|Year : 2016 | Volume
| Issue : 3 | Page : 163-170
High-risk penetrating keratoplasty
Shilpa Ajit Joshi, Madan Deshpande
Department of Cornea and Ocular Surface, PBMA's H V Desai Eye Hospital, Pune, Maharashtra, India
|Date of Submission||15-Jul-2015|
|Date of Acceptance||09-May-2016|
|Date of Web Publication||19-Sep-2016|
Shilpa Ajit Joshi
Department of Cornea and Ocular Surface, PBMA's H V Desai Eye Hospital, Hadapsar, Pune - 411 060, Maharashtra
Source of Support: None, Conflict of Interest: None
Background: Loss of immune privilege has important connotations for graft survival, often in clinical scenarios where the other eye is irreversibly blind. This article looks at the state of the evidence-based treatment available for high-risk penetrating keratoplasty (P.K.). Materials and Methods: Review of pathophysiological and immunological mechanisms present was done. Conclusion: Pre-, intra-, and post-operative considerations in P.K. in high-risk situation along with the role of immune-suppression are discussed. Success in high-risk keratoplasty depends on an ongoing effort during as well as life-long after P.K. The role of nonimmunological factors such as glaucoma, reactivation of infection, and unstable ocular surface are important determinants in graft failure.
Keywords: Graft rejection, immunologically high-risk keratoplasties, pre-, intra-, and post-operative management, systemic immunosuppression
|How to cite this article:|
Joshi SA, Deshpande M. High-risk penetrating keratoplasty. J Clin Ophthalmol Res 2016;4:163-70
Traditionally, the corneal transplant has been described as the most successful among solid organ transplants. The success rate for keratoplasty in the 1st year can be as high as 90%. The reasons for this are many fold, most important being, corneal tissue enjoys certain immunoprivilages, due to lack of blood vessels and lymphatics. However, this is the only half-truth, holding true for quiet eyes with inactive corneal scars and nonvascularized host beds. The results of penetrating keratoplasties (P. Ks.) done in these “low risk” cases contrast sharply with those done on “high-risk beds.” The allograft rejection rate in high-risk cases is in the range of 70% even with maximum local and systemic immunosuppression. In this article, we attempt to define corneal allograft rejection, the pathophysiology, various high-risk factors, prevention of rejection, overview of different immunosuppressives, and outcome of high-risk P. Ks.
Corneal graft rejection is defined as a specific immune-mediated process, in which a graft that has been clear for at least 2 weeks postoperatively develops graft edema and anterior segment inflammatory signs. This is different from primary graft rejection (and failure) in which the graft is edematous from day 1, due to severe endothelial damage pre- or intra-operatively. Clinical signs are as follows:
- Development of epithelial and/or endothelial rejection line and stromal rejection band. This is because of infiltration of inflammatory cells. Endothelial rejection is the most common, classically described by Khodadoust, in recognition to him, the hallmark sign of keratic precipitates and leukocytic infiltration of endothelium is called Khodadoust's line
- Recent unilateral anterior chamber reaction
- Increase in corneal thickness/graft edema.
Clinically, graft rejection is defined as:
- Mild: If there is localized graft edema, increased stromal thickness but no aqueous cells and 1–5 K. Ps
- Severe: If there is diffuse graft edema with >5 K. Ps., inflammatory cells in the stroma, endothelial rejection line or increased corneal thickness with aqueous cells.
Reported incidence of graft rejection varies from 2.3% to 68% depending on the preoperative conditions or prognosis of the case. The frequency of episodes of graft rejection is lower in normal-risk keratoplasty as compared to high-risk keratoplasty. Khodadoust reported rejection reactions in 3.5% of avascular cases, 13.3% in mildly vascular cases, 28% in moderately, and 65% in heavily vascular corneas.
There is no universally accepted definition of high-risk keratoplasties but various reports in literature suggest that recipient corneas can be divided into low-, medium-, and high-risk categories depending on the number of quadrants of stromal vascularization viz avascular, 1–2 quadrants, and 3 or all quadrants. Previous failed grafts, unstable ocular surface with repeated breakdown, prior inflamed eyes, for example, postchemical injuries, herpes simplex virus (HSV) keratitis and cases with disorganized anterior segment, for example, large adherent leukomas, also constitute high-risk cases.,
| Pathophysiology of Allograft Rejection|| |
The immune privileged status of the eye is maintained by multiple mechanisms such as (1) lack of blood vessels, (2) lack of lymphatics, (3) blood eye barrier, (4) relative paucity of antigen presenting cells (APC) in the central cornea, (5) presence of immunomodulatory factors in aqueous humor, and (6) constitutive expression of CD95 L (Fas ligand) within the eye. This privilege is lost by inflammation and neovascularization.
