The diagnosis and treatment of limbal stem cell disease (LSCD) can be a complex and challenging situation at the primary care level. We have known for decades of abnormal stem cell physiology, and its subsequent impact on the corneal surface. But only recently have definitive treatments for more advanced patients become a reality. Once you have a good sense of the condition and its severity, you will be able to target your response appropriately.

What You’ll See
Patients who experience LSCD can have a variety of symptoms and signs. For example, these patients may present with complications as simple as decreased vision, tearing, photophobia and hyperemia (which is usually accompanied by inflammation). In more severe cases, patients will present with pain and significant loss of visual function.

These cases are typically accompanied by clinical signs indicative of severe cell damage, including intense hyperemia at the limbal junction and the development of a unique, whorl-like pattern of corneal staining, which produces a dimensional change in the quality of the corneal epithelium.

In less severe cases, such as those caused by contact lens overwear, this is typically observed as an abnormality of surface quality. This corneal irregularity can be seen beginning at approximately the 10 o’clock location and extending over to two o’clock, with a triangular-like, saw-toothed shape that leads towards the apex of the cornea.

This clinical abnormality occurs because the absence of normal limbal stem cells causes the regeneration of corneal epithelial cells to be irregular; therefore, the section that is abnormal will produce an atypical regenerative pattern that extends towards the apex. Because the remaining limbal cells are normal, their natural contribution will account for the remaining aspect of the cornea. The clinical appearance will be such that 75% to 80% of the cornea is relatively normal while the remaining 20% to 25% demonstrates the atypical regenerative pattern.

In more severe cases, patients may experience non-healing epithelial defects. Also, it is possible for the cornea to become conjunctivalized—a condition in which the natural limbal barrier is disrupted, allowing cells from the conjunctiva to invade the corneal surface and produce an abnormal pattern and stratification of epithelial cells.

Patients with partial limbal stem cell deficiency make up less than one half of the afflicted population, while greater than one half of the population has the condition known as sub-total LSCD; the differentiation is by magnitude of tissue damage.

There are numerous etiologies for LSCD, which can range from a condition as simple as contact lens overwear syndrome or adverse solution reaction to a more severe presentation, such as an ocular cicatricial surface disease (e.g., Stevens-Johnson syndrome or cicatricial pemphigoid).

Other causes of LSCD are typically related to toxicity from medications, chemical burns or radiation exposure. Additionally, a number of surgical interventions have been cited as etiologic factors, and patients who have experienced cases of severe microbial keratitis are sometimes left with LSCD presentations.

In addition to visual identification, LSCD can be diagnosed using impression cytology—a process that identifies and reviews the presence of goblet cells on the corneal surface. Impression cytology can be used to determine if the limbal stem cell barrier has been breached, indicating that LSCD is present.

Other diagnostic technologies include the use of ocular computed tomography to identify corneal epithelial characteristics unique to the disease and confocal microscopy to assess specific cellular morphology and identify the underlying disease state.

What to Do
Appropriate treatment of LSCD will derive from the severity of the presentation. The vast majority of cases seen at the primary care level are related to toxicity, overwear of contact lenses, previous surgical intervention or infectious disease tissue trauma. For cases such as these, traditional therapies using a bandage contact lens (BCL) with non-preserved lubricant drops and ointments can be extremely effective in reversing the damage.

Typically, I will add a topical steroid (e.g., loteprednol etabonate) on a QID basis for several weeks to one month to decrease the inflammatory response at the limbal junction, which is in part responsible for the abnormal cellular proliferation.

As previously mentioned, a number of interventional therapies have proven to be efficacious in the lesser stages of the deficiency, and in many cases, can rejuvenate the corneal epithelium. These options include lubrication, cessation of contact lens wear, non-preserved lubrication, ointments and topical applications, removal of the offending agents (e.g., chemical and/or mechanical) and the introduction of a topical anti-inflammatory in the initial phase of therapy.

I would recommend extending the duration of therapy for patients who present with cases of LSCD that take weeks or months to resolve. In such cases, it is important that the clinician be vigilant, as chronic therapy may lead to additional complications, such as toxicity or IOP issues. In more severe cases, I tend to implement additional intervention, such as oral doxycycline 100mg PO for four to six weeks. This provides inhibition of MMP9-induced inflammation and improves meibomian function.

Occasionally, you will encounter patients resistant to topical therapy. In such cases, I will debride the affected area and place a BCL (along with a topical anti-infective) over it while maintaining the previous regimen. Because LSCD eyes that are debrided can heal more slowly than typical epithelial defects, I will usually leave the BCL on for several days to a week to enhance the corneal healing. In my experience, patients presenting with recalcitrant healing may benefit from pressure patching and, in some cases, an amniotic membrane placement.

Patients who present with significant LSCD as a result of more traumatic concerns (e.g., chemical or thermal burns, surgical complications or severe microbial infectious disease), which leave the limbal region damaged, typically require more aggressive intervention. Over the last several decades, significant work has been done examining the use of tissue replacement, such as stem cell transplants, conjunctival limbal autografts (CLAU), living-related conjunctival limbal allografts and amniotic membrane transplantation. These techniques have been shown to have a greater level of success than previously used therapies.

In patients with advanced LSCD, treatment protocols are based in part on whether the disease is a unilateral or bilateral condition. For example, in unilateral disease presentations, the use of stem cell transplantation from the unaffected eye can be an effective therapy. Additionally, once the original abnormal cellular zone has been removed, amniotic membrane transplantation has been shown to be successful, and new cell growth can be enhanced by stem cell transplantation.

When both eyes are involved, or a significant segment of the limbal architecture is damaged, limbal tissue can be grafted into the arcade. Once the tissue is successfully grafted in place, those cells will expand and repopulate the corneal surface.
Another option for surgical intervention beyond amniotic membrane and limbal stem cell transplantation is the use of conjunctival limbal allografts.

This procedure involves harvesting healthy limbal tissue with a conjunctival carrier from a living relative and then transplanting it into the patient. One significant concern with this intervention is the need for extended—if not life-long—immunosuppression therapy. As such, this technique should be only be selected in patients who have been unresponsive to traditional interventions.

Patients with unilateral LSCD may benefit from CLAU surgery, as the harvesting is done from the fellow eye. This technique involves the acquisition of two trapezoid-shaped segments, each of which must contain approximately 6mm of tissue.
Other surgical techniques, such as kerato-limbal autografts and combined conjunctival and kerato-limbal autografts, have been used in more severe presentations.

There have been significant advances made in stem cell technology in just the last decade—specifically in the ability to differentiate types of stem cell lines that are available for different purposes. Human embryonic stem cells, tissue stem cells and pluripotent stem cells have all evolved as potential interventions for significant limbal stem cell deficiency. Currently, all of these modalities are being inversigated, and hold great promise for the future as a mechanism to improve healing characteristics of LSCD.

Unfortunately, treatments such as penetrating keratoplasty have not been shown to be particularly successful in LSCD. As such, the recent trend has been to replace the abnormal limbal stem cell beds and manage the resulting cell growth to replace the corneal epithelial surface.
Corneoscleral Junction, What's Your Function?
Limbal stem cells—composed of non-keratinized, stratified squamous epithelium—are located at the basal level of the epithelium, in the zone between the cornea and conjunctival epithelial cells. The primary role of limbal stem cells is to barricade or protect the cornea from the invasion of conjunctival epithelium, which typically occurs as a result of trauma—creating and subsequently maintaining a clear, distinct boundary between two critical tissues in the anterior segment. It is also responsible for the regeneration of new epithelial cells during normal physiology and following trauma.