Tutorial
Introduction
Therapeutic Keratoplasty For Microbial Keratitis
Therapeutic Keratoplasty for Bacterial Infections
Therapeutic Keratoplasty for Mycotic Infections
Therapeutic Keratoplasty for Acanthamoeba Infections
Therapeutic Keratoplasty for Herpetic Infections
Conclusion
References

Slides

Post Test

Therapeutic Keratoplasty for Infectious Keratitis

Renée Solomon, MD · Eric D. Donnenfeld, MD · Henry D. Perry, MD

None of the authors has a proprietary or financial interest in any material or method mentioned.

Introduction

The primary purposes of therapeutic keratoplasty are to restore the structural integrity of the eye (tectonic keratoplasty) or to resolve an infectious/inflammatory keratitis, which is refractory to conventional medical therapy. One or both of these indications may be present. Generally, therapeutic keratoplasties are emergent or semi-emergent procedures in which the survival of the globe is at risk. Unlike with an optical penetrating keratoplasty (PKP), in which visual restoration is the primary goal, acute visual rehabilitation is of secondary importance in therapeutic keratoplasty. Visual rehabilitation, if necessary, can be achieved at a later time under more controlled circumstances.

Therapeutic Keratoplasty For Microbial Keratitis

Despite new developments in antimicrobial agents, a subgroup of bacteria, fungi, parasites, and viruses that does not respond to medical therapy remains.^1-7 Therapeutic keratoplasty is indicated when inflammatory or infectious corneal disease is advancing despite maximum medical therapy, and the integrity of the globe is compromised. Medical therapy should be continued or altered until there is no reasonable expectation that the infection or inflammation is able to be controlled or until a significant risk of corneal perforation or scleral extension is present.

Corneal perforation dramatically increases the risk of endophthalmitis, while infectious scleritis should be avoided due to the severe morbidity of this disease.^8-11 Noninvasive surgical treatment, such as tarsorrhaphies and conjunctival flaps, can be attempted if indicated.

A therapeutic keratoplasty offers a surgical debridement of an infectious process. The objective of therapeutic keratoplasty is to remove the infectious inoculum or to decrease the organisms in the cornea to a level at which exogenous anti-infective/anti-inflammatory agents and the patients’ endogenous host defense mechanisms can be effective.¹²

Robin and colleagues¹³ reviewed 497 PKP buttons and noted that PKP was performed for active ulcerative keratitis in 7% of these patients and for viral keratitis in 6% of patients.¹³

Killingsworth¹² reviewed 80 consecutive therapeutic keratoplasties performed over a 9-year period. Twenty-six therapeutic keratoplasties were performed for bacterial infections, 15 for fungal infections, 11 for active herpetic keratitis, four for persistent epithelial defects after herpes simplex keratitis, 12 for dry eyes, 10 for non-herpetic persistent epithelial defects and two for Acanthamoeba keratitis.

Similarly, a review in India of 100 cases by Sony and colleagues¹⁴ demonstrated that most therapeutic keratoplasties were performed for bacterial keratitis refractory to maximum medical therapy, while fewer cases were for fungal keratitis unresponsive to maximum medical management.

SLIDE 1

When an acute ulceration threatens perforation, the patient should be prescribed systemic as well as topical therapy to reduce the likelihood of intraocular involvement. Subconjunctival antibiotics do not appear to offer a significant advantage over aggressive topical therapy.^15-16 Once an acute infectious corneal perforation has occurred, topical antimicrobials should be continued, but the physician and patient should be aware of the risk of intraocular toxicity.^17-19

An attempt to seal the perforation with cyanoacrylate adhesives is an option.^20-22 After the integrity of the anterior chamber has been re-established, topical antimicrobial treatment can be re-instituted safely without the risk of intraocular toxicity. Sealing the perforation with cyanoacrylate may often be definitive management, but if the perforation progresses to require therapeutic keratoplasty, the patient will have been temporized with additional antimicrobials and the ulceration will have been sterilized. When cyanoacrylate is applied, the patient must be monitored closely because bacterial infections have been shown to progress beneath the cyanoacrylate glue.²³

Generally, when perforations or pre-descemetoceles are treated with therapeutic keratoplasties, outcomes are satisfactory. Jonas and colleagues²⁴ examined a series of 60 cases of keratoplasties for these indications and found that 90% achieved some improvement in preoperative visual acuity. Ten cases (17%) required repeat keratoplasties for recurrent corneal ulcers.

