Limbal stem cell deficiency can develop from various congenital, infectious, inflammatory and malignant conditions and is characterized by chronic irritation and pain accompanied by photophobia, excessive tearing, and either partial or total vision loss. The diagnosis is made on clinical criteria, findings from slit-lamp examination and impression cytology. Various forms of transplantation are currently used in practice with excellent results.
Depending on the nature of the condition, LSCD may be either unilateral or bilateral . Persistent photophobia, reduced vision, epiphora, recurrent episodes of pain that occur due to a breakdown of the epithelium and a previous history of chronic inflammatory changes accompanied by redness of the eye are main clinical features of LSCD  . Diplopia and impaired ocular motility are also reported .
Signs and symptoms indicating an ocular distress must be evaluated through a slit-lamp examination, which can reveal pathological changes in the cornea, most prominent being loss of the palisades of Vogt and persistent secondarily infected epithelial defects , but the key finding is conjunctivalization . To confirm the invasion of conjunctival cells into the corneal epithelium, fluorescein staining should be performed, revealing a thinner and irregular epithelium that is prone to recurrent erosions and neovascularization . To make the diagnosis, it is necessary to perform impression cytology , a procedure that comprises placement of a filter paper on the affected cornea that is previously anesthetized . After obtaining the superficial corneal cells, identification of goblet cells and corneal/conjunctival cells by periodic acid-Schiff (PAS) staining is performed  , while increased cytokeratin 19 (CK19) expression, together with reduced CK3/12 expression may also be detected when using this procedure . Most recent reports suggest that CK7 and mucins1 and 5AC are more specific markers of LSCD than CK19 and CK3/12 . Newly introduced techniques - in vivo confocal microscopy (IVCM) and anterior optical coherence tomography (OCT), may be of significant value in the diagnostic workup, as they are able to inspect the anatomical structures of the eye at the cellular level, but their use in regular practice is yet to be achieved .
Management of patients suffering from LSCD has greatly improved with the introduction of limbal cell transplantation   . Conjunctival limbal autograft (CLAU) transplantation from the healthy eye of the individual is preferred in the setting of unilateral LSCD , while the introduction of simple limbal epithelial transplantation (SLET), comprised of CLAU and in vivo expansion through the use of amniotic membrane that is transplanted during this process as well, has shown even better results . In the setting of bilateral LSCD, living or cadaveric transplantation (termed living-related conjunctival limbal allograft - Lr-CLAL and cadaveric keratolimbal allograft KLAL, respectively) is performed, but these procedures carry a lower rate of cellular proliferation and a somewhat reduced capacity for corneal epithelization, but more importantly, immunological rejection can occur  . For this reason, adequate immunosuppressive therapy is necessary . Having in mind the fact that bilateral LSCD develops as a result of systemic conditions such as Stevens-Johnson syndrome and severe trauma that include a high level of immune system activity, treatment using these strategies is not as effective compared to CLAU and SLET . Because of such results, cultivation of residual limbal epithelial cell has proven to be a successful therapeutic strategy in the setting of bilateral LSCD  , and ex vivo expansion of remaining limbal epithelial stem (LEST) cells with subsequent cultivation under specific conditions is now being performed . Although the newly introduced procedures show favorable results, their long-term effects remain to be seen .
Because LSCD can cause severe vision loss that may result in blindness, early recognition of the disease is detrimental . Fortunately, a major progression in LSCD management has been made in recent years and current therapeutic principles can significantly improve visual acuity and relieve associated complaints in the vast majority of patients .
Any condition or event that causes corneal damage can induce LSCD  . Pterygium, congenital tumors of the limbus, aniridia and various forms of keratopathy (keratitis-ichthyosis-deafness syndrome, congenital dyskeratosis, but also radiation or contact lens-induced) are diseases that are described as causative agents of LSCD in the literature   . Drug-induced conditions such as Stevens-Johnson syndrome and toxic epidermal necrolysis, extensive cryotherapy, radiation, surgery, chemical and thermal burns, but also herpes simplex disease affecting the epithelium can lead to pathological changes in the cornea as well   . Some systemic conditions - diabetes, vitamin A deficiency, graft-versus-host disease (GVHD), cicatricial pemphigoid and rosacea may trigger loss of limbal stem cells and lead to various symptoms .
Approximately 2.5 million individuals suffer an eye injury in the United States every year . A prevalence rate for Steven-Johnson syndrome is established at 2.6-7.1 per 1 million individuals, while cicatricial pemphigoid appears between 0.87-1.16 per 1 million individuals in European countries such as France and Germany . Pterygium is a condition that rarely occurs in the Caucasian population (a global prevalence rate of 1.2%), whereas prevalence rates are as high as 23.4% in countries that belong to the "pterygium belt", located around the equator . The exact proportion of patients that develop LSCD is unknown .
