Recurrence of ACD as well as granular and lattice dystrophies has been documented after treatment by PTK and PRK.11,12
Worsening ACD has also been reported after LASIK.13–19
The deposits were described clinically and histologically to be located in the LASIK flap interface and the stroma anterior to it. Three reports have so far described histopathologic findings in eyes with ACD after LASIK. One of those reports, published by Aldave and associates, describes the findings of the right eye corneal graft of our patient.16
The findings consisted of eosinophilic materials staining positive with the Masson trichrome stain with no uptake with Congo red stain. Most of the deposits were described to be located in the LASIK interface, the stroma of the flap, and the anterior portion of the stromal bed. In the second report, by Lee and associates, the deposits were mainly seen in the interface, and they stained heavily with the Masson trichrome and with Congo red, interpreted by the authors as showing both granular and amyloid nature, respectively. However, electron microscopy performed by the same authors showed only granular features, not amyloid.14
The third report, by Chiu and associates, describes a similar clinical presentation with confirmatory deoxyribonucleic acids (DNA) analysis and histopathology showing positive staining with the Masson trichrome and negative Congo red staining.18
The histopathologic findings of our patient confirm as well as reconcile the histopathologic features of the previous reports and extend their findings farther. The deposits were not solely confined to the interface, but were present just underneath the Bowman layer and all along the underlying stroma anterior to the interface. However, deposits were heavily scattered throughout the interface, centrally, with no involvement of the stromal bed. The deposits stained weakly with Congo red, but did not exhibit birefringence with cross-polarized light, nor did they reveal fluorescence after thioflavin T staining. The absence of apple-green birefringence and lack of fluorescence on thioflavin T indicate that the beta-pleated sheet configuration, responsible for the birefringence, had not yet formed, and that the myriad of individual filaments are still in disarray, and therefore nonbirefringent.21–23
These findings are consistent with the report of Lee and associates, in which the deposits stained strongly with Congo red, but did not show amyloid features of parallel packing of fibrils on electron microscopy.14
Hence, collectively, these findings indicate that the deposits laid could harbor pre-amyloid features and could ultimately develop a similar amyloid picture as late stage ACD.
The mechanism for the worsening of ACD after LASIK remains elusive, much as the corneal dystrophies. After LASIK, the epithelial basement membrane and the Bowman layer remain intact, and hence there is minimal increase in TGF-beta and other inflammatory products, as opposed to PRK or PTK, where TGF-beta increases in the first few months postoperatively in the ablated area, and becomes undetectable only after six months.24–26
Hence, whether the keratoepithelin source is the epithelium or the keratocytes, the stimulation of the mutated keratoepithelin protein in ACD corneas after LASIK seems to be independent of TGF-beta. One prevailing theory for keratoepithelin-derived corneal dystrophy is that the mutated keratoepithelin protein, secreted predominantly by the epithelium, diffuses posteriorly through the Bowman membrane and aggregates with itself and possibly other molecules to form the final deposits characteristic of the corresponding disorder.2,9,10,27
An indirect evidence of the epithelial nature of keratoepithelin and its diffusion ability is the slow progression from anterior to posterior stroma of the lattice, granular, and Avellino corneal dystrophies, as well as the initial confinement of the recurrence to the epithelium after keratoplasty or PTK.28
Additional credits to this theory are provided by ultra-structural studies.27
In ACD, the granular lesions appear earliest and more superficially, whereas the lattice lesions usually develop at a later stage and are typically found more posteriorly in the cornea. Interestingly, in the case of lattice corneal dystrophy, keratoepithelin forms amyloid early in the course of the disease and more anteriorly in the stroma. The introduction of antibodies specific for the N terminal and C terminal portions of the keratoepithelin protein (KE-15 and KE-2, respectively) has elucidated this phenomenon and contributed significantly to our understanding of the different keratoepithelin-derived corneal dystrophies and the various clinical and histological situations engendered.2,10,29
It has been shown that keratoepithelins that bind both KE-15 and KE-2 tend to stain with the Masson trichrome and develop into granular deposits, while keratoepithelins exclusively binding to KE-2 are the ones which develop into amyloid deposits.9
Proteolysis in the epithelial area is believed to act on the N-terminal of keratoepithelins, leading to configurations that don’t bind to KE-15 and hence are prone to aggregate to form beta-pleated sheets.2,10,22,30
In a patient with classic lattice corneal dystrophy, frequent epithelial erosions occur with subsequent proteolysis, promoting the synthesis of both mutant and wild type keratoepithelin, leading to keratoepithelin that binds only to KE-2, and hence is receptive to aggregate and form amyloid.2
The quick surge in synthesis and proteolysis of keratoepithelin favors the molecules, which are now found in high concentration next to the epithelial entourage, to aggregate and form amyloid products early in life and in the anterior stroma. In ACD, the epithelial proteolysis is slow and mainly dependent on aging, as the erosions are infrequent and hence the amyloid deposits appear later in life than the granular ones, and are more posterior.2,9
After LASIK, however, the epithelium reactively secretes products like collagen III and undergoes a hyperplastic and hypertrophic response as documented by confocal microscopy.31–33
This epithelial reactivity could possibly result in an increase in keratoepithelin synthesis and proteolysis, leading to a relatively rapid development of granular and potentially pre-amyloid deposits. The clinical and histological findings in our case and the ones reported so far lend some credit to this theory. In addition, the total absence of the deposits posterior to the LASIK interface and the presence of the deposits in increasing number and size from the Bowman layer to the interface suggest a possible epithelial origin for the keratoepithelin. The LASIK interface being a large loose potential space, the aggregated keratoepithelin would tend to diffuse alongside of it, polymerizing even further to produce large deposits.
In summary, the pathophysiology of the worsening of Avellino corneal dystrophy after LASIK is likely to be similar to the original disease, but with an enhanced pace, possibly attributable to epithelial reactivity to keratocyte injury, and independent of TGF-beta. The staining with Congo red in our report and in a previously published one, in the absence of birefringence, or ultra-structural evidence of parallel packing of fibrils, suggests the production of amyloid-forming keratoepithelin configurations. The latter should be binding with KE-2, but not with KE-15. Immunohistochemical studies evaluating the binding of those two antibodies to the corneal deposits in ACD eyes after LASIK would shed more light on this intriguing phenomenon.