**6. Corneal and refractive surgeries**

The changