Ординатура / Офтальмология / Английские материалы / Hyperopia and Presbyopia_Tsubota, Boxer Wachler, Azar_2003

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Refractive regression is defined as a gradual, partial, or total loss of the initial correction. It limits the predictability of all refractive surgery procedures performed on the cornea. It has been hypothesized that changes occurring as a result of corneal wound healing lead to addition of new tissue. Epithelial hyperplasia and stromal remodeling are the two mechanisms that are thought to underlie this phenomenon (3,11,12).

1.Keratocytes Disappear in Response to Epithelial Injury—Keratocyte Apoptosis

One of the earliest observations that debunked the prior dogma regarding the quiescence of keratocytes was detection of disappearance of superficial keratocytes following corneal epithelial scrape injury. This observation was made first by Dohlman and coworkers in 1968 (16). Studies by later investigators confirmed that keratocytes in the anterior stroma disappear following corneal epithelial scrape injury (17–20) as well as thermokeratoplasty (21). The mechanism of disappearance of the keratocytes was not elucidated in these studies. The authors of these studies suggested that the disappearance of the keratocytes was attributable to several factors, such as osmotic changes from the loss of epithelium, exposure to the atmosphere, or even artifact.

In 1996, Wilson and coworkers (20) first demonstrated that the early disappearance of keratocytes that follows epithelial injury is mediated by apoptosis (13–15,22–29). Cell shrinkage, blebbing with formation of membrane bound bodies, condensation, fragmentation of the chromatin, and DNA fragmentation consistent with apoptosis were detected in anterior stromal keratocytes after epithelial scrape wounds by transmission electron microscopy. Nuclear DNA fragmentation was confirmed by the TUNEL assay for 3′- hydroxyl DNA ends.

Apoptosis is a programmed form of cell death that occurs without the release of lysosomal enzymes or other intracellular components that could damage the surrounding tissue or cells. Uncontrolled release of cellular contents is characteristic of necrotic cell death (26). Studies have suggested that apoptosis is mediated by cytokines released from the injured epithelium, such as interleukin 1 (IL-1) (22), the Fas/Fas ligand system (27), bone morphogenic proteins (BMP) 2 and 4 (28), or tumor necrosis factor (TNF) alpha (29).

Virtually any type of epithelial injury induces keratocyte apoptosis. These include mechanical scrapes (22–25), corneal surgical procedures like PRK and LASIK (24), herpes simplex keratitis (14), incisions (25), and even a plastic ring pressed firmly against the epithelial surface (24).

Keratocytes undergo apoptosis after epithelial injury to a depth of one-third to onehalf the stromal thickness, depending on the species and the type of injury. Cellular processes, known as gap junctions, connect keratocytes in the unwounded cornea to form a syncytium (31,32). It is possible that signals transmitted by cytokines to the most superficial keratocytes are relayed to deeper keratocytes via these intercellular communication channels. Alternatively, the proapoptotic cytokines may penetrate into the stroma after injury.

The keratocyte apoptosis response in the stroma varies with the type of corneal epithelial injury (25). Thus, injuries such as scraping of the epithelium (25) or viral infection of the epithelium (14) triggers keratocyte apoptosis in the superficial stroma. A lamellar cut across the cornea produced by a microkeratome also induces keratocyte apoptosis. This can be detected at the site of epithelial injury and along the lamellar interface (Figure

Figure 1 (A) Apoptosis detected along the lamellar interface by TUNEL assay in rabbit eye that had LASIK and (B) on the surface in rabbit eye that had PRK.

1). Localization of keratocyte apoptosis in LASIK is thought to be attributable to tracking of epithelial material, including proapoptotic cytokines, into the interface by the microkeratome blade (22–25). Alternatively, cytokines from the injured peripheral epithelium could diffuse along the lamellar interface and into the central stroma (22–25).

Apoptosis has also been correlated with severe complications. Meitz et al. (33) reported a severe case of acute corneal necrosis following PRK for hyperopia that required penetrating keratoplasty. Histopathological studies of the excised tissue were negative for micro-organisms. Utilizing light microscopy, an anterior zone of corneal necrosis was found to be present, with a moderate amount of acute inflammation at the interface between necrotic and viable corneal stroma; in addition, keratocytes with typical features of apoptosis were detected by TUNEL assay and electron microscopy (Figure 2).

