Developing a Logical Paradigm for the Clinical Management of Severe Ocular Surface Disease

Choosing the appropriate management plan for the patient with severe ocular surface disease, specifically from stem cell deficiency, requires a careful assessment of the nature of the surface pathology as well as its extent. Important factors to consider include laterality of disease, the extent of injury to the limbal stem cells, and the presence and cause of conjunctival inflammation.

The first determination that must be made is whether one or both eyes are involved. Laterality of disease is the most significant prognostic factor for restoration of the ocular surface and for visual prognosis. One of the first decisions is whether to operate on patients with only one involved eye, since they still have good vision in the opposite eye. Factors that influence the decision to operate include the occupational need for binocular vision, the integrity of the injured eye, or the degree of disruption of the patient’s life secondary to chronic pain and inflammation in the injured eye. Figure 26.1 is a flow diagram outlining our approach to decisionmaking in management of the patient with unilateral stem cell deficiency. The discussion that follows will amplify the information in the diagram.

Unilateral Disease

important not to harvest limbal tissue in order to avoid unnecessary insult to the limbal stem cell population. If autologous donor conjunctiva is not available, amniotic membrane can be used as a conjunctival substitute; the latter, however, is a less effective treatment than conjunctival autograft.

Unilateral Limbal Disease

In the patient with unilateral limbal disease, the appropriate treatment is determined by the extent of the limbal deficiency. For patients with partial limbal disease, especially with less than 50% stem cell involvement, a sequential conjunctival epitheliectomy may be an effective procedure. If this procedure fails, a stem cell replacement procedure should be considered.

Total unilateral limbal deficiency (or partial limbal deficiency that failed conservative treatment) without significant conjunctival disease requires a source of stem cell replacement. The fellow eye is clearly the best source of replacement stem cells, since autologous tissue eliminates the risk of allograft rejection. In these cases, a conjunctival limbal autograft (CLAU) is the most appropriate procedure. An alternative procedure may be an autograft of ex vivo expanded limbal stem cells, although at this writing the procedure is still in developmental stages.

Unilateral Conjunctival Disease

In the patient with unilateral disease, we must decide if the disease is primarily conjunctival, primarily limbal, or a combination of the two. A patient with unilateral disease limited to the conjunctiva does not require a limbal stem cell transplant procedure for surface restoration. A conjunctival autograft from the same eye or from the healthy fellow eye is the appropriate treatment. Indeed, if the disorder is limited to the conjunctiva, it is

Unilateral Combined Conjunctival

and Limbal Disease

In this circumstance, the prognosis is more guarded due to both limbal stem cell disease and conjunctival dysfunction. Sources of stem cell replacement for these patients are similar to those for patients with unilateral limbal disease. However, in these patients amniotic membrane may be used because of the presence of con-

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Figure 26.1. Flow diagram for management of the patient with unilateral stem cell deficiency.

E.J. Holland, M.J. Mannis, and G.S. Schwartz

UNILATERAL OCULAR

SURFACE DISEASE

junctival inflammation. In this circumstance, ex vivo stem cell expansion may also be employed.

Bilateral Disease

A far more challenging clinical problem is the patient with severe bilateral surface disease. Figure 26.2 is a flow diagram that outlines our approach to the patient with bilateral stem cell deficiency. The key differentiating point in these patients is the extent and activity of conjunctival inflammation.

Limbal Disease with Normal Conjunctiva

With partial limbal involvement ( 50%), sequential conjunctival epitheliectomy may be effective. However, in the vast majority of cases, limbal involvement requires a limbal stem cell transplant procedure. We feel that the procedure of choice in these patients is a keratolimbal allograft (KLAL), since it affords the most abundant source of stem cells and employs (relatively) readily accessible cadaveric donors. Conjunctival replacement is not required in these situations.

Figure 26.2. Flow diagram for management of the patient with bilateral stem cell deficiency.

BILATERAL OCULAR

SURFACE DISEASE

Limbal Disease with Prior

Conjunctival Disease

This category includes patients who have suffered past injury or disease of the conjunctiva and have had time to allow for the resolution of inflammation and acute surface injury. In such patients, the decision will be whether to use a KLAL, or a living-related conjunctival limbal allograft (lr-CLAL). If the residual conjunctival damage is minimal, a KLAL may be the procedure of choice. If there are no living relatives available as donors, KLAL may be the only choice. However, if the extent of residual conjunctival injury is significant, the lr-CLAL, which provides conjunctiva as well as limbal tissue, may be a better choice of procedure. Ex-vivo expansion of a living related stem cell donation may be applicable in the future.

The decision to add amniotic membrane to the stem cell transplant procedure will be dictated by the presence of significant conjunctival disease.

Limbal Disease with Inflamed Conjunctiva

Bilateral limbal stem cell deficiency accompanied by conjunctival inflammation represents the worst prognostic category. Prior to any surgical intervention, every effort must be made to mitigate conjunctival inflammation. To this end, we employ both topical and systemic immunosuppression and anti-inflammatory therapy. It may also be extremely important to defer surgical intervention until inflammation has partially subsided, and the surface has stabilized.

The first choice of treatment in this group of patients is a living-related conjunctival allograft (lr-CLAL), since this donor procedure provides conjunctival epithelium and goblet cells in addition to limbal stem cells. Amniotic membrane transplantation is a useful adjunct in such cases because it helps in suppressing conjunctival inflammation.

If a living relative is not available as a source of donor tissue, KLAL is the next option with adjunct amniotic membrane transplantation. Ex vivo stem cell expansion may also be employed in such cases.