Corneal graft rejection is primarily a cell-mediated response controlled by CD4+ T-cells. This process has an afferent arm and an efferent arm. In the afferent arm, the APCs like macrophages, Langerhans cells in the peripheral cornea cause sensitization of host to the donor antigens by presenting them to T cells. This allorecognition process can happen by:
- Indirect pathway in which the host APCs go to the graft, take up donor antigen, migrate to draining lymph nodes, and present the antigens to naïve T cells. This type of immune response is seen in low-risk grafts
- Direct pathway involves donor APCs that sensitize the host directly when T cells recognize the donor Class II major histocompatibility complex, resulting in a rapid immune response. This mechanism is functional in high-risk grafts, where rejection can occur as early as 1–2 months after surgery because of “prior sensitized host” and the presence of immunological memory. Hence, this mechanism is more at play in high-risk grafts.
The efferent phase is responsible for the actual attack on the graft. This consists of proliferation of T-cells, mainly CD4 + T helper cells, which release interleukin-2 (IL-2), interferon gamma, and lymphotoxins to eradicate the offending pathogen by promoting inflammation.
The host is apparently sensitized within a week but it is the ability of effector cells to reach the graft that manifests in the rejection phenomenon.
Anterior chamber-associated immune deviation is another regulatory process that requires time to develop and may be insufficient to prevent active sensitization to foreign antigen. Fas-positive mononuclear cells infiltrating the anterior segment rapidly become apoptotic but may cause some damage before they die.
| Risk Factors for Immune Rejection|| |
- Corneal stromal vascularization: The host bed may be classified into low risk, medium risk, or high risk, depending on the degree of vascularization [Table 1]. In the collaborative corneal transplant study (CCTS), the risk of rejection was doubled in cases with all four quadrants stromal vascularization. The degree and depth of preoperative vascularization determine onset and severity of rejection. The average time between surgery and rejection was about 10 months in avascular corneas, 4 months in mildly vascular corneas, and 2 months in heavily vascularized corneas. Fine and Stein reported that rejection was reversible only in 50% of patients with vascularized corneas, compared with 66% with avascular ones 
- Previous failed graft: Is a significant predisposition to graft rejection as it presensitises the host leading to mounted immune response [Figure 1]. Other causes can be – residual of previous surgery such as corneal neovascularization, peripheral anterior synechiae (PAS), more strategically localized immune mediators. Rejection rates in patients with comparably vascularized host beds are approximately 40% after the first graft, 68% after second, and 80% after third 
- Graft diameter and eccentric graft: Larger grafts are closer to limbal vessels and contain more antigenic material. The correlation is further strong if in a previously failed graft case, the surgeon increases the graft size to completely excises previous opaque cornea. Most surgeons have a consensus that eccentric grafts fare poorer than the central grafts because of their proximity to limbal vasculature
- Anterior synechiae: Direct contact of the graft with host vascular system through PAS is believed to increase the risk of graft failure, due to immunological rejection. In addition, these eyes can have increased incidence of glaucoma, or synechiae can produce traction on corneal endothelium resulting in chronic endothelial cell loss. In the CCTS, the failure rate from any cause doubled if the eye had 3 or 4 quadrants of synechiae
- Previous intraocular surgery: Like lensectomy, vitrectomy, different types of glaucoma surgeries were associated with higher graft failure rates in the CCTS
- Herpes simplex virus keratitis: Inflammation and corneal neovascularization are considered major risk factors for graft survival in the herpetic eye. Several studies have proved that HSV keratitis predisposes the eye to graft rejection, and 70% of these are irreversible [Figure 1]., The use of oral antivirals for prophylaxis has significantly reduced the recurrence rate of herpes [Figure 2] (none versus 44% in control group not on oral acivir) as well as graft failure rate too (14% versus 56%), in a study by Barney and Foster. Apart from rejection and recurrence, these grafts are also at risk for nonimmunological failure due to wound healing problems and neurotrophic keratopathy
- Anterior segment inflammation: Inflammation at the time of P.K. is a major risk factor for graft failure. Active microbial (bacterial/fungal/viral) keratitis, acute hydrops in keratoconus, acute stage of chemical burns with severely inflamed eye, etc., are likely to result in graft rejection and failure. Hence, whenever possible, optical P.K. should be delayed until inflammation is well controlled and eye is quiet for 6–12 months, depending on underlying diagnosis
- Ocular surface diseases: Ocular surface diseases such as ocular cicatricial pemphigoid, Steven Johnson syndrome, limbal stem cell deficiencies, dry eye syndromes, and chemical injuries are at high risk of “nonrejection” graft failures. Procedures such as correction of the lid and nasolacrimal abnormalities, amniotic membrane grafting, living-related and cultivated limbal stem cell transplantation procedures, and various types of keratoprosthesis may be required in this scenario. However, given the myriad possibilities of presentation and therapy, discussion related to ocular surface disease is beyond the scope of this article
- Young age of the recipient, bilateral grafts is some other risk factors.