2. Keratocyte Proliferation and Migration: Myofibroblasts

After the loss of keratocytes caused by apoptosis within the first few hours of corneal epithelial injury, there will be an area of stroma devoid of keratocytes. Zieske and coworkers (34) demonstrated that remaining keratocytes in the posterior and peripheral cornea begin to undergo mitosis about 12 to 24 hours after the injury (34). Keratocyte mitosis can be detected using bromodeoxyuridine incorporation or immunocytochemical staining for a mitosis-specific antigen called Ki-67 (34).

there was better predictability and stability than with an ablation zone of 5.5 9.0 mm (70). One possible explanation for this observation is that the corneal flap size may have been smaller than the periphery of the hyperopic treatment. In such settings, a smaller ablation zone may be preferable.

Excimer laser surgery for hyperopia may induce more astigmatism than for myopia. Significant change in the astigmatism power and axis was noted 3 months following hyperopic spherical LASIK in a two-step approach for treating hyperopic or mixed astigmatism (71). This could be related to centration issues in the treatment of hyperopia relative to myopia.

Attempts to shrink the peripheral corneal collagen with thermal energy (thermokeratoplasty) were first reported by Lans over a century ago (72). Central steepening of the cornea is achieved by thermal shrinkage of the midperipheral corneal tissue. The use of different types of lasers and radiofrequency energy in the corneal stroma to shrink the collagen lamellae is an active topic of study and is discussed elsewhere in this book. Recent reports have shown that these procedures may be effective in correcting low hyperopia, although corrections were subject to regression (73). Age-dependent corneal factors were shown to influence the effectiveness of thermal energy on stromal collagen and regression (74). Stability following thermokeratoplasty may be related to the type of lesion produced. A perfect thermal lesion, delivered at the perfect depth, with a perfect geometry, and for the perfect length of time would cause a permanent change in the collagen fibers in the cornea, so that regression would be less likely to occur. It remains to be seen whether such a “perfect thermal lesion” that is permanent can be created or whether ever-vigilant keratocytes will eventually detect these anomalies in the collagen fibers and repair them.

Corneal iron pigmentation lines or rings can be observed after hyperopic corneal surgery (75–78). Corneal iron deposition has been seen in the normal cornea with aging (Hudson-Stahli line) and in pathological corneal conditions such as keratoconus (Fleischer ring), pterygia (Stocker-Busacca line), and filtering blebs (Ferry’s line). Stellate iron lines were also described after radial keratotomy (79) and in cases of central island (80). The most likely explanation for the formation of such lines is that the iron is derived from the tear film and deposited in the corneal epithelium in those areas where there is tear pooling. Since keratorefractive procedure for hyperopia sculpts the cornea to resemble a convex lens, a furrow-like ring zone in the corneal periphery is produced. This can be observed when looking at the corneal elevation map after H-LASIK. (Figure 4). Tear pooling occurs and subsequently triggers iron deposition. It may also prolong the exposure time to tear film cytokines (81,82) causing epithelial hyperplasia in this midtransition zone (junction of the optical and ablated zones) (11).

C. MECHANISMS OS REGRESSION

A complete understanding of the mechanisms underlying regression after keratorefractive surgery in vivo require the study of the wound-healing response and factors related to biomechanics. A thorough understanding of corneal microstructure can now be obtained using new methods. High-frequency (50-MHz) ultrasound biomicroscopy (UBM and VHF) (83–86) (Figure 5) and optical coherence tomography (OCT) (87–89) are two promising technologies that have the capacity to measure the thickness of each layer within the cornea. These measurements could help us to distinguish between epithelial hyperplasia and stromal remodeling as the cause of the refractive regression in individual eyes. Confocal microscopy allows for optical sectioning through intact living cornea, obtaining images

Figure 4 Elevation map before and after hyperopic LASIK.

of the cornea at its cellular level in four dimensions (x, y, z, and t-time) (3,10,90,91). It has been difficult, however, to obtain reliable measurements of epithelial thickness using this technology. Slit-based videokeratography instruments like the Orbscan (Bausch & Lomb, Orbtek, Inc., Salt Lake City, UT) may be useful for assessing pachymetric values through the entire cornea as well as for measuring posterior curvature (92,93). However, uncertainty regarding the meaning of values derived from the posterior surface of the cornea is a limiting factor. Studies have shown that corneal thickness measurements are inaccurate with this instrument (94,95). At the present time, therefore, it appears that high-frequency ultrasound or OCT provides the best opportunity for monitoring epithelial thickness following refractive surgery procedures. Studies are in progress using these methods.

Animal model studies have been performed to characterize corneal wound healing following surgery for hyperopia (11,21,96–99). It is important to recognize the possible limitations of the rabbit model in assessing the nature of the wound-healing response in humans. Wound healing is thought to be more vigorous in rabbits, and qualitative as well as quantitative differences may exist. It is feasible to perform studies in patients who