ml/ per affected quadrant was injected at the site of neovascularization in each patient at the end of surgery and/or at follow up visits. One or two injections were applied. At each visit a full eye examination with photo documentation was performed. Follow-up period was 2 to 8 months (mean 7.1 months).
Decrease of corneal neovascularization was observed in eleven patients (78.6%). Regression of neovascularization with fading of small vessels was demonstrated. Despite high- risk patient pool, twelve grafts (85.7%) remained transparent for the period of observation, and patients maintained good visual acuity. In two patients with initial graft rejection and vascularization, subconjunctival and perilimbal application of bevacizumab was beneficial in overcoming the corneal inflammation and initial rejection. No adverse reactions have been detected to date in patients with subconjunctival, perilimbal, and/or intrastromal injection of bevacizumab.
Bevacizumab is an efficient and safe additional treatment option for improvement of prognosis in high-risk corneal transplantation with pre- and postoperative corneal neovascularization.
Graefes Arch Clin Exp Ophthalmol (2009) 247:17011706 DOI 10.1007/s00417-009-1170-y
CORNEA
Avastin use in high risk corneal transplantation
Petja Ivanova Vassileva &
Tatyana Georgieva Hergeldzhieva
Received: 28 February 2009 /Revised: 24 July 2009 /Accepted: 27 July 2009 /Published online: 13 August 2009 # Springer-Verlag 2009
AbstractBackground Corneal neovascularization is a major risk factor for graft failure after corneal transplantation. The purpose of this study was to investigate the effect of subconjunctival, perilimbal, and/or intrastromal bevacizumab (Avastin) on corneal neovascularization in patients with penetrating keratoplasty (PKP).
Methods Fourteen eyes of 14 patients with high risk corneal transplantation and corneal neovascularization after PKP (nine men and five women with a mean age of 63 years) were included in this non-comparative interventional case series. Indications for PKP were: vascularized leucomas after herpetic keratitis and chemical burn, advanced pseudophakic bullous keratopathy with superficial and deep corneal vascularization, keratoconus, severe infection in hereditary corneal dystrophy, and failed corneal grafts. Subconjunctival, perilimbal, and/or intrastromal bevacizumab of dose of 2.5 mg/ 0.1 ml/ per affected quadrant was injected at the site of neovascularization in each patient at the end of surgery and/or at follow up visits. One or two injections were applied. At each visit a full eye examination with photo documentation was performed. Follow-up period was 2 to 8 months (mean 7.1 months).
Results Decrease of corneal neovascularization was ob-served in eleven patients (78.6%). Regression of neovascularization with fading of small vessels was demonstrated. Despite high- risk patient pool, twelve grafts(85.7%) remained transparent for the period of observation, and patients maintained good visual acuity. In two patients with initial graft rejection and vascularization, subconjunctival and perilimbal application of bevacizumab was beneficial in overcoming the corneal inflammation and initial rejection. No adverse reactions have been detected to date in patients with subconjunctival, perilimbal, and/or intrastromal injection of bevacizumab.
Conclusions Bevacizumab is an efficient and safe additional treatment option for improvement of prognosis in high-risk corneal transplantation with pre- and postoperative corneal neovascularization.
Keywords Corneal transplantation . Penetrating keratoplasty. Corneal neovascularization . Subconjunctival Avastin
Introduction
Corneal transplantation was the first tissue transplantation performed in medicine, and it is still the most common allotransplantation. Corneal graft remains clear in majority of patients in low-risk keratoplasties. This success relies on site-specific characteristics, such as corneal immune privilege and corneal avascularity [1]. On the other hand, graft rejection rates of more than 50% have been reported in patients with high-risk keratoplasties with pre-existing corneal neovascularization (NV). Corneal NV occurs when the balance between angiogenic and antiangiogenic factors shifts toward angiogenic factors [2]. Vascular endothelial
Presented in part as oral presentation at the 106th Annual Meeting of the German Society of Ophthalmology, Berlin, September 2008
The authors have full control of all primary data, and agree to allow Graefes Archive for Clinical and Experimental Ophthalmology to review our data upon request.