|Figure 1: Postherpes simplex virus keratitis corneal scar with deep vessels|
Click here to view
| Pre- and Intra-Operative Considerations for High-Risk Penetrating Keratoplasties|| |
Controlling ocular inflammation and undertaking P.K. in remission phase are very important for many chronic diseases such as HSV keratouveitis, ocular cicatricial pemphigoid, and Mooren's ulcer. Stabilization of ocular surface is also necessary. Treatment of blepheromeibomitis, correction of entropion, trichiasis, punctal occlusion, tarsorrhaphy and ocular surface reconstruction with living-related donor conjunctivo-limbal grafts or cultured limbal stem cell transplants, etc., may be needed for many of these cases.
Corneal neovascularization is a strong risk factor for P. Ks, with the survival rates for corneal grafts placed into vascularized beds decreasing to <50% even with local and systemic immunosuppression. Current treatments for corneal neovascularization (NV) include pharmacological approaches such as corticosteroids and nonsteroidal anti-inflammatory agents, both of which can lead to severe side effects such as ocular hypertension and corneal melting, respectively. Other treatments include laser photocoagulation, fine needle diathermy, and photodynamic therapy., However, vessel recanalization and stromal injury have been associated with these treatments. Surgical treatments like amniotic membrane transplantation, which can reduce the vascularization and restore the ocular surface, have also been described. Vascular endothelial growth factors (VEGFs) mediate angiogenesis and it has been shown that VEGF is upregulated in inflamed and vascularized corneas. VEGF inhibitors such as bevacizumab and ranibizumab have been shown to significantly reduce corneal NV in animal models. Moreover, topical application of ranibizumab is effective in reducing the severity of corneal vascularization, mostly through decrease in vessel caliber rather than invasion area, has been shown by a prospective, open-label, noncomparative study.
The role of glaucoma in corneal graft rejection and failure has been recognized for many years but poorly understood. In The CCTS, graft failure rate increased from 29 to 48% in cases with preexisting glaucoma. Opinions are divided between whether P.K. is to be undertaken after intraocular pressure (IOP) has been controlled surgically or trabeculectomy should be done first. In a retrospective review of 26 cases, in the first group of cases, a trabeculectomy was done first followed by P.K. and in the second group, combined glaucoma surgery and P.K. were done. Hazard ratio for IOP control and graft survival between two groups suggests a combined surgery may offer a better prognosis. Increased inflammation following P.K. may predispose to bleb fibrosis and development of PAS. In such failed trabeculectomies with advanced glaucomatous damage or cases with extensive anterior segment disorganization, Glaucoma drainage device is a better choice of surgery. Different studies report the difference in the outcomes depending on the type of implant-valved or nonvalved, limbal-based or pars plana implants. Moreover, there is a difference of opinion regarding the timing of two surgeries. However, most studies report IOP control in the range of 70–90% and reasonable survival rate of corneal grafts in the range of 50–60% at 3–5 years.,,,
Minimizing antigenic differences between host and donor by tissue matching and its effect on allograft survival has been widely discussed by various authors in the literature. So far, the only randomized, prospective, clinical trial of histocompatibility matching done has been The CCTS., It was found that:
- Neither Class I human leukocyte antigen (HLA-A, B) nor Class II (HLA-DR) antigen matching substantially reduces the likelihood of corneal graft failure
- A positive donor–recipient crossmatch (preformed antibodies in the host, directed against donor) does not dramatically increase the risk of graft failure
- ABO blood group matching which can be achieved with relatively little effort may be effective in reducing the risk of graft failure.
