Limbal stem cell deficiency: Which procedure, when

Take-home message: Cornea experts discuss the roles of ocular surface transplantation and keratoprosthesis implantation in the management of eyes with severe limbal stem cell deficiency.

By Cheryl Guttman Krader; Reviewed by Clara C. Chan, MD, and Edward J. Holland, MD

Modifications in device design and postoperative management have led to improved outcomes with the Boston keratoprosthesis type 1 (“Boston KPro”; Massachusetts Eye and Ear Infirmary).

However, presence of severe ocular surface failure portends a poorer prognosis.

Therefore, in eyes with severe limbal stem cell deficiency (LSCD) (>50%) and significant conjunctival deficiency, the indications for Boston KPro implantation are limited, and ocular surface transplantation (OST) should be considered as the primary procedure for the majority of patients, according to cornea specialists Clara C. Chan, MD, and Edward Holland, MD.

Dr. Holland observed that the relative ease of the surgery combined with the opportunity to avoid treatment with immunosuppressant medications likely explains why more and more surgeons seem to be choosing Boston KPro implantation over OST for patients with severe ocular surface failure.

However, as both Dr. Holland and Dr. Chan point out, the latter eyes are at increased risk for serious Boston KPro-related complications, which can lead to explantation, permanent vision loss, and even loss of the eye.

In contrast to the Boston KPro, OST offers several important advantages in this high-risk population. Therefore, the gravitation toward Boston KPro implantation represents a concerning trend, said Dr. Holland, director of cornea service, Cincinnati Eye Institute, and professor of ophthalmology, University of Cincinnati, Cincinnati, OH.

“OST can provide good visual acuity with surface stability in eyes with LSCD and severe conjunctival disease, such as those with symblepharon or conjunctival inflammation. It allows for accurate follow-up of IOP, and its complications do not lead to loss of the eye but rather may result in loss of the surface, in which case we can repeat the OST or default to a Boston KPro,” he explained.

KPro considerations

The Boston KPro is only one of several available keratoprosthesis options. However, Dr. Chan and Dr. Holland focused their comments on that device because it has the widest access and greatest use worldwide.

Discussing Boston KPro use in eyes with severe ocular surface failure, Dr. Chan cited a treatment algorithm for eyes with LSCD affecting the visual axis developed by a Cornea Society Working Group. According to its recommendations, a keratoprosthesis should be reserved for patients who have severe bilateral disease after failing an OST procedure.

However, in addition to such last resort cases, Dr. Chan and Dr. Holland noted a Boston KPro may be considered instead of OST in patients who decline or have contraindications to systemic immunosuppression or in elderly individuals.

“In older patients, there is less concern about the impact of glaucoma sequelae,” said Dr. Chan, assistant professor of ophthalmology and vision sciences, University of Toronto, Ontario. 

“In addition, patients at high risk for corneal graft failure, such as those with multiple prior graft failures with stromal neovascularization, aniridia fibrosis syndrome, or hypotony, may also be considered ‘ideal candidates’ for the Boston KPro.”

Eyes that are not “ideal” for the Boston KPro are those with severe dry eye with a keratinized ocular surface, and those with chronic conjunctival inflammation, symblepharon, lid abnormalities, or contact lens intolerance.

Eyes described by these features included those affected by Stevens-Johnson syndrome, ocular cicatricial pemphigoid/mucous membrane pemphigoid, or severe chemical injury, and results from various Boston KPro studies demonstrate eyes with those diagnoses (which are associated with severe ocular surface failure), have poorer visual outcomes along with higher device failure rates relative to eyes that undergo the procedure for other indications.

In addition, they are at increased risk for corneal melts, endophthalmitis, and infectious keratitis.

As another consideration, regardless of diagnosis, glaucoma remains the leading cause of significant loss of vision after Boston KPro implantation.

In a series of 128 Boston KPro cases from the Cincinnati Eye Institute, 47% lost 2 or more lines of vision because of glaucoma during follow-up of about 2.5 years [presented at ASCRS 2012]. Data from the University of California Davis also shows the impact of glaucoma on vision loss-among 40 eyes in that series, 54% of 40 eyes did not retain BCVA ≥20/200 as a glaucoma-related complication [Ophthalmology. 2011;118:1543-1550].