Therapeutic Keratoplasty for Bacterial Infections

SLIDE 2

Some bacteria, notably Pseudomonas aeruginosa,²⁵ can infect the cornea and progress to corneal perforation in approximately 24 to 48 hours. These bacteria may produce collagenase, which results in rapid corneal thinning. Most bacterial infections, when managed expediently, respond to therapy. However, due to delay in seeking or obtaining medical treatment, bacterial infections may rapidly progress to corneal perforation.^26-27 Bacterial keratitis has been treated with lamellar and penetrating keratoplasty in an attempt to reduce the infectious organism count in the cornea when medical treatment has been unsuccessful. Lamellar and penetrating grafts have also been used to prevent and treat perforation.

Malik and Singh³ managed 36 Pseudomonas ulcers with lamellar and penetrating grafts. Eight of the lamellar grafts became reinfected and one eye was enucleated. Four of the 28 penetrating therapeutic grafts became reinfected. The authors conclude that penetrating grafts are more efficient in treating active infection than lamellar grafts.

SLIDE 3

Hill¹ in 1986 presented 23 patients with deep, indolent ulceration and descemetocele that were treated with therapeutic keratoplasty. Early surgery did not jeopardize the final outcome of the keratoplasty. The period of morbidity was shorter and more rapid visual rehabilitation occurred with early keratoplasty, possibly secondary to the fact that corneal neovascularization was prevented by earlier surgical management. Removal of the infected cornea may necessitate a larger than customary keratoplasty to debride the infected tissue.

Cowden and colleagues²⁸ presented 14 patients undergoing PKP using 9.5-mm or larger diameter grafts (Slide 1, Slide 2). Five of these patients had bacterial keratitis. They conclude that larger diameter penetrating keratoplasties can salvage an eye that may have otherwise been lost, with reasonable visual rehabilitation. Although visual prognosis is best when the surgery is performed in a sterilized, minimally inflamed eye, perforation or threatened perforation with uncontrolled progression of the disease and a necrotic stroma mandate early intervention.

Lam and Cooper²⁹ presented 13 patients treated with therapeutic keratoplasty for bacterial suppurative keratitis with satisfactory long-term optical results.

A distinct subset of bacterial keratitis, which may require therapeutic keratoplasty, is bacterial infections unresponsive to conventional medical therapy. These infections are generally opportunistic and indolent, but continue to progress despite aggressive treatment. This subgroup includes crystalline keratopathy (most commonly due to alpha-hemolytic Streptococcus),^12,30-31 but can be seen with a variety of bacteria as well as Candida and Mycobacterium fortuitum.^2,12

These infections are most commonly seen after corneal surgery and will progress until a therapeutic keratoplasty is performed. Although more than 50% of patients with infectious crystalline keratopathy fail to respond to medical management, because of minimal inflammation in this disorder, therapeutic keratoplasty is successful.³¹

Therapeutic Keratoplasty for Mycotic Infections

SLIDE 4

The advent of topical antifungal agents has reduced the need for therapeutic PKP for fungal keratitis and has also improved the prognosis and visual outcome of patients with medically uncontrolled fungal ulcers.

Forster and Rebell⁴ emphasized the importance of intensive antifungal treatment before therapeutic keratoplasty to help stabilize the cornea and improve the prognosis. They reviewed 61 eyes with corneal fungal infections, of which 13 were considered treatment failures. Nine of the 13 treatment failures underwent therapeutic keratoplasty. Five of these nine patients achieved a visual acuity of 20/70 or better. In nine patients who underwent PKP, the fungal disease process was halted by the therapeutic keratoplasty.⁴

SLIDE 5

Polack and colleagues³² had reviewed 30 patients with keratomycosis. Of the 22 treated surgically, PKP was superior to lamellar keratoplasty. Pathological examination revealed that fungal elements appeared to penetrate Descemet’s membrane, causing a high recurrence rate in lamellar keratoplasty grafts.

