Any alteration of the ocular surface (OS), can influence the result of a keratoplasty, and its influence will be more negative the greater the severity of the pathology. When we perform a keratoplasty in these patients, the risk of postoperative complications increases and worsens the prognosis and survival of the transplant. Among the pathologies of the OS that can affect the evolution of a transplant we can include: dry eye syndrome, chronic blepharoconjunctivitis and keratoconjunctivitis, chemical injuries and limbal insufficiencies in general, neurotrophic keratopathy and, finally, mucocutaneous syndromes. Being complex patients, we must always assess the risk-benefit ratio of the surgery in each case before proceeding. However, even in patients without previous evidence of OS alterations, this must be evaluated as an integral part of the preoperative examination.

ASSESSMENT PRIOR TO KERATOPLASTY

In the presence of pathology of the OS, before proposing a keratoplasty we should stabilize it and correct as much as possible all the existing alterations. The “hot” keratoplasty, without previously stabilizing the OS, should only be performed in cases of urgent need (corneal perforations or imminent risk of perforation), since the risk of failure is high. Whenever possible, we will defer surgery until a more favorable situation is achieved. The preoperative assessment and eventual treatment of these patients should include:

State of the eyelids

The state of the eyelids, the frequency of blinking and if the palpebral occultation is correct should be assessed. In case of blepharitis, the measures for its control should be applied from the hygiene and palpebral massage until the treatment with oral doxycycline. Any alteration of the position or dynamics of the eyelids, eyelashes or fornixes should be corrected surgically before transplantation. In the case of mucosal blistering diseases, or with inflammatory activity, the medical treatment indicated for them should be initiated before the surgery, so that they are as much as possible in remission at the time of surgery.

State of the tear film

Mild or moderate lacrimal film deficits are not a contraindication to performing a keratoplasty but should receive intensive treatment with artificial tears without preservatives before and after surgery. Patients with Schirmer’s test <5 mm will have a higher incidence of persistent epithelial defects in the postoperative period, and therefore a higher risk of complications. If intensive treatment with lubricants is not enough, the occlusion of the inferior lacrimal point should be assessed preoperatively. Lateral tarsorrhaphy is a very effective measure to treat persistent epithelial defects that appear in the postoperative period. Patients with Schirmer's test (without anesthetic) = 0 mm should not be operated on because no type of transplant is viable in complete absence of tear.

State of limbus

Before a possible limbal insufficiency, its degree and reversibility must first be assessed. It should be considered that in some cases the limbal insufficiency can be reversible if we treat the cause that originated it. In cases of irreversible but partial limbal insufficiency, a sectorial conjunctival epitheliectomy¹, either prior to or at the time of transplantation, may be sufficient to achieve a correct epithelialization with a corneal phenotype at the center of the keratoplasty. Adding a coating with amniotic membrane at the end of surgery helps to improve the postoperative epithelization and the final result in these patients.

In cases of total or subtotal limbal insufficiency, the population of corneal epithelial stem cells should be restored before considering keratoplasty. This can be achieved by a limbus transplant (autologous or allogeneic, depending on whether the lesions are unilateral or bilateral) (Figure 1), or by autologous transplant of patient's own stem cells cultured in the laboratory (in unilateral cases). With this last technique, from a small fragment of limbus of the healthy eye, we can transplant a large number of stem cells to the affected cornea (Figures 2a, b). A few weeks after confirming that the limbal insufficiency has been corrected satisfactorily and that the cornea is covered by epithelium of corneal phenotype, we can proceed with the keratoplasty (Figures 2c, d).

State of the corneal surface

Any epithelial defect or corneal ulceration must be treated before performing the transplant until a stable corneal surface situation is obtained, provided this is feasible and there is no imminent risk of perforation.

Inflammatory state

Before proposing a transplant, we must eliminate to the maximum any inflammation of the OS and the anterior segment of the eye. For this, we will use corticosteroids without preservatives, controlling the ocular pressure and providing antibiotic prophylaxis in the case of epithelial defects. In chemical injuries, both stem cell transplantation and keratoplasty get worse results when surgery is performed on one eye with significant inflammation of the OS.