The epithelial lining of the cornea is the first layer that interacts with the external environment. This epithelium serves as a physical barrier to water and external elements, but it also enables transmission of light to achieve visual perception  . To sustain this ability, the corneal epithelium must be continuously regenerated and replenished by new cells that replace damaged ones, a feat that is possible due to the presence of stem cells in the basal limbal epithelium, located just below the corneal epithelium . Specifically, the niche of limbal epithelial stem cells is located in the palisades of Vogt (PV), fibrovascular structures that lie 1-2 mm from the limbo-corneal junction . Every 9-12 months, the corneal surface is completely replaced with new cells and stem cells firstly differentiate into transit-amplifying (TA) cells that move across the limbus and into the peripheral cornea, eventually becoming terminal cells embedded in the corneal epithelium . Various growth factors have been implicated in this process, including insulin-like growth factor, fibrocyte growth factor, epidermal growth factor, but also chemokine receptors and the Dickkopf family member of genes . In addition to their vital role in corneal regeneration, limbal stem cells also protect the cornea from an invasion of the conjunctival epithelium, acting as a physical barrier for conjunctival cells. In the setting of infection, trauma or any other condition that causes abnormalities of the corneal surface and depletion of stem cells, the phenomenon of "conjunctivalization" occurs  . This process includes migration of conjunctival cells into the cornea with subsequent vascularization of this previously avascular tissue  . Because the changing epithelial events in the cornea, subsequent ocular discomfort and vision loss occurs .
Apart from proper management of diseases that may predispose individuals to LSCD, other preventive strategies are currently unknown.
Limbal stem cell deficiency (LSCD) is a condition in which the cornea is unable to regenerate itself due to infections, malignant diseases, traumatic events (including mechanical and chemical incidents) and autoimmune disorders . Under physiological conditions, the cornea, responsible for transmission of light and protection of the eye against external substances, is able to replenish its epithelium through a formation of new cells from limbal stem cells, which reside in the limbus, specifically in the palisades of Vogt (PV)  . Additionally, the limbus and the limbal stem cells continuously prevent the conjunctival cells from migrating to the corneal surface, but in the case of their deficiency, the process of corneal conjunctivalization occurs, the main feature of LSCD . During this pathological event, the conjunctival cells invade the cornea and induce development of blood vessels (having in mind that the corneal epithelium is avascular), but also inflammation, leading to the appearance of various symptoms  . Photophobia, visual deficits, epiphora, diplopia, reduced ocular motility and recurrent pain episodes are typical signs of LSCD, together with redness of the eye as a result of chronic inflammatory changes   . To make the diagnosis, it is necessary to perform a slit-lamp examination, which will identify erosions and neovascularization of the cornea, but impression cytology is necessary for confirmation of LSCD  . Various strategies exist when it comes to treatment, but the introduction of limbal cell transplantation (LCT) has dramatically improved the outcome of patients, even in those suffering from total vision loss. Conjunctival limbal autograft (CLAU) and simple limbal epithelial transplantation (SLET) are procedures that are most commonly used in the setting of unilateral LSCD, whereas transplantation of limbal allografts from either living relatives or cadavers is performed in patients with bilateral LSCD   . Although the prognosis is very good, timely recognition of the disease is necessary to ensure optimal patient outcomes and reduce the burden of the condition on the quality of life.
Limbal stem cell deficiency (LSCD) is a condition characterized by an inability of the cornea to regenerate itself due to depletion of cells that are the base of this process - limbal stem cells. The cornea is the outermost layer of the eye that serves to protect the eye from external substances such as water and dust and because it is constantly under siege, it possesses the ability to replace damaged cells with new ones, which occurs through the activity of limbal stem cells and their differentiation into corneal epithelial cells. Limbal stem cells reside in the limbus, a tiny structure situated between the cornea and the sclera (the white part of the eye). Apart from the ability to regenerate cornea, limbal stem cells continuously prevent conjunctiva (the mucous membrane covering the entire eye except the cornea) from invading the corneal epithelium. In that way, the cornea remains intact, transparent and without any blood vessels in its epithelium, allowing proper vision. However, various conditions, including aniridia, pterygium, tumors of the limbus, systemic conditions (diabetes mellitus, Stevens-Johnson syndrome, cicatricial pemphigoid), but also trauma due to chemical or thermal burns can cause damage to the eye and lead to a significant disruption of the physiological state. Inflammatory changes that occur in the setting of these conditions cause invasion of the cornea by the conjunctiva and subsequent damage. Conjunctival cells induce development of new blood vessels, while inflammatory changes developing on the ground of the underlying disease cause symptoms such as pain, redness of the eye, impaired motility of the eye and either partial or total vision loss, which is why early recognition of the disease is necessary. To make the diagnosis, a slit-lamp examination performed by an ophthalmologist is necessary and is comprised of a detailed inspection and visualization of the eye. A test called impression cytology is used for confirmation of LSCD and comprises a sampling of superficial corneal cells by a filter paper and subsequent identification of various cell types under the microscope. Even though patients may experience severe vision loss, treatment has substantially improved in previous years and can resolve symptoms in virtually all individuals suffering from this condition. The principal method of therapy is transplantation of limbal stem cells from the healthy eye into the affected eye (also known as simple limbal epithelial transplantation - SLET), which will aid in regeneration and restoration of the normal architecture. This is the preferred procedure if only one eye is affected by the disease, but if LSCD involves both eyes, transplantation of limbal cells from either living relatives or cadavers may be performed. These procedures, however, require careful follow-up and administration of immunosuppressive drugs to prevent rejection of the graft, as much lower rates of success have been observed compared to SLET. Although LSCD may be treated efficiently, its timely recognition may substantially reduce the burden it has on the quality of life of patients.