Haze after PRK, LASIK tied to faulty epithelial regrowth

Reviewed by Steven E. Wilson, MD

Defective regeneration of the epithelial basement accounts for most late haze following injury to the epithelium and anterior stroma, according to Steven E. Wilson, MD. 

“Refractive surgeons have called this late haze, but it’s fibrosis,” said Dr. Wilson, professor of ophthalmology and director of corneal research, Cole Eye Institute, Cleveland Clinic, Cleveland, OH.

Surgeons performing photorefractive keratectomy (PRK) can reduce the risk of the scarring that causes this haze by properly maintaining their lasers, he said, adding that future treatments might provide “missing elements” that aid in complete healing of the epithelial basement membrane.

The fibrosis can occur not only with PRK, but at the edge of LASIK flaps, corneal transplants, and after infections that cause ulcers.

“If you have the right kind of injury, it could happen to any patient,” Dr. Wilson said.

A rough stromal surface or the destruction of many keratocytes can interfere with epithelial membrane regeneration, he noted.

Growth factor influence

Defects in the epithelial basement membrane allow two epithelium-derived growth factors, TGF-beta and PDGF, to penetrate the stroma and  drive the development of myofibroblasts. The cells depend on high levels of TGF-beta to prevent autocrine interleukin-1 from triggering apoptosis of myofibroblasts.

Myofibroblasts produce small amounts of the crystallins that create a disordered extracellular matrix, causing opacities which patients experience as late haze.

“They secrete massive amounts of collagen and other extracelluar matrices that aren’t normally in the cornea,” he said.

In higher myopia corrections, haze is greater because of the rough stromal surface and greater apoptosis of keratocytes. In a human PRK model, it only occurs if there is a high-level PRK without mitomycin C, he said.

Some patients may have genetic abnormalities affecting epithelial basement membrane regeneration, but only 2% to 5% of human patients will develop this severe fibrosis without mitomycin C treatment, he said.

“There are likely some genetic factors we don’t understand yet," he added. "There is also the possibility the extent of injury in one 9 D PRK may not be the same in another -9 D PRK.”

Laser maintenance

Lasers producing more stromal surface irregularity are associated with higher incidence of severe haze, and haze at lower levels of correction.

“In these situations, there is a mechanical impediment to the basement membrane healing,” he said. “Poorly maintained excimer lasers are more likely to produce such irregularities.”

Haze can occur after infection as well, he said, citing a pseudomonas rabbit model in which defects in the epithelial basement membrane led to the development of fibrosis.

The epithelial basement membrane slowly regenerates in many corneas with severe haze, causing localized myofibrobast apoptosis and reabsorption of abnormal extracelluar matrix by the repopulating keratocytes. The keratocytes form lacunae which coalesce in a clear cornea.

Mytomycin C can prevent haze after PRK by inhibiting proliferation of myofibroblast precursors.

Haze developing despite retreatment--“breakthrough haze”--is less likely to resolve over time, probably due to a prolonged decrease in normal anterior keratocyte density or altered keratocyte function.

Breakthrough haze is more common in humans with a 0.01% concentration than with a 0.02% concentration of mytomycin C.

In most eyes, transient early mild haze following PRK is caused by corneal fibroblasts, not myofibroblasts. In rabbits, haze can be associated with fibroblasts in normal riboflavin-UV cross-linking and with RK or AK incisions.

A future gene therapy may transiently express components--such as nidogen-1 and nidogen-2, perlecan, or laminin alpha-3-- which would be provided by keratocytes to regenerate the basement membrane, he predicted.

Steven E. Wilson, MD

E: Wilsons4@ccf.org

This article was adapted from a presentation presented at the Refractive Surgery Subpecialty Day during the 2016 American Academy of Ophthalmology meeting. Dr. Wilson is a consultant to Allergan, Cambium Medical Technologies, and Seattle Genetics.