P. I. Vassileva : T. G. Hergeldzhieva (*)
University Eye Hospital Prof. Pashev,51 Emanuil Vaskidovich Street,Sofia 1517, Bulgariae-mail: [email protected]: [email protected]
1702 Graefes Arch Clin Exp Ophthalmol (2009) 247:17011706
growth factor (VEGF) has been found to be a significant angiogenic factor in corneal NV in human and animal models [3]. Inflammatory processes may stimulate varying degrees of vascularization. Corneal NV is a major risk factor for graft failure after penetrating keratoplasty. Vascularization of the graft may be the result of a poorly prepared recipient eye, the expression of intolerance to the suture material, or a defense mechanism against a suture abscess or graft infection [4]. Vascularization of the graft is also a sign of immune reaction.
Inhibition of VEGF may contribute to the treatment of patients with vascularized corneal grafts. Evidence on efficacy and safety of locally applied bevacizumab on corneal NV as an off-label treatment was obtained in human and animal models [57].
Bevacizumab (Avastin; Roche, Welwyn Garden City, UK) is a recombinant, humanized, monoclonal antibody against VEGF-A. Recently, small case series and isolated case reports have been discussed in the literature, demonstrating safety and good results after off-label application of bevacizumab for corneal neovascularization.
The purpose of this study was to investigate the effect of subconjunctival, perilimbal, and/or intrastromal bevacizumab on corneal NV in patients with penetrating keratoplasty (PKP).
Material and methods
The study was approved by the Institutional Review Board. All patients were asked to sign a written informative consent before any treatment had been initiated.
Fourteen eyes of 14 patients, nine men and five women, with a mean age of 63.4 years (range 3083) with a high-risk corneal transplantation and corneal NV after PKP were included in this non-comparative interventional case series (Table 1).
Indications for penetrating keratoplasty included: vascularized leucoma after herpetic keratitis in three patients and chemical burn in two patients, advanced pseudophakic bullous keratopathy with superficial and deep vascularization of the recipient cornea in four patients, keratoconus in two patients, graft failure in two patients, and severe infection in hereditary corneal dystrophy in one patient. Patients with advanced PBK were referred to our hospital 3 to 5 years after cataract extraction.
Subconjunctival, perilimbal, and intrastromal bevacizumab of a dose of 2.5 mg/ 0.1 ml per affected quadrant was injected at the site of NV before PKP in two patients with graft failure, and subconjunctivally and perilimbally at the end of PKP in ten and/or at follow-up visits in four patients. One to two injections were applied depending on progression of vascularization.
Special instructions for regular examinations and report on possible adverse events were given to all participants.
All PKP patients were treated with topical corticosteroids and artificial tears. We did not change the routine corticosteroid topical regiment depending on injection.
The effect of bevacizumab application was accessed on the first and seventh day after the injection, as well as every month thereafter. At each visit a full eye examination with photo documentation was performed. Corneal photographs were analysed by the same reviewer, who was not masked. The state of neovascularization before and after intervention was determined by comparing the size, number and centricity of vessels as well as the number of affected quadrants. The effect of bevacizumab application on corneal NV was assessed as mild in cases with only temporal effect on superficial and deep vessels when they eventually invade the graft despite treatment, good in cases with partial regression of vascularization and a need for another injection, and excellent when both superficial and deep vascularization disappeared and no additional injection of the medication was indicated.
All PKPs and bevacizumab injections were performed by the same surgeon.
The follow-up period was 2 to 8 months (mean7.1 months).
Results
A majority of patients (71.4%) had both superficial and deep corneal NV. A decrease of corneal NV was observed in 11 patients (78.6%), with regression of NV and fading of small vessels (Figs. 1, 2 and 3). In nine patients (64.3%) the result of bevacizumab application was excellent, and there was no need for another injection. In these cases, new vessels were not observed to cross the grafthost interface and invade the corneal graft after the intervention. Two patients (14.3%) showed initial good results with decreased size of the new vessels, but since the effect was temporary and corneal neovascularization progressed again, another bevacizumab injection was performed. In three patients(21.4%) there was little change in corneal NV.