Intraoperative modifications in surgical technique:
- Using the central corneal graft, removal of donor epithelium, and using corneas stored in organ culture medium  are strategies that may reduce donor antigenic load
- Use of diluted adrenaline for hemostasis during trephination of highly vascularized cornea, in iridocorneal scars, gentle dissection to preserve iris, proper management of intraocular lenses, automated anterior vitrectomy when needed, interrupted suturing of grafts, and burying knots on the graft side  are the techniques recommended for high-risk cases
- That allograft rejection is the major cause of P.K. failure has been widely reported in the literature.,
Depending on the clinical indication, selective anterior lamellar keratoplasty (deep anterior lamellar keratoplasty [DALK], ALK, etc.,) or posterior lamellar keratoplasty (Descemet stripping endothelial keratoplasty, Descemet's Stripping Automated Endothelial Keratoplasty etc.,) are promising techniques that may help to minimize the rates of graft rejection.,
For corneal diseases involving stroma, for example, corneal dystrophies, keratoconus, etc., DALK seems to be a promising approach with higher long-term survival. The advantages over P.K. consist of eliminating graft rejection, reducing graft failure, preserving graft integrity against blunt trauma, faster visual rehabilitation because of early suture removal and longer graft survival because of a lower rate of endothelial cell loss.,,
For patients with conditions involving endothelium, for example, Fuchs endothelial dystrophy, pseudophakic bullous keratopathy, etc., endothelial keratoplasty (EK) is a viable option instead of P.K. As a far smaller amount of tissue is transplanted in EK and due to the absence of sutures, it has been hypothesized that rejection rate is lower. Because EK does not cause an anesthetic cornea, the risk of ocular surface complications is less. There are many studies presenting lower rejection episodes with EK., In centers where a high number of operations are performed, the endothelial cell loss is becoming comparable to that after P.K. These EK techniques can also be used to replace the endothelial layer in failed penetrating grafts.
| Postoperative Considerations|| |
P.K. in HSV keratitis is a common but challenging situation. Much better prognosis has been reported if there is no active inflammation at the time of surgery. The postoperative course can be quite eventful due to factors such as neurotropism, recurrence of HSV, and rejection. Allograft rejection and herpetic corneal endotheliitis can have similar clinical appearance causing a diagnostic as well as management dilemma. In the postoperative management of P.K. in HSV keratitis, intense corneal neovascularization outgrowth is a common phenomenon. 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. Hence, apart from antiviral treatment, anti-angiogenic therapy should be applied early, possibly even prior to transplantation. That postoperative acyclovir is useful in preventing graft failure has been shown by many studies,, oral acyclovir is better than topical  and it is a standard norm to continue prophylactic oral acyclovir for one year after P.K. Immunosuppressive drug mycophenolate mofetil has been tried along with acyclovir for the prevention of acute allograft rejection and HSV recurrence  with favorable results.
Postoperative management of immunologically high-risk grafts is perhaps most important in determining their outcome. Like all other P. Ks., corticosteroids are the most commonly used agents for these cases too. They block many pathways of local and systemic inflammatory response, inhibiting both afferent and efferent arms of the immune system. A typical regimen involves a large dose of systemic steroid prednisolone (1 mg/kg) postoperatively which is tapered off over next few days on the merits of the individual case. Taking into consideration the adverse effects of long-term use of steroids such as osteoporosis, weight gain, cushingoid features, their use needs to be minimized. Except in cases of severe postoperative anterior segment inflammation, systemic steroids do not provide any benefit over topical steroids in preventing graft rejection.
Mayweg et al. suggested that in normal risk keratoplasties, sole topical steroid application seemed to be an effective immune prophylaxis. That topical steroids have good ocular penetration and they are very effective as immunosuppressives is also shown by many other studies., A standard regimen consists of prednisolone acetate (1%) every 1–2 hourly for first few weeks which is tapered off gradually to once daily dose over next several months. In high-risk P. Ks, prolongation of steroid treatment beyond 18 months of surgery is often required for survival of the grafts. Many surgeons continue treatment with low dose steroids indefinitely. However, this is known to cause cataracts, glaucoma, delayed wound healing, and infectious keratitis. Nowadays, difluprednate is a new synthetic steroid emulsion and is also being used instead of prednisolone acetate. Many surgeons use loteprednol etabonate and fluorometholone in keratoplasty patients who require long-term maintenance therapy or those who are steroid responders. However, their efficacy in preventing or treating graft rejection has not been established.
