Endothelial dystrophies

CHED

Cues: AD/AR inheritance · graft recurrence +++ high ++ intermediate + low · bold = key terms · Differential diagnosis (blue) and Treatment (amber) boxes.

To be distinguished from early-onset PPCD (AD)

Genetics: AR Autosomal recessive (AR).
Mutation: 20p13, mutation of the sodium borate membrane co-transporter gene (SLC4A11). This transporter regulates the intracellular concentration of borate, which plays a role in the growth and terminal differentiation of neural crest cells.
Laterality: Bilateral
Symmetry: often asymmetric.

Associated factors:

Age of onset: Often at birth or early in the postnatal period, with very limited progression.
Location: Descemet membrane and endothelial cells. Due to incomplete central migration of the endothelial cell precursors.

Appearance:

Direct illumination: a hazy, blue-grey, ground-glass cornea. The cornea often shows marked thickening, up to 3 times normal, with stromal oedema and a diffuse whitish or ground-glass haze. Descemet membrane is thickened.

Retroillumination:

Pain or recurrent erosion: No
Visual acuity: Often preserved, patients often asymptomatic, rarely associated with a progressive decrease in visual acuity.

Diagnosis:

Broadly, one notes a thickened, laminated Descemet membrane with rare atrophic endothelial cells.

Histology: Descemet membrane is thickened, measuring 20 to 24 microns. The posterior non-banded portion is strongly PAS positive. The endothelial cells are reduced in number, or in a state of degeneration, or in fibroblastic metaplasia. As a result, thickening of the stroma up to 3 times normal is observed, with alteration of the collagen lamellae and accumulation of interstitial fluid; in some cases a degeneration of the stromal collagen fibrils is observed. In some cases of corneal oedema the corneal epithelium is altered, with vacuolization and even subepithelial fibrosis, calcification, and loss in places of Bowman layer.
Electron microscopy: Descemet membrane is thickened in CHED. The anterior banded zone is often preserved intact. The posterior non-banded zone, by contrast, is abnormal and forms the posterior collagenous layer. This zone often appears multilayered and does not contain basement membrane alone, but rather a mixture of basement-membrane-like material (12 nm fibrils), medium-sized collagen fibrils (25–48 nm), and bands of 55 to 100 nm. This indicates good functioning of the endothelial cells in utero and that the abnormalities develop later. The endothelium is either absent or reduced in number, vacuolated and dystrophic. The stroma is then altered secondarily to the corneal oedema, with stromal thickening, disorganization, and alteration of the lamellar appearance.

Differential diagnosis

Congenital white cornea, or white cornea occurring during childhood:
Congenital glaucoma: raised intraocular pressure, large corneal diameter, Haab striae, and buphthalmos.
Axenfeld anomaly: anterior segment anomaly with raised IOP and corneal opacification.
Peters anomaly: anterior segment anomaly with raised IOP and corneal opacification.
Congenital rubella: often associated with marked episcleral injection reflecting infection, transient corneal oedema, nuclear cataract, raised IOP, posterior synechiae, miosis, and chorioretinitis.
Dystrophies:
CHSD: opacification of the full thickness of the cornea, with a feathery clouding but normal corneal thickness.
DCPP
Mucopolysaccharidoses: develop during the first years of life, but since these are only deposits the corneal thickness is normal. Moreover, the mucopolysaccharidoses are often associated with systemic sequelae.

Treatment

Treatment often consists of PK. Depending on the severity of the symptoms, recourse to surgery may occur early. Graft rejection is often significant and occurs earlier the lower the age at surgery (age at presentation at birth vs after 4 months). Lamellar surgeries such as DSAEK and DMEK have been described in these patients and are now feasible if the stroma is not severely damaged.

Recent therapeutic approaches

DMEK (Descemet Membrane Endothelial Keratoplasty) has established itself as the reference technique for endothelial keratoplasty, with faster visual recovery and a lower risk of rejection than DSAEK.

In selected patients (central guttae with a healthy peripheral endothelium), Descemetorhexis without grafting (Descemet Stripping Only, DSO) allows reconstitution of the central zone by migration of the peripheral endothelial cells. Postoperative instillation of a Rho-kinase (ROCK) inhibitor — such as ripasudil (Glanatec 0.4%, approved in Japan since 2014) — promotes endothelial migration and proliferation and accelerates corneal clearing; it is also used as a rescue treatment in the event of failure to clear.

Finally, approaches currently under clinical evaluation include intracameral injection of cultured corneal endothelial cells combined with a ROCK inhibitor, as well as gene therapies targeting the CTG18.1 expansion of the TCF4 gene.