Neurotrophic keratitis: from the trigeminal ganglion to the cornea

Chapter from the "Corneal wound healing" course. Mechanistic framework drawn from the review "Corneal wound healing: a reading through epithelial-stromal interactions." All figures in this series are taken from the reference publication: Saad S, Abdelmassih Y, Saad R, Guindolet D, El Khoury S, Doan S, Cochereau I, Gabison EE. Neurotrophic keratitis: frequency, etiologies, clinical management and outcomes. Ocul Surf 2020;18(2):231-236. Iconography and clinical cases: course "Les Kératites Neurotrophiques" (Neurotrophic Keratitis), Pr E. Gabison, Tours 2018.

Neurotrophic keratitis (NK) is the clinical demonstration that corneal wound healing depends on the nerve as much as on the cell and the matrix. Trigeminal innervation does not only provide nociception: it delivers continuous trophic support — NGF, substance P, CGRP, PACAP, VIP — without which the epithelium no longer proliferates, migrates, or adheres.

One concept structures the whole chapter and predicts severity: the level of the lesion relative to the Gasserian ganglion. A pre-ganglionic or partial ganglionic lesion spares the cell body and the peripheral axon — sensitivity falls but trophic support persists, and the picture remains a superficial punctate keratitis. A post-ganglionic or total ganglionic lesion interrupts axonal transport of trophic factors: this is the neurotrophic ulcer.

The disease can then be read within the epithelial-stromal interaction framework of this course: the trophic deficit creates delayed healing (> 7 days), then a persistent epithelial defect (> 14 days) — the main risk factor for stromal melting; the basement membrane fails to mature, the epithelium and keratocytes enter direct contact, and the EMMPRIN/CD147 → MMP pathway tips the tissue toward keratolysis. NK is the clinical archetype of the lytic side of wound healing.

It is far more common than assumed — 11/10,000 patients — dominated by herpes (32.2%), iatrogenic causes (31.9%), central neurological causes (27.7%) and diabetes (10.5%). Visual prognosis depends on the initial Mackie stage, initial visual acuity and age. Three therapeutic targets structure management: limiting inflammation and iatrogenic injury, promoting epithelial healing, limiting stromal melting.

Corneal innervation: functional anatomy

A unique density and organisation

Fibers arising from the ophthalmic branch of the trigeminal nerve (V1) enter the stroma peripherally, lose their myelin sheath, run forward and successively form the sub-epithelial (sub-basal) plexus, intra-epithelial arcades, and then free nerve endings between epithelial cells. Nerve density is maximal centrally and decreases toward the periphery — which explains the preferential central or paracentral topography of neurotrophic lesions.

Functionally, 30% A-delta fibers (myelinated, fast-conducting) and 70% C fibers (unmyelinated) provide intense nociception, responding to mechanical, thermal and chemical stimuli (Müller et al., Exp Eye Res 2003).

Three functions, one too often overlooked

Corneal innervation provides a sensory function (defense), a reflex function (blinking, lacrimal secretion via the trigeminal-facial arc) and a trophic function. It is this last one that underlies the disease: nerve endings continuously release NGF, substance P, CGRP, PACAP and VIP, in a bidirectional dialogue — the epithelium and stroma in turn producing the NGF and growth factors required for the survival and regeneration of the nerves themselves.

The key concept: pre- versus post-ganglionic

This is the major conceptual contribution of the field (Dhillon et al., Acta Ophthalmol 2016; Dua HS et al., Prog Retin Eye Res 2018), and the only element that allows severity to be predicted before the cornea is even examined.

The cell body of the sensory neuron sits in the trigeminal (Gasserian) ganglion. It synthesizes the neuromediators, which are then carried by anterograde axonal transport to the corneal nerve endings. The consequence is immediate:

• Pre-ganglionic lesion (upstream of the ganglion: nucleus, root, brainstem) or partial ganglionic lesion → the cell body and peripheral axon remain intact. Sensory transmission to the CNS is interrupted — the eye is hypoesthetic or anesthetic — but trophic support is preserved. The picture is typically limited to superficial punctate keratitis (stage I), slow-evolving and generally favorable.
• Post-ganglionic lesion (downstream: V1 branch, ciliary nerves, corneal nerves) or total ganglionic lesion → the peripheral axon degenerates, and transport of trophic factors ceases. This is the setting for the neurotrophic ulcer, the persistent defect and melting.