Finally, if there is significant preoperative keratinization of the bulbar conjunctiva and cornea and/or no aqueous tear production, stem cell surgery has a very poor prognosis. In such cases, a keratoprosthesis may be the only alternative available to the patient.

Case Presentations

The following clinical examples illustrate management decision-making in severe ocular surface disease:

Case 1: A 42-year-old Caucasian farmer presents with a unilateral nasal pterygium in the left eye and is symptomatic with chronic waxing and waning redness and irritation and, more recently, distortion of vision.

Diagnosis: Pterygium.

Procedure: Conjunctival autograft.

Comment: Conjunctival autograft is the procedure of choice for limited conjunctival pathology, as exemplified by a pterygium. An alternative approach is amniotic membrane transplantation (AMT). However, AMT may be associated with a higher rate of recurrence, and is more costly.

Case 2: An 82-year-old woman has a history of extracapsular cataract extraction, a subsequent trabeculectomy, and a 15-year history of treatment with pilocarpine. From the 11 to 1 o’clock meridians, there is a wedge-shaped area of abnormal epithelium with vascular pannus representing sectoral stem cell deficiency. She complains of redness and blurred vision.

Diagnosis: Sectoral iatrogenic stem cell deficiency. Procedure: Sequential conjunctival epitheliectomy. Comment: In the setting of partial limbal deficiency of

less than 50% of the limbal tissue, surgical removal of the abnormal epithelium is a possible option. This technique may require several sequential resections. If this procedure fails, then stem cell replacement with a sectoral KLAL should be considered.

Case 3: A 24-year-old construction worker sustained a severe alkali injury to the left eye. There was no involvement of the right eye. After management of the acute disease and a waiting period of 6 to 8 months to allow surface inflammation to subside, surgical treatment was undertaken.

Diagnosis: Severe unilateral alkali injury with conjunctival and limbal deficiency.

Procedure: Conjunctival limbal autograft (CLAU). Comment: This procedure is well established and re-

mains the preferred treatment for unilateral stem cell and conjunctival deficiency. The risk to the fellow donor eye is minimal in the absence of any previous injury to that eye, and this approach avoids the need for immunosuppression. In the presence of continued conjunctival inflammation, amniotic membrane can be employed.

Case 4: A 38-year-old woman has a history of aniridia and progressive conjunctivalization of the entire cornea. There is significant anterior stromal scarring associated with the epitheliopathy. Visual acuity is 20/400 OU. Her best recorded acuity was 20/80, and in the past foveal hypoplasia was documented. The patient also has unstable intraocular pressure despite the use of multiple topical antiglaucoma medications.

Diagnosis: Limbal stem cell deficiency secondary to aniridia and poorly controlled glaucoma.

Treatment: (1) Glaucoma tube shunt; (2) keratolimbal allograft; (3) lamellar keratoplasty (staged procedures).

Comment: We recommend surgical intervention for glaucoma management if the patient requires more than one topical glaucoma medication. When the glaucoma is controlled, a KLAL should be carried out for rehabil-

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itation of the ocular surface. If significant corneal stromal scarring remains after a successful stem cell transplant procedure, consideration of lamellar or penetrating keratoplasty is reasonable. We chose a lamellar keratoplasty for this patient due to her limited visual potential. Although technically challenging, lamellar keratoplasty avoids the added risk and morbidity of an intraocular procedure in this patient. Additionally, it avoids the risk of endothelial rejection following penetrating keratoplasty.

Case 5: This 56-year-old farmer has a history of injury to both eyes from anhydrous ammonia 25 years prior to this examination. There is total conjunctivalization of both corneas and subconjunctival fibrosis, but no active conjunctival inflammation. There is foreshortening of the inferior fornices bilaterally.

Diagnosis: Old alkali injury without active inflammation.

Treatment: Options for treatment include KLAL or lr-CLAL.

Comment: If there is extensive conjunctival scarring and symblepharon formation, lr-CLAL is the preferred procedure. If conjunctival involvement is less severe and/or a relative is not available, a cadaveric donor for KLAL is a reasonable option. Adjunct amniotic membrane may also be employed.

Case 6: A 48-year-old woman took an oral nonsteroidal anti-inflammatory agent for joint pain and developed severe Stevens–Johnson syndrome one year prior to presentation. Clinical findings include conjunc-

E.J. Holland, M.J. Mannis, and G.S. Schwartz

tival injection, symblepharon, total corneal conjunctivalization, and trichiasis of the upper and lower lids.

Diagnosis: (1) Conjunctival and limbal deficiency secondary to Stevens–Johnson syndrome; (2) cicatricial entropion and trichiasis.

Treatment: (1) Repair of the anatomic lid abnormalities prior to stem cell transplantation; (2) living-related conjunctival limbal allograft and amniotic membrane transplantation.

Comments: Living related conjunctival tissue is necessary because of the extensive conjunctival damage. Amniotic membrane is useful because of the active conjunctival inflammation.

Although there is certainly more than one way to manage this spectrum of problems, the ophthalmologist should take into account, as illustrated in the foregoing cases, the laterality and extent of the disease. In addition, any consideration of surgical rehabilitation of the patient with ocular surface disease must first take into account the function of the ocular adnexa, as well as the adequacy of the tear film. Finally, many of these patients have both complex general medical as well as other eye problems requiring close monitoring. The local and systemic immunosuppressive agents required as adjuncts to surgical treatment add yet another layer of complexity to their safe and successful management. Therefore, comprehensive management using a team approach including ophthalmologist, internist, and technical support will best ensure a successful outcome.