“There is an inability to measure IOP accurately in Boston KPro eyes, and glaucoma progression occurs even with close monitoring of IOP,” Dr. Holland said.

Citing a report from investigators at Massachusetts Eye and Ear Infirmary who followed 106 eyes for an average of 3.3 years after Boston KPro implantation, Dr. Chan noted that 66% of eyes had pre-existing glaucoma and 26% developed it de novo after the procedure [Cornea. 2014;33:349-354]. In addition, two-thirds of patients with glaucoma went on to need glaucoma surgery. Only 60% of patients had reliable visual fields.

“IOP, measured by finger palpation, was not significantly elevated, and interestingly, one-third of patients had disc pallor where the cup-to-disc ratio seemed to be <0.8,” Dr. Chan said. “Therefore, it seems the mechanism of optic neuropathy in these eyes may involve something other than increased IOP.”

In addition to the challenges of measuring IOP and risk for glaucoma development in eyes with a KPro, these patients also need to remain on lifelong topical antibiotics to prevent endophthalmitis. Antifungal prophylaxis may also be considered for high-risk eyes.

Other complications that can occur with the Boston KPro include retroprosthetic or retro-backplate membrane formation as well as posterior segment problems, including retinal detachment, choroidal detachment, and vitritis.

Achieving success with OST

Dr. Holland cited outcomes from a group of patients with LSCD operated on at his institution to highlight the favorable outcomes of OST. The series, which he presented at the World Cornea Congress in 2010, included 258 eyes, of which 125 had severe deficiency with severe concomitant conjunctival disease. The majority of eyes were aniridic, and the next most common diagnoses were chemical injury and autoimmune conjunctivitis.

During follow-up of about 4 years, stability of the ocular surface was achieved in 72% of eyes and mean visual acuity improved from count fingers preoperatively to 20/300.

“Keep in mind that more than half of these patients had aniridia and so had foveal hypoplasia with limited visual acuity potential,” Dr. Holland said.

In eyes with severe ocular surface failure and conjunctival deficiency, Dr. Holland and colleagues at the Cincinnati Eye Institute/University of Cincinnati perform OST using what they call “The Cincinnati Procedure,” an approach that combines living related conjunctival limbal allograft with a keratolimbal allograft.

Published outcomes for a series of 24 eyes demonstrate its effectiveness in eyes with severe conjunctival and limbal disease [Cornea. 2011;30:765-771]. In that series, 80% of the eyes underwent keratoplasty after OST, and after a mean follow-up of about 3.5 years, 75% of eyes maintained a stable ocular surface and 70% achieved 20/125 or better visual acuity.

Dr. Holland noted that a team approach plays an important part in those favorable outcomes as varying expertise is needed to manage all of the challenges accompanying OST. He suggested the absence of a collaborative team combined with fear of side effects from systemic immunosuppression may be barriers to greater use of OST.

Dr. Holland explained that the OST team at the Cincinnati Eye Institute/University of Cincinnati is led by the cornea surgeon and includes oculoplastics, retina, and glaucoma subspecialists along with an internal medicine physician who specializes in immunosuppression for organ transplant recipients. In addition, there is a registered nurse dedicated full-time to patient education and long-term follow-up.

The exact immunosuppression regimen is individualized to the patient, taking into account donor type (living HLA identical, living non-HLA match, cadaveric), the patient’s preoperative immunologic status (pre-transplant % panel reactive antibody), and history of previous transplants and failures. A review of a series of 136 OST patients on immunosuppression supports it safety [Cornea. 2012;31:655-661].

During a mean follow-up of 4.6 years, there were no deaths, no cases of secondary tumors, and only 3 severe events, comprised 2 cardiovascular events and 1 pulmonary embolism, but none of the involved patients had any long-term sequelae.

“Published papers reporting on serious side effects of immunosuppression are based on organ transplant recipients who often have multiple comorbidities,” he said. “OST patients tend to be relatively younger and healthier and don’t have to get sick just because they are receiving immunosuppression.” 

Clara C. Chan, MD

E: clara.chan@gmail.com

Edward J. Holland, MD

E: eholland@holprovision.com

This article was adapted from a presentation by Dr. Chan and Dr. Holland during Cornea Subspecialty Day at the 2014 meeting of the American Academy of Ophthalmology. Dr. Chan and Dr. Holland have no relevant financial interests to disclose.