Two patients with vascularized failed corneal grafts, one
after PKP for PBK, and the other one after corneal transplantation for keratopathy as a result of radial keratotomy, were included in this series. Bevacizumab was applied 1 and 2 months respectively before re-penetrating keratoplasty. Anti-VEGF therapy was performed before corneal re-transplantation, in order to induce regression of existing NV and improve prognosis for graft survival. The effect on vessel regression was excellent in patient #12 and good in patient #13. Patient #13 needed another bevacizumab injection because superficial vessels
Graefes Arch Clin Exp Ophthalmol (2009) 247:17011706 1703
s.c.,perilimbal28monthsmildandgraft
failure
atPKPs.c.,perilimbal18monthsexcellent
12monthsexcellent
atPKPs.c.,perilimbal18monthsexcellent
atPKPs.c.,perilimbal17monthsmildandgraft
failure
Effecton
vascularization
atPKPs.c.,perilimbal18monthsexcellent
atPKPs.c.,perilimbal18monthsexcellent
atPKPs.c.,perilimbal18monthsexcellent
atPKPs.c.,perilimbal18monthsexcellent
2yearsafterPKPs.c.,perilimbal27monthsgood
2monthsafterPKPs.c.,perilimbal18monthsexcellent
2monthsafterPKPs.c.,perilimbal18monthsexcellent
atPKPs.c.,perilimbal16monthsmild
Timeafterlast
injection
25monthsgood
1monthbeforere-PKPs.c.,perilimbal,
intrastromal
No.number,Ptspatients,Mmale,Ffemale,PBKpseudophakicbullouskeratopathy,PKPpenetratingkeratoplasty,RKradialkeratotomy,s.c.subconjunctival
No.of
injections
application
s.c.,perilimbal,
intrastromal
Siteof
Timeofapplicationandno.of
affectedquadrants
atPKP&3monthsafter
PKP
2monthsbeforere-PKP&at
re-PKP
vascularization
superficial&deep
in4quadrants
superficialin2
quadrants
superficial&deep
in2quadrants
superficial&deep
in2quadrants
superficial&deep
in2quadrants
superficial&deep
in2quadrants
superficialin3
quadrants
superficialin2
quadrants
superficial&deep
in4quadrants
superficial&deep
in4quadrants
superficial&deep
in2quadrants
GenderAgeDiagnosisTypeof
1M59vascularizedleucomaafterchemical
burn
2M74vascularizedleucomaafterchemical
burn,monocularpatient
3F50vascularizedleucomaafterherpetic
keratitis
4M83vascularizedleucomaafterherpetic
keratitis
5M61vascularizedleucomaafterherpetic
keratitis
6F70PBK,bilateralblindnesssuperficialin4
quadrants
7M67PBKsuperficial&deep
in4quadrants
8F67PBK,bilateralblindnesssuperficial&deep
in4quadrants
9M76cornealgraftvascularization,PKP
forPBK
10M37keratoconus,initialgraftrejection,
bilateralblindness
11M30keratoconus,initialgraftrejection,
bilateralblindness
12M80graftfailure,PKPforPBK,bilateral
blindness
13F56graftfailure,PKPforkeratopathy
afterRK
14F78severeinfectioninhereditarycorneal
dystrophy
Table1Patientpopulation
No.
ofpts
1704 Graefes Arch Clin Exp Ophthalmol (2009) 247:17011706
Fig. 1 Photograph of patient #7 with PBK prior to PKP and bevacizumab applicationmarked neovascularization is seen, especially superiorly and nasally
Fig. 3 Photograph of the same patient 8 months after PKP and bevacizumab application, showing stable results concerning corneal neovascularization and transparency
progressed and invaded the graft in one quadrant. Avastin injection led to marked regression of these vessels.
In ten patients, bevacizumab was applied at the end of the penetrating keratoplasty. In six of these patients, both deep and superficial vascularization were suppressed, and did not appear in the graft for the period of observation.
In four patients, bevacizumab was applied at different time periods after PKP depending on vascularization, with a varying effect on the vessels. In two of these patients with initial graft rejection and vascularization (patients #10 and11), bevacizumab was beneficial in overcoming the corneal inflammation and initial rejection. Case #10 had mycotic keratitis and inflamed corneal ulcer at the time of corneal transplantation. About a month after PKP a recurrent ulcer developed close to the grafthost junction, with initial graft rejection. Topical anti-mycotic preparation was used in this patient also. In case #11 the keratoconus was advanced, with severe thinning of the cornea, which led to permanent corneal defect for more than a month. Mild inflammation
with invading vessels was observed. Amniotic membrane transplantation was performed in both patients. The graft oedema disappeared, and the rejection line did not advance in patient #10 and the corneal defect healed in patient #11. Despite application of amniotic membrane in both patients, superficial new vessels advanced to the graft, and we decided to use bevacizumab application. In both patients, corneal neovascularization regressed after a single injection (Figs. 4 and 5 of patient #10). Corneal transplants have remained clear without signs of rejection for more than 8 months.
