Chronic corneal ulceration
Authors: Pr Éric Gabison (lead author) and Muriel Catanese — ophthalmology, cornea & ocular surface. Updated 2026.
Introduction & definitions
A corneal ulcer is defined as an epithelial defect associated with underlying stromal involvement — a thinning of the stroma. This course addresses the pathogenesis and management of chronic sterile ulcers (duration > 2 to 3 weeks), of which neurotrophic keratitis is the prototype.
Two neighboring entities must be distinguished from it:
- the persistent epithelial defect (PED) — an epithelial defect that fails to close after 10 to 14 days of well-conducted treatment, without initial stromal loss, but which carries the risk of ulceration;
- the healed residual ulcer, responsible for a re-epithelialized stromal thinning that produces fluorescein pooling, without true dye uptake.
An ulcer may be infectious, immunological (peripheral ulcers) or sterile / non-inflammatory. Whatever the presumed cause, ruling out an infectious cause remains the first priority in any ulcer.
Every chronic ulcer begins with a failure of epithelial healing. The denuded stroma is exposed to proteases (MMP) and neutrophils: this is the starting point of stromal melting. The cause is most often multifactorial — look for all the components (dryness, exposure, corneal anesthesia, iatrogenic factors). Treatment combines correction of contributing factors with stimulation of healing, in a stepwise escalation.
Pathophysiology: epithelial & stromal healing
Understanding sterile ulcers requires examining the processes of epithelial and stromal healing, along with the role of the tear film, the nerves, the proteolytic enzymes and the cytokines. Ulcers always begin with a failure of epithelial healing.
Epithelial healing
Within minutes of an abrasion, the edge cells migrate centripetally at 60–80 µm/h; for extensive erosions, a latency of 4 to 5 hours precedes movement (reduced basement-membrane adhesion, cellular synchronization). The basement membrane is essential to this migration: its abnormalities (trauma, Cogan dystrophy) promote persistent erosions.
After 24–30 h, the epithelial population is restored by mitosis, fed by the limbal stem cells. Limbal deficiency, congenital (aniridia) or acquired (chemical burn), prevents adequate healing. In herpetic keratitis, the cytopathic effect of the virus prevents the edge cells from re-forming their adhesion system: fluorescein penetrates beneath the epithelial edges, marking herpetic involvement.
Stromal healing: paracrine dialogue, then direct interactions if the basement membrane fails to regenerate
Stromal healing proceeds through migration and proliferation of the keratocytes, which adopt a myofibroblast phenotype under the effect of epithelium-derived TGF-β, then through deposition of extracellular matrix (collagen III, fibronectin, laminin, glycosaminoglycans). As long as the epithelial basement membrane remains intact, this epithelial-stromal dialogue stays indirect and diffusible (paracrine), with no direct cell-cell contact between the two compartments and no involvement of EMMPRIN/CD147 (reserved for the direct interactions, see box). It runs on two-way soluble signalling: from epithelium to stroma, IL-1α/β is one of the key drivers of this phase — it triggers both the keratocytes' initial apoptosis and a first, physiological and controlled induction of MMPs needed for matrix remodelling (distinct from the pathological amplification via EMMPRIN seen in DESI, see box) —, alongside EGF (mainly of tear-film and epithelial origin), which in turn nourishes and supports the underlying keratocytes; from stroma to epithelium, HGF and KGF support epithelial migration and proliferation in return; TGF-β, for its part, drives myofibroblast differentiation [2,3,4].
Direct epithelial–stromal interactions (DESI) are never physiological: they occur only when the epithelial basement membrane fails to regenerate. After injury, the underlying keratocytes first undergo apoptosis; in normal healing they then recolonize the anterior stroma while the basement membrane reforms, which keeps them separated from the epithelium. When this regeneration fails, that same recolonization instead results in direct cell-to-cell contact between keratocytes and epithelial cells: this is DESI. This breakdown is often accompanied by disappearance of Bowman's layer: unlike the epithelial basement membrane, which can reform, Bowman's layer, once destroyed, does not regenerate — which perpetuates the direct contact in prolonged ulceration. This contact triggers epithelial expression of EMMPRIN/CD147 (Extracellular Matrix Metalloproteinase Inducer, basigin), which induces stromal MMP synthesis (MMP-1, -2, -3, -9). Weakly expressed in the healthy cornea, it is strongly up-regulated in ulcerated corneas: this dysregulation sustains collagenolysis, stromal melting and delayed wound healing, and represents a potential therapeutic target [3,4].
Stromal melting (MMP), corneal nerves, tear film & prognosis
Stromal lysis and degradation: the role of the MMPs
Corneal repair is tightly linked to a finely orchestrated inflammatory response. Unlike skin, excessive monocyte/macrophage infiltration is harmful to the cornea because it releases excess matrix metalloproteinases (MMP). These zinc- and calcium-dependent endopeptidases degrade the matrix and the basement membrane. Barely detectable in a healthy cornea, they are strongly induced by various cytokines (IL-1, IL-6, TNF-α, EGF, PDGF, FGF), with the inducer EMMPRIN/CD147 amplifying this production [3,4]. Physiologically, their activity is restrained by tissue inhibitors (TIMP) and by non-specific serum inhibitors (α2-macroglobulin) — which explains part of the value of autologous serum.
During ulceration, the synthesis/degradation balance tips toward collagenolysis and the stroma thins. Collagen breakdown products are chemotactic for neutrophils, which in turn release MMP-8 and superoxide radicals: the process becomes self-sustaining, worsened by the difficulty epithelial cells have migrating over denatured collagen.
MMP inhibitors have been studied: divalent-ion chelators (EDTA, N-acetylcysteine) and above all tetracyclines (doxycycline), whose anti-collagenolytic effect is independent of antibacterial action. In rheumatoid arthritis, a TIMP deficiency adds to collagenase induction, explaining the severity of central keratolysis.
Role of the corneal nerves
The cornea is one of the most densely innervated tissues in the body (ophthalmic branch of the trigeminal nerve, V1). The corneal nerves have a major trophic role: they release substance P, CGRP and growth factors that sustain epithelial homeostasis and reflex tear secretion. Any corneal hypo-/anesthesia (post-herpetic, post-surgical, diabetic, tumor or surgery of the cerebellopontine angle) is a major risk factor for ulceration, up to perforation. The classic Sigelman experiment showed that neurotrophic changes persist despite tarsorrhaphy: it is indeed the loss of neuronal trophic support that is responsible. The combination substance P + IGF-1 facilitates epithelial migration and adhesion, and the first NGF trials (Bonini) opened the way to today's recombinant nerve growth factor treatments [2].
Tear film and cytokines
The tear film supplies oxygen, trophic factors and protease inhibitors, but may also carry harmful cytokines, lytic enzymes and neutrophils. The hyperosmolarity of dry eye activates inflammatory pathways (MMP-9) and sustains epithelial damage. Autologous serum and cord blood serum, rich in EGF, TGF-β, vitamin A, fibronectin, substance P, IGF-1 and NGF, partly reproduce this trophic microenvironment.
Prognosis
The visual consequences of ulcers are often underestimated. Any delay in healing affects corneal transparency (opacity) and regularity (irregular astigmatism). A prolonged delay leads to thinning up to perforation, to stromal neovascularization and to a subepithelial fibrosis all the denser as healing was delayed. The speed of etiological diagnosis and treatment therefore determines the functional prognosis.