Forster³² observed that 17 of 29 corneas infected by fungi remained culture-positive at the time of keratoplasty, and 26 of the eyes had viable hyphal elements on pathology (Slide 3, Slide 4, Slide 5).³³

Killingsworth and colleagues¹² obtained a 100% cure rate in 15 fungal ulcers treated with therapeutic keratoplasty (Slide 6).¹² Postoperatively, fungal infection may infiltrate the grafted tissue.^34-36

SLIDE 6

Xie and colleagues³⁷ studied 108 eyes with fungal keratitis in which therapeutic keratoplasty was performed. Eighty percent of eyes remained clear during follow-up with no recurrence of infection and visual acuity ranging from 20/100 to 20/20.

SLIDE 7

A later study by Xie and colleagues³⁸ investigated the effectiveness of lamellar keratoplasty in treating fungal keratitis. They achieved therapeutically beneficial results in 93% of eyes (51 of 55 cases performed) with a resulting visual acuity ranging from 20/63 to 20/20.³⁸ In four patients, fungal infection recurred within 2 weeks. The authors point out that corneal tissue used in lamellar keratoplasty may be obtained more readily than healthy tissue used in PKP and lamellar keratoplasty is a viable option for treating fungal keratitis.³⁸

The standard treatment after therapeutic keratoplasty has been corticosteroids to prevent allograft rejection and control postoperative inflammation. However, in the management of mycotic keratitis, corticosteroids have been discouraged because of the risks of exacerbating an existing infection or introducing a superinfection.³⁹

In a prospective, non-randomized interventional case series of three patients, topical cyclosporine A (tCSA) 0.5% has been shown to be a safe and useful adjunct in the treatment of therapeutic keratoplasties for fungal keratitis to avoid or reduce the use of corticosteroids.⁴⁰ Furthermore, compared to corticosteroids, tCSA has been shown in vitro to have a statistically significant suppressive effect on fungal growth.^41,42

The most common fungal organisms isolated preceding and during therapeutic keratoplasty include Fusarium, Aspergillus, and Candida.^4,43

Therapeutic Keratoplasty for Acanthamoeba Infections

SLIDE 8

The roles of medical and surgical intervention in Acanthamoeba keratitis are controversial. Some patients diagnosed early have been successfully treated with medication alone.^44-45 Early PKP has been advocated to remove the bulk of infection and reduce the risk for intractable scleral contamination.⁴⁶

In a report by Ficker and colleagues,⁴⁷ graft survival for Acanthamoeba keratitis was poor with more than 50% incidence of recurrence in the graft. Cullen and colleagues,⁴⁸ based on his experience with seven patients, concluded that early diagnosis helped with successful medical treatment, but PKP continues to have a central role in the management of cases that are advanced or unresponsive to medical therapy.

Cryotherapy of the host cornea has also been suggested in conjunction with PKP for cases unresponsive to medical treatment.⁴⁹ The acute management of these active cases is to sterilize the infection as rapidly as possible and to delay surgical management until the patient receives adequate anti-amoebic therapy.⁵⁰

Therapeutic Keratoplasty for Herpetic Infections

SLIDE 9

Herpes simplex keratitis often requires surgical intervention. Surgery is performed most commonly for significant corneal scarring and is performed under quiescent, controlled circumstances. Recently, adjunctive medical management has made possible successful PKP in the active stromal stage of herpes simplex keratitis. Therapeutic keratoplasty can be used for significant ulceration and perforation, or to remove viral antigenic material responsible for repeated immune inflammatory episodes (Slide 7, Slide 8, Slide 9, Slide 10).

SLIDE 10

As noted by Langston and colleagues,⁵¹ success of the keratoplasty depends on the degree of inflammation, presence of neovascularization, use of fine (10-0 nylon) sutures, and high doses of topical steroids in the immediate postoperative period.

Recently, adjunctive use of oral acyclovir has been shown to improve prognosis as well (Slide 11, Slide 12, Slide 13).^52,53 Topical antiviral prophylaxis during the immediate postoperative period and during allograft rejection episodes while topical corticosteroids are used may prevent recurrent herpetic disease.⁵⁴

SLIDE 11

Ficker and co-researchers⁵⁵ found that the combination of prophylactic antivirals and corticosteroids increased the success rate in inflamed eyes undergoing therapeutic keratoplasty for herpes simplex keratitis to a rate comparable to that of quiescent eyes. The use of interrupted sutures, prompt removal of loose sutures, and the previously noted antivirals and topical steroid treatment combination reduced the recurrence of herpes simplex virus to 15%.

