Keratoconus &
corneal ectasias
A reference course: understanding keratoconus and pellucid marginal degeneration as the failure of a matrix — detecting it at the earliest stage, stabilising it, regularising it, then reconstructing it once transparency is lost.
The techniques described in this course (cross-linking, intracorneal rings, double-docking DALK) are illustrated by the site's surgical videos:
Definitions & nosological framework
Keratoconus (KC) is a progressive corneal ectasia, bilateral but asymmetric, long described as non-inflammatory in the classic sense — a dogma now qualified. It combines stromal thinning and a paracentral or inferior conical protrusion, producing a progressive irregular myopic astigmatism.
Pellucid marginal degeneration (PMD) is an ectasia with an inferior peripheral band of thinning (typically 4 to 8 o'clock, 1-2 mm from the limbus), the corneal protrusion sitting above the thinnest zone, generating a strong against-the-rule astigmatism.
The ectasia spectrum
Around these two entities gravitate Terrien marginal degeneration (inflammatory, vascularised), keratoglobus (diffuse global thinning) and iatrogenic post-LASIK/PRK ectasia. All share a biomechanical failure of the stromal framework; their distinction rests on the topography of the thinning.
The "crab-claw" topography is seen in both: it is the pachymetry map that decides. In keratoconus the thinnest point is para-central, under the apex; in PMD it is inferior peripheral, with the protrusion sitting above the thin band.
Clinical background & risk factors
Epidemiology
The classic prevalence of 1/2000 has been revised upward (≈ 1/375 to 1/500 in some tomography-screened populations), because subclinical forms are under-diagnosed. Keratoconus begins at puberty, progresses into the 3rd-4th decade, then tends to stabilise — a slowing attributed to age-related natural cross-linking and glycation. Earlier, more severe forms predominate in populations with high consanguinity, high sun exposure (UV) and high atopy prevalence.
Risk factors — the true "background"
| Factor | Mechanism | Practical consequence |
|---|---|---|
| Eye rubbing | Mechanical + pro-inflammatory trauma, dose-dependent, often asymmetric | Lever #1 Explains asymmetry and the sleeping side; must be stopped systematically. |
| Atopy | Eczema, asthma, rhinoconjunctivitis, vernal keratoconjunctivitis (VKC) | Surface inflammation + rubbing: a self-sustaining loop. |
| Genetic/familial background | Family history, polygenic inheritance | Question relatives + tomographic screening. |
| Syndromic | Down syndrome, Leber congenital amaurosis, Ehlers-Danlos, Marfan, mitral prolapse, Brittle Cornea Syndrome (ZNF469/PRDM5) | Targeted screening; sometimes early and severe. |
| Floppy eyelid, sleep apnoea | Side-sleeping position, eyelid laxity | Look for OSAS; correct sleep posture. |
| Hormonal | Flares at puberty, during pregnancy | Closer monitoring during hormonally sensitive periods. |
Clinical signs
Functional: progressive visual loss, unstable evolving astigmatism, halos, monocular diplopia, growing spectacle intolerance. Placido/retro-illumination signs: "scissors" reflex on retinoscopy, Charleux "oil-droplet" shadow on fundus examination.
Slit-lamp: Fleischer ring (ferritin deposits at the base of the cone), Vogt striae (deep vertical stromal folds, disappearing on pressure), apical thinning, Munson sign (V-shaped deformation of the lower lid on downgaze), Rizzuti sign (nasal focusing of the limbal beam), apical scars (advanced forms), and acute hydrops from Descemet rupture (see dedicated chapter).
Any progressive astigmatism, any unusual against-the-rule or oblique astigmatism, any atopic patient or eye-rubber → tomography + epithelial mapping, even with preserved acuity. Subclinical forms are clinically silent.
Advanced genetics
Mode of transmission
Keratoconus is mostly sporadic; 6 to 10 % of familial forms. Inheritance is complex, polygenic, with incomplete penetrance and variable expressivity, and a strong multifactorial component: genes × rubbing × atopy × UV.
Candidate genes and loci
Identified by exome/genome sequencing in a 4-generation KC family (Khaled, Bykhovskaya… Rabinowitz & Liu, Sci Rep 2019): the missense variant rs35471301, p.Ser419Ala co-segregates with keratoconus, on a highly conserved residue. PPIP5K2 is a bifunctional kinase/phosphatase of inositol pyrophosphates (InsP7/InsP8).
Causal validation by mouse model: the gene-trap Ppip5k2 mouse develops irregular corneal surfaces and stromal thinning reproducing the KC phenotype (confirmed 2024, IOVS, Akoto et al., across three lines): localised "KC-like" thinning in the heterozygote → diffuse "keratoglobus-like" in the homozygote. One of the few KC genes whose causality is supported by a concordant animal model.
GWAS & practical relevance
Genome-wide association studies show a strong overlap with the genes determining CCT (FOXO1, FNDC3B, RXRA-COL5A1, MPDZ-NFIB…): keratoconus appears as the "extreme" of a continuum of corneal thinning in a predisposed subject. In practice, genetic counselling and screening of relatives today rest on tomography rather than routine molecular testing; the LOX/cross-linking, proteolytic (MMP/TIMP) and oxidative-stress axes outline future therapeutic targets.
Pathophysiology — the mechanistic core
Three interdependent pillars converge toward loss of structural integrity of the stroma: proteolytic imbalance, oxidative stress, defective cross-linking — all mechanically amplified by rubbing.
1. Proteolytic imbalance (front line)
- MMP over-expression: MMP-1 (collagenase), MMP-2 and MMP-9 (gelatinases), MMP-13 → degradation of collagen I/III and matrix.
- Fall in inhibitors: ↓ TIMP-1 (even TIMP-3) → increased net gelatinase activity.
- Cathepsins (B, G, V/L) and other serine proteases increased.
- Epithelium→stroma loop: rubbing stimulates pro-inflammatory mediators (IL-1) and stromal MMP synthesis by keratocytes → localised matrix degradation at the cone apex.
2. Micro-inflammation (the "non-inflammatory" dogma revised)
↑ IL-6, TNF-α, IL-1, MMP-9 in tears and at the surface; IL-1-mediated keratocyte apoptosis, reduced keratocyte density. Keratoconus is not a keratitis, but a surface low-grade inflammation sustains the proteolytic cascade.
3. Oxidative stress & defective cross-linking
↑ ROS, ↓ antioxidant defences (SOD1, ALDH), mitochondrial DNA damage, accumulation of nitrotyrosine and lipid peroxidation products; ROS activate pro-MMPs (synergy). In parallel, ↓ LOX activity leads to insufficient collagen cross-linking, with proteoglycan abnormalities and disorganisation of fibril diameter and spacing.
4. Biomechanics — the measurable translation
The ORA shows ↓ corneal hysteresis (CH) and ↓ corneal resistance factor (CRF). The Corvis ST translates softening into dynamic indices: SSI (Stress-Strain Index), CBI (Corvis Biomechanical Index) and above all TBI (Tomographic-Biomechanical Index by Vinciguerra/Ambrósio), the best subclinical-detection tool by combining tomography and biomechanics.
thinning → ↑ local stress → protrusion → thinning: a self-aggravation that only cross-linking (CXL) durably interrupts.
genetic predisposition (LOX/collagen/CCT) + rubbing/atopy → surface inflammation (IL-1) → ↑MMP/↓TIMP + ROS → proteolysis + defective cross-linking → focal thinning → biomechanical failure → ectasia.