This framework also sheds light on a therapeutic finding developed in Chapter 18: RGTA works better in NK of central origin (thus often pre-ganglionic, with a preserved peripheral axon) than in herpetic NK (post-ganglionic, with a destroyed axon). The treatment's cellular target still exists in the former case.

Investigations

Esthesiometry — a frayed cotton wisp for screening, Cochet-Bonnet for quantification — remains the diagnostic gesture. In vivo confocal microscopy objectifies and quantifies sub-basal plexus rarefaction (Benítez del Castillo, IOVS 2007; Hamrah, Ophthalmology 2010; Labbé, IOVS 2012; Dhillon 2016; Stephan 2018). MRI has its place when the etiology is not obvious — the series includes the case of a 60-year-old woman in whom SPK with hypoesthesia discovered on preoperative cataract work-up led to the diagnosis of right trigeminal nucleus hypoplasia.

Pathophysiology: from delayed healing to keratolysis

Normal epithelial healing: a precise and fragile organisation

After epithelial injury, a latency phase of about 6 hours opens: cytoskeletal reorganization, changes in intercellular junctions, cleavage of hemidesmosomes and cell-matrix junctions, and apoptosis of the underlying keratocytes. Sheet migration, proliferation and finally stratification follow.

Two balances govern this process, and NK disrupts both:

• Cellular migration / proliferation balance. Harmonious healing requires that migrating cells do not proliferate: proliferation occurs outside the defect zone. This sequencing is orchestrated by the TGF-β (inhibits proliferation) / EGF (migration and proliferation) balance and by neurotrophic factors.
• Matrix synthesis / degradation balance. A transient extracellular matrix (fibrin, fibronectin, laminin, tenascin) is synthesized for focal adhesion and migration, then degraded by proteases (uPA/plasmin, MMP-1, MMP-9). Too little proteolysis: the cell stays stuck. Too much: it loses its support.

Delayed healing and persistent epithelial defect: the definitions that matter

Two time thresholds, to be remembered as they stand:

• Delayed healing: beyond 7 days.
• Persistent epithelial defect: beyond 14 days.

The switch to proteolysis: the EMMPRIN/MMP sequence

What follows is described in the course's general review, and NK is its purest clinical model:

1. Trophic deficit → persistent epithelial defect.
2. The epithelial basement membrane fails to regenerate — yet it is both the physical barrier to epithelial-stromal contact and the "valve" that controls TGF-β entry into the stroma (Wilson's model).
3. Opening of direct epithelial-stromal interactions (DESI): keratocytes, which underwent apoptosis at the time of the initial injury, normally recolonize the anterior stroma behind a reformed basement membrane. With no basement membrane interposed — or even loss of Bowman's layer, which does not regenerate once destroyed — that same recolonization instead results in direct cell-cell contact with the epithelium: this is DESI, which is always pathological.
4. EMMPRIN/CD147 comes into play and reverses the logic of TGF-β. On direct contact, EMMPRIN — itself under the control of TGF-β and EGF — simultaneously induces MMPs and myofibroblastic differentiation. TGF-β, anti-proteolytic as a diffusible signal, becomes pro-lytic: the result is a lytic myofibroblast, not a fibrotic one.
5. Keratolysis → thinning → perforation, with a vicious circle maintained by collagen degradation products, which are chemotactic for neutrophils.

Historically, it was a collagenolytic activity identified as early as the late 1960s in explants of ulcerated corneas — and absent from healthy corneas — that opened up this field, before the identification of matrix metalloproteinases and their induction by epithelium-stroma interaction (Fini et al., JBC 2003; Gabison et al., Prog Retin Eye Res 2009).

An amplifier: dryness

Dryness is almost constant in NK — loss of the lacrimal reflex, reduced blinking, associated lagophthalmos. Tear film hyperosmolarity increases EMMPRIN and MMP-9, which cleave occludin at tight junctions and disorganize the epithelial barrier (Huet et al., Am J Pathol 2011). Dryness and trophic deficit therefore converge on the same molecular pathway — hence the clinical aphorism: "one ulcer may hide another," and the rule of testing sensitivity in any dry-looking keratitis that fails to heal.

A new concept: denervation induces a "functional limbal insufficiency"

An important experimental study (Okada Y. et al., Lab Invest 2018) shows that trigeminal denervation in mice does not merely slow wound closure: it alters the limbal stem cell compartment itself — loss of ABCG2 expression, a drop in pro-NGF, and collapse of proliferation (BrdU) at the periphery and limbus. Restoring TRPV4 signaling (via AAV) partially corrects the phenotype.