Despite a high-risk patient pool, 12 grafts (85.7%) remained transparent for the period of observation, and patients maintained good visual acuity.
No adverse reactions have been detected to date in patients with subconjunctival, perilimbal, and/or intrastromal injection of bevacizumab.
Fig. 4 Photograph of patient #10 with initial graft rejection and superficial vascularization advancing towards the grafthost junction before bevacizumab application
Fig. 2 Photograph of the same patient 2 months after PKP and bevacizumab application, showing dramatic reduction of corneal neovascularization
Graefes Arch Clin Exp Ophthalmol (2009) 247:17011706 1705
Fig. 5 Photograph of the same patient 1 month after bevacizumab application, showing regressed graft oedema, no progression of the rejection line, and disappearance of corneal neovascularization
Discussion
Corneal neovascularization is a major risk factor for graft failure after penetrating keratoplasty. Its prevention and treatment may improve the prognosis for graft transparency and visual rehabilitation of patients with corneal transplantation.
All patients with penetrating keratoplasty are strictly instructed to immediately report symptoms of graft rejection, such as decrease of visual acuity, redness, pain, irritation, and photophobia. Meticulous examination for limbal injection, postoperative infection, new vessels threatening or invading the graft, epithelial defects, graft oedema, stromal infiltrates or signs of endothelial rejection (Khodadoust line, keratic precipitates, anterior chamber reaction, etc.) is performed at follow-up visits in all cases with PKP at our hospital. Since patients with graft rejection may be asymptomatic, they are asked to come for regular examination after hospital discharge on the 7th, 14th and 30th postoperative day, once monthly in the first 6 months after PKP and every 2 months till the end of the first year. After this period, observation continues with an individual approach but generally at longer time intervals.
Different treatment modalities have been used to manage corneal neovascularization (argon laser photocoagulation, photodynamic therapy, pharmacologic agents, etc), with varying success. Our observations concerning the short-term effect of subconjunctival, perilimbal, and/or intrastromal injection of bevacizumab on corneal new vessels are similar to those reported by other investigators. The medication is well-tolerated, and associated with a partial regression of corneal NV [8].
For many years, ophthalmologists have been using local and systemic corticosteroids as a powerful and effective
treatment against vascularization of the graft. The dosage of corticosteroids should be increased in cases with vascularization of recipients cornea advancing towards the grafthost interface and the graft. Adverse effects such as secondary glaucoma and cataract formation are common complications in these cases. Other immunosuppressive drugs such as azathioprine and cyclosporine have permitted a significant reduction in the corticosteroid dosage, and a greatly reduced incidence of graft vascularization. All patients with PKP at our hospital are treated with topical corticosteroids and artificial tears. Application of bevacizumab may be considered as an additional strategy for management of corneal neovascularization. Other authors have published similar results [9].
A possible role of bevacizumab in the management of graft rejection with vascularization may be discussed, as stated by other authors as well [10].
One disadvantage of our investigation is the lack of a control group. As a referral hospital, our patient pool consists mostly of young patients with bilateral blindness or monocular patients. Sometimes these people live in remote areas, with no possibility for frequent examinations. We decided to inject bevacizumab in cases with vascularization instead of just observing these patients.
Superficial vascularization in the recipient cornea tends to disappear after penetrating keratoplasty. Even so, there is a greater risk for graft failure in cases with advanced superficial vascularization in all quadrants of the cornea. That is why we consider this indication for intervention and application of bevacizumab.
Since penetrating keratoplasty is not a planned surgical procedure in our country, the period between bevacizumab application and PKP differs in the two patients with pre-existing NV and failed corneal grafts. Anti-VEGF therapy was performed before corneal retransplantation in order to induce regression of existing NV and improve prognosis for graft survival. Nevertheless, graft failure was diagnosed in one of these patients 8 months after corneal transplantation. Other factors in addition to corneal vascularization are of great importance in transplantation immunobiology.
Data on topical application of bevacizumab are controversial. Further controlled and long-term studies are needed to evaluate the effect of this new treatment.
Based on our observations, bevacizumab (Avastin) may be considered as an efficient and safe additional treatment option for improvement of prognosis in high-risk corneal transplantation with pre- and postoperative corneal neovascularization.
Conflict of interest None
1706 Graefes Arch Clin Exp Ophthalmol (2009) 247:17011706
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