SELECTION OF SURGICAL TECHNIQUES

Type of keratoplasty

Given that these patients may suffer postoperative complications that make the transplant fail and sometimes force it to be repeated, it is preferable to perform lamellar keratoplasties to the penetrating ones whenever possible, for the safety they provide when working with a closed eye, the lowest rejection rate and their ease for an eventual replacement. Penetrating keratoplasty (PK) should be reserved for cases with endothelial involvement in addition to the superficial and stromal. In cases with endothelial dysfunction without irreversible stromal involvement – something that is not common in OS disorders, endothelial keratoplasty (DSAEK or DMEK, see sections 6 and 7 of this book) allows these patients to be treated by means of small incision surgeries that have less impact on the OS.

In most cases with stromal involvement and preserved endothelium, the indication will generally be anterior lamellar keratoplasty, which completely avoids the possibility of endothelial rejection. For limited lesions up to 200 μm deep, superficial anterior lamellar keratoplasty (SALK) can be performed with the help of a microkeratome or a femtosecond laser (see section 4 of this book). When the lesions are deeper, we must perform a deep anterior lamellar keratoplasty (DALK), either in its descemetic variant (Figures 3 and 4) or in a predescemetic one (Figure 5) (see section 5 of this book). The second technique is, in our opinion, the one of choice in cases with a high risk of suffering postoperative complications and graft failure, such as patients with OS alterations, in whom we prefer to be less ambitious in terms of visual recovery, in the interest of improving the safety of the procedure.

Coating with amniotic membrane

In some patients, because of their underlying pathology, we know that there may be epithelization problems during the postoperative period. This occurs when there is some degree of limbal insufficiency, significant neurotrophic alteration or severe tear deficit. In these cases, it is extremely important to favor the epithelialization of the transplanted corneal button – which is often devoid of epithelium. in the first days of the postoperative period, since the presence of a persistent epithelial defect can lead to infection or graft opacification (Figure 6). In these cases, at the end of the transplant, we can associate a corneal lining with an amniotic membrane that, in addition to providing growth factors, provides a mechanical effect of epithelial protection against blinking, similar to that of a therapeutic contact lens^2-3. We implant it with the stroma onward, completely covering the cornea until it surpasses the limbus, and we fix it with a continuous nylon 10-0 suture that surrounds the sutures of the keratoplasty. Two weeks later, the suture and remnants of the amniotic membrane can be easily removed in the slit lamp (Figure 7).

Lateral tarsorrhaphy

An alternative to the amniotic membrane to promote postoperative epithelization is lateral tarsorrhaphy^4-5. In addition to protecting the OS from the external environment and minimizing blink trauma, it also reduces the evaporation of the tear, improving epithelialization. When the effect is of interest only in the first days of the postoperative period, the direct tarsal-tarsal suture at the end of the surgery, including a few millimeters of temporal eyelid, is sufficient. We remove this suture in the clinic about 2 weeks after the transplant. In patients in whom there is a severe baseline alteration and in which we want to keep the tarsorrhaphy for a long time, we must perform surgical opening of the edges and suture so that the union is permanent (Figure 8).

Protection of the epithelium

As long as the donor corneal button that we are going to transplant has a viable epithelium, this must be protected and preserved during surgery. Although some authors report a lower risk of rejection when de-epithelializing the donor cornea (generally in PK)⁶, others defend the opposite⁷. In patients with underlying OS problems, having the epithelialized cornea from the immediate postoperative period reduces the risk of related complications, in comparison with those in which the graft is de-epithelialized. To protect the epithelium during surgery, a viscous solution of 0.1% hyaluronate would be more effective than saline solutions⁸ or even those based on methylcellulose, and would also accelerate the epithelization after keratoplasty⁹.