Birnbaum et al. and Maris et al. have reported the intracameral application of steroid (triamcinolone acetonide) as a treatment for severe and resistant endothelial graft rejections., Subconjunctival  and intravitreal triamcinolone  have also been shown to be effective in the treatment of graft rejections.
However, topical corticosteroids which are the gold standard in the management of low- or normal-risk P.K. patients have shown unsatisfactory results in high-risk cases. The efferent pathway for allograft rejection consists of clonal expansion of graft specific cells in lymphoid tissue. As topical steroids do not reach and even systemic steroids do not interfere sufficiently with proliferation of T cells, it is essential to administer systemic immunosuppressives in order to achieve graft survival. Systemic immune suppression is indicated in such situations, as with other organ transplants. However, unlike in other solid organ transplants, the need for systemic immunosuppression is a debatable question. For people requiring organ transplants, life of a patient is at stake, so the risk of complication from systemic immunosuppression is a lesser evil, whereas in corneal transplants, except for poor vision patients are generally healthy, so side effects of these drugs are not easily justifiable. Perhaps this is the reason that the need for systemic immunosuppression is not widely accepted even in high-risk corneal grafts. Moreover, efficacy, long-term systemic safety, and cost to the patient have to be borne in mind while prescribing and continuing such medication.
Cyclosporine A (Cs A) is a calcineurin inhibitor which has action on transcription of many factors, especially IL-2, necessary for T cell activation. Local application of Cs A has been shown to suppress corneal neovascularization
Topical cyclosporine A
Its penetration into corneal stroma and anterior chamber is hindered by its hydrophobic nature but it achieves high levels in the corneal epithelium on topical application. The immunosuppressive effects appear to be mediated through the ocular surface. A prospective case series by Price and Price using topical Cs A 0.05% four times daily showed, it is not as effective as topical prednisolone for prevention of graft rejection. Another randomized clinical trial by Sinha et al. using topical Cs A 2% in high-risk keratoplasty patients, in addition to topical steroids showed that topical Cs A does not prevent graft rejection; however, eyes receiving it stand a better chance of reversal of episode of graft rejection. At present, in clinical practice, topical Cs A is used as an adjunct to topical steroids in the postoperative management of high-risk grafts.
Cs A has also been in use as an episcleral implant, which releases the drug in a sustained manner over long periods (usually 1 year). Anglade et al. observed more predictable pharmacokinetic and pharmacodynamics properties and four-fold greater calcineurin inhibition with the implant.
In very high-risk cases, topical Cs A may not be sufficient to prevent graft rejection. Several studies, for example, one by Hill reported improved long and short term survival in high-risk cases on oral cyclosporine with topical steroids, compared to patients receiving topical steroids alone. On the other hand, a prospective study on systemic cyclosporine in high-risk corneal transplants has found no remarkable difference in either rejection or graft clarity in forty eyes of Cs A and control group. Hence, while systemic Cs A may have a role in high-risk P. Ks., [Figure 3] and [Figure 4] particularly in one eyed patients, starting a patient on oral medication is a matter of discretion of the treating surgeon. Side effects of Cs A are hypertension, nephrotoxicity, and hepatotoxicity, so careful monitoring is required while on systemic Cs A.
Tacrolimus (FK-506) and everolimus
Tacrolimus (FK-506) and everolimus are also calcineurin inhibitors with a similar mechanism of action like Cyclosporine. Topical tacrolimus has been found effective after lamellar keratoplasty done for Mooren's ulcer. Systemically, it has been found to be effective for high-risk grafts, but rejection episodes can occur shortly after stopping the treatment. In a retrospective case series by Sloper et al., 17 high-risk P.K. patients including 6 with P.K. with limbal transplants were kept on oral tacrolimus. There were three cases of reversible rejection, but no failure occurred while patients were on tacrolimus. Side effects are similar to CsA.