SLIDE 12

Killingsworth and associates¹² divided 15 patients who required therapeutic PKP for herpes simplex keratitis into two groups. The first group included patients with severe stromal keratitis who did not respond to medical treatment and patients who progressed to perforation. The second group consisted of patients who developed corneal perforation secondary to persistent epithelial defects with little or no active stromal inflammation. Only four of the 11 patients in the first group achieved clear grafts, while all four patients in the second group were successful.

The prognosis for therapeutic keratoplasty in herpes zoster keratitis is generally worse than for herpes simplex keratitis. Patients with herpetic corneal disease commonly have neurotrophic corneas. However, the anesthesia tends to be more severe for herpes zoster than for herpes simplex. One of the most important prognostic variables for herpes zoster therapeutic keratoplasty is the level of corneal sensation. Therapeutic keratoplasty in patients with herpes zoster keratitis perforations often requires adjunctive therapy, such as conjunctival flaps or tarsorrhaphies.

Careful management of external and corneal disease can improve the outcomes in therapeutic keratoplasty for varicella-zoster keratitis. Tanure and colleagues⁵⁶ published results from a series of 15 keratoplasties performed for varicella-zoster keratopathy from 1989 through 1998 (12 with zoster and three with varicella), and found that 87% of grafts remained clear at an average follow-up of 50 months. To decrease complications from neurotrophic keratopathy, four eyes received lateral tarsorrhaphies in conjunction with the keratoplasties, and frequent lubrication was prescribed.

Conclusion

SLIDE 13

The ultimate visual outcome for therapeutic keratoplasties depends on multiple variables. The infecting organism and its susceptibility to treatment are important. Therapeutic keratoplasty for bacterial keratitis has a much better prognosis than for Acanthamoeba or fungal infections.

Killingsworth and colleagues¹² reported clear therapeutic grafts in 73% of bacterial corneal ulcers, 60% of fungal corneal ulcers, 50% of Acanthamoeba corneal ulcers, and 36% of herpes ulcerations with inflammation. Underlying corneal pathology also affects postoperative visual rehabilitation. Ocular surface diseases, including neurotrophic disease and dry eye, significantly decrease the viability of the donor cornea. In severe ocular surface disease, the visual prognosis is poor and the keratoplasty is generally performed for tectonic rather than visual purposes.

The severity of ocular inflammation at the time of surgery has direct impact on graft survival. Active inflammation increases the risk of corneal neovascularization, anterior synechiae, glaucoma, and graft rejection. Although eradication of the corneal infection is paramount, control of inflammation is also important. Superimposing the trauma of a PKP on an underlying inflammatory condition can result in increased inflammation in the donor cornea.^29,43 This inflammation can progress to donor cornea melting, vascularization, and allograft rejection.

When a therapeutic keratoplasty is semi-emergent and the infection is controlled, a short pulse of topical corticosteroids prior to surgery may improve visual outcome. Corneal neovascularization also decreases the success of therapeutic keratoplasty. The more extensive the stromal vascularization, the more likely graft rejection will occur.

Furthermore, the size of the therapeutic keratoplasty is important in graft survival. Keratoplasty of more than 9.5-mm diameter appears to have a significantly decreased chance of long-term viability.^12,28 Larger transplants that are closer to the limbus can increase the risk of allograft rejection and peripheral anterior synechiae with glaucoma. These larger keratoplasties often provide tectonic support for smaller optical penetrating keratoplasties, which can be performed later.

In conclusion, therapeutic keratoplasty is generally an emergent, high-risk procedure that challenges the surgical and medical skills of a corneal surgeon. A therapeutic keratoplasty requires meticulous attention to detail and careful postoperative monitoring. Nevertheless, advances in microsurgical technique, antimicrobial therapy, and control of inflammation have resulted in an improved prognosis for a patient undergoing therapeutic keratoplasty.

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