POSTOPERATIVE TREATMENT

All the postoperative treatment that we prescribe in patients with OS disorders should aim to minimize its local toxicity. We should avoid any drug that is not strictly necessary, choose those less harmful active ingredients and eliminate, whenever possible, the use of preservatives. At present, both antibiotics and corticosteroids without preservatives are available, the main agents in the postoperative treatment of a keratoplasty. The antibiotic is usually used 3 or 4 times a day prophylactically while there is an epithelial defect and must be stopped once the corneal and conjunctival epithelialization have been completed (with a minimum of 7 days of treatment). The potency and frequency of corticosteroid administration may vary depending on the underlying pathology as well as the duration of treatment.

In general, copious use of artificial tears without preservatives is recommended, especially those containing hyaluronic acid which, in addition to having a high capacity for hydration and lubrication, has been shown to increase migration and epithelial replication^10-11. In case of requiring ocular hypotensive treatment, in these cases it is preferable orally (acetazolamide, as long as there is no contraindication) or, as a second option, a topical drug without preservatives.

In patients with a history of herpetic keratitis oral antivirals should be used prophylactically, p. ex. Acyclovir 400 mg every 12 hours for 6-12 months. This has been shown to reduce recurrences of herpetic or orofacial ocular disease by 45%^12,13. Also Valacyclovir at a dose of 500 mg every 12-24 hours has been shown to be effective in these cases.

Treatment of persistent epithelial defect

Achieving a complete and stable epithelization of the OS in these patients is the first step to achieve a favorable result with the transplant. The most common lesion to all the alterations of the OS is the persistent epithelial defect (PED) and therefore constitutes one of the main postoperative complications in these cases. It is defined as an area with loss of epithelial cells of full thickness and more than 2 weeks in duration despite treatment.

PED can be reached by different mechanisms such as limbal insufficiency, maintained inflammation of OS, dry eye syndrome, neurotrophic keratopathy or alterations in palpebral occlusion/dynamics¹⁴. Sometimes, more than one of these factors converge in an OS disease, which complicates postoperative management. For example, in severe chemical injuries, there is a destruction of the stem cells of the limbus, but the inflammation present in the OS also affects the functionality of those cells that are still viable. Or, in neurotrophic keratopathy, epithelial regeneration is affected while a dry eye syndrome occurs, since loss of corneal sensitivity reduces tear production and increases tear evaporation by decreasing the blink reflex.

The incidence of PED after keratoplasty in general is around 3-4%¹⁵, but this figure increases significantly when we treat patients with underlying OS disorders. For example, the presence of vernal keratoconjunctivitis multiplies the risk of postoperative PED by 6 in patients with keratoconus¹⁵. Once a PED appears, it should be treated quickly to avoid the development of other complications that can threaten vision, such as infectious keratitis, ulcers, neovascularization and stromal opacification.

The treatment of an epithelial defect is based, in the first place, on the general measures mentioned above such as the suppression of unnecessary drugs, of any preservative and the frequent use of lubricants. Pharmacological toxicity can be the cause of a PED in some cases, and in the rest, it will hinder the epithelial regeneration. In cases of significant deficit in lacrimal production (Schirmer’s test <5 mm) occlusion of the inferior tear duct should be considered. In patients with a history of corneal calcification, all phosphate-containing products should be avoided, either in the agent (e.g., dexamethasone) or in the excipient.

If with these measures there is no improvement in the situation in a few days, other treatments should be considered, such as the blood derivatives – autologous serum, platelet-rich plasma (PRP) or plasma rich in growth factors (PRGF) – or the regenerators of the extracellular matrix such as carboxy-methyl-glucose poly-sulfate (Cacicol®).

The use of a therapeutic contact lens helps to stabilize the epithelium and protects it from continuous trauma from blinking. However, adaptation in the immediate postoperative period is usually not easy because the transplanted cornea does not yet have a normal curvature. It may be necessary to adapt a large diameter flat lens to achieve centering. Whenever a therapeutic contact lens is adapted, a prophylactic topical antibiotic should be administered, since the presence of an epithelial defect and local immunosuppression by topical corticosteroids favors the appearance of infections. Finally, if the aforementioned measures do not achieve the complete resolution of the PED, a lateral tarsorrhaphy should be evaluated. Although it may be poorly accepted by the patient for reasons of aesthetics, it is very effective in curing PED and it is possible to reopen it without sequelae when it is no longer necessary.