Methotrexate is a folic acid antagonist which has been used extensively as systemic immune suppression for a variety of autoimmune ocular conditions. It has been also used as a cytotoxic agent for treatment of malignancies due to its action of inhibition of purines and pyrimidines synthesis and as disease-modifying antirheumatic drugs in rheumatoid arthritis. Its proposed mechanisms of action are antiproliferative by inhibiting DNA synthesis, diminution of size, and reactivity of T lymphocytes by induction of apoptosis, promotion of adenosine release which mediates suppression of inflammation. In ophthalmology, it has been used in ocular cicatricial pemphigoid, in different types of uveitis, peripheral ulcerative keratitis and necrotizing keratitis in rheumatoid arthritis, and Mooren's ulcer.,, There are case series of methotrexate being used postoperatively in tectonic corneal grafts done for peripheral corneal melts and in high-risk P.K.s., Side effects of methotrexate such as bone marrow suppression, liver toxicity (elevated serum aminotransferases), and stomatitis are mainly due to its antifolate action and can easily be prevented or reversed by supplementation of 10 mg folic acid daily.
Mycophenolate mofetil (MMF) is an antimetabolite which blocks the proliferation of T cells. It has been used extensively in organ transplants, as a single agent or with cyclosporine. In a study by Birnbaum, Reinhard et al., long-term results of high-risk grafts on either MMF or Cs A were assessed. Clear graft survival after 1 and 3 years was 92% and 77% in Cs A and 96 and 87% in MMF, respectively. The side effects of MMF are mainly myelosuppression and gastrointestinal disturbances, which are dose-related and reversible.
Azathioprine is also an antimetabolite which blocks the proliferation of dividing cells by inhibiting purine synthesis. Currently, its role is limited as an adjunct to Cs A or tacrolimus in high-risk cases resistant to other treatment. Its main side effect is dose-related bone marrow suppression.
There are few reports of a new drug, rapamycin (Rapa) which has been used as monotherapy or in combination with other agents. A study by Stanojlovic et al. showed that combined treatment with low-dose Rapa and Cs A resulted in superior graft survival and effectively modulated the mRNA expression of inflammation and infiltration markers.
Basiliximab is an antibody directed against α subunit of IL-2 receptor, which inhibits T cell proliferation. It is approved for treatment in patients after kidney transplantation. In a study by Birnbaum et al., ten patients in basiliximab received 20 mg of drug following surgery and 4 days postoperatively, versus ten patients in control group received cyclosporine for 6 months. Four patients in the basiliximab group showed rejection out of which two grafts failed, whereas two patients in Cs A group showed immune rejection out of which one failed. There were no side effects with basiliximab. The primary advantage of monoclonal antibodies is their specificity toward target antigen and their safety profile.
A lot of experimental modalities are being tried out for immunomodulation, for example:
- To reduce donor APCs by pretreating donor cornea in vitro with low-dose ultraviolet light or hyperbaric oxygen
- Blockade of T-cell activation by cytotoxic T lymphocyte-associated antigen 4 immunoglobulin has shown to prolong graft survival in animal models
- Cytokines IL-4 and IL-10, when introduced in donor corneal epithelium by gene transfer, have been shown to increase graft survival.
To summarize, management of high-risk P. Ks. continues to be a challenge, despite the developments in reducing donor antigenic load, advances in surgical techniques, availability of newer immunosuppressives and ongoing research in this field. The current standard practices of corneal grafting in such cases consist of appropriate pre-, intra-, and post-operative measures. Preoperatively, controlling the inflammation, glaucoma, treatment for corneal vascularization and treating ocular surface disease are important steps. Adopting newer surgical techniques is also another milestone. Because rejection is a major cause of failure in first P. Ks, reducing the risk of rejection using lamellar techniques, EK for Fuchs dystrophy and pseudophakic bullous keratopathy, and DALK for keratoconus should help to reduce the risk of failure of first-time grafts and thus the need for regrafts. The use of EK for failed vascularized P. Ks may also be considered. Postoperatively, closer patient follow-up and stepwise approach to immunosuppression are required. Topical steroids are needed to be used for a much longer time, perhaps indefinitely, for these cases. Topical immunosuppressives are also indicated for long-term use. The evidence to use systemic immunosuppressives is inconclusive, but they are recommended for very high-risk, bilaterally blind patients who are dependent on graft clarity for functional vision. Immunotherapy should be continued not just for 1 year but as long as the graft is at risk for acute rejection. In multiple failed grafts or in cases with multiple high-risk factors, where a conventional keratoplasty has almost nil probability of survival, a keratoprosthesis has become the standard norm rather than the last resort. Finally, patient education, counseling, and compliance are needed for prevention and management of graft rejections and for improving the outcomes of high-risk corneal transplants.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]