Ocular surface implant

Advances in immunosuppression and surgical techniques improve safety and outcomes for patients with severe ocular surface disease and limbal stem cell deficiency, while careful evaluation helps match the broadening range of options with specific patient needs, Edward J Holland MD, University of Cincinnati, Ohio, US, told the XXIX Congress of the ESCRS.

“New immunosuppression protocols give better results, and new data support the safety of immunosuppression. New surgical techniques with keratoprostheses along with ocular surface transplants and ex-vivo techniques are certainly exciting news for our patients,†Dr Holland said.

Reducing immunosuppression risk

Dr Holland noted that ocular surface disease and even blindness are not life threatening, while immunosuppression may expose patients to significant health risks. So is the risk of immunosuppression in ocular surface transplantation worth the benefit of improving vision? Dr Holland believes it is for several reasons.

First, ocular transplant patients generally are younger and healthier than organ transplant candidates, so they are less susceptible to immunosuppression complications. Second, ocular surface transplant patients need lower doses, and many can be weaned off oral immunosuppressants over time. Third, newer immunosuppressant agents reduce or eliminate the need for prednisone.

“The biggest complaints patients have are from systemic steroids, so we use low doses or no corticosteroids orally, and all patients are off them by three months,†Dr Holland said.

Dr Holland tailors immunosuppressant regimen to each individual patient based on factors such as HLA match, panel reactive antibodies and blood type. Transplants from living related donors with high HLA match are lower risk for rejection than cadaveric donors, and primary grafts are lower risk than repeat grafts.

For high-risk patients, Dr Holland induces immunosuppression intravenously with the powerful new agent basiliximab on the day of surgery and in the early post-op period. His basic protocol combines tacrolimus, microphenolate and a low dose of oral prednisone. The prednisone is rapidly tapered off at three months. He tapers low-risk patients off tacrolimus at six to 12 months, and high-risk patients at 24 months. He tapers microphenolate at 12 to 24 months, and aims for low-risk patients completely off oral suppressants at 24 months, based on labs and assessment of side effects.

Dr Holland reported good success with this approach. He followed 225 eyes in 136 patients for a mean 4.5 +/-2.7 years. At presentation, 56 per cent of patients had no systemic co-morbidities. Mean duration of immunosuppression was 3.5 years, and 105 patients, or 77 per cent, had stable ocular surface at the last follow-up. Thirty-seven patients, or 35 per cent, were successfully tapered off immunosuppression. The majority of remaining patients were on monotherapy, mostly microphenolate.

There were no deaths or secondary tumours. Three severe events including a myocardial infarction and a pulmonary embolism occurred in two patients with pre-existing risk factors. Nineteen minor events including transient hypertension, increased blood sugar and liver enzymes, and pneumonia occurred in 19 patients (Holland et al. Cornea in press).

Although a legitimate concern, Dr Holland believes that fears of systemic immunosuppression side effects are overblown.

“The bigger problem in the patients I inherit is not enough suppression. Once allograft rejection is under way, the immune system is sensitised to corneal and conjunctival antigens and we have a much higher risk for future procedures.â€

In surgery, Dr Holland now uses tissue glue to secure the ocular surface transplanted tissue instead of multiple sutures.

“It significantly shortens the duration of surgery, which is good for the patient and the surgeon, and we see a lot less inflammation.â€

For patients with severe conjunctival and limbal disease, often in conjunction with Stevens-Johnson syndrome, Dr Holland recommended the “Cincinnati Procedure,†which combines living-related conjunctival limbal allograft (LR-CLAL) tissue transplant combined with cadaveric cornea tissue transplant, keratolimbal allograft (KLAL).

“If we did the LR-CLAL only, we would  not have enough tissue to surround the diseased limbus and we had failure at three and nine o’clock. If we just did cadaveric cornea, we have enough tissue to cover the limbus, but no conjunctival tissue which is vital for the rehabilitation of the ocular surface in these patients,†he explained.

Augmenting the conjunctival and limbal cells from the LR-CLAL with cadaveric limbal tissue from the KLAL tissue completely surrounds the recipient limbus and provides more stem cells. This increases goblet cell and mucin production, increasing ocular surface stability and improving the environment for keratoplasty, Dr Holland said.

Success with the “Cincinnati Procedure†has been high. In a study of 24 eyes in 19 patients with severe ocular surface failure, almost all with Steven-Johnson syndrome, 79 per cent underwent staged keratoplasty and 75 per cent had stable corneal surface at a mean follow up of 43 months. Mean best corrected visual acuity before surgery was 20/400 or worse in 87.5 per cent of eyes, improving to 20/125 or better in 71 per cent of eyes after surgery (Biber et al. Cornea 2011; 30(7):765-771).

Keratoprostheses may also give good results in patients with severe ocular surface disease, with some reports showing one-quarter of patients achieving 20/40 vision and most 20/200 or better, Dr Holland noted. But while keratoprostheses are technically similar to PK, and rejection and immunosuppression are not an issue, corneal melt, infectious keratitis and endophthalmitis are risks. Risks are much higher in patients with severe dry eye or with conjunctival deficiency. Older patient in poor health and thus not ideal candidates for ocular surface transplantation and immunosuppression are good keratoprosthesis candidates.

“Both techniques of ocular surface transplant and keratoprosthesis are very appropriate based on the patient’s presenting symptoms. Corneal surgeons should become accomplished in both techniques and their complication management,†Dr Holland said.

Ex-vivo cultures of corneal cells also show great promise. A recent review found no difference in success rates for corneal cells cultured from a limbal biopsy on an amniotic membrane or a suspension culture of epithelial cells on amniotic membrane or plastic. A total success rate of 76 per cent was achieved for 194 eyes using cultured limbal tissue and 27 receiving culture oral mucosal cells with 70.6 per cent autografts (Short et al, Surv Ophthal 2007; 52(5):483-502).“I think ex-vivo will be more popular in the future,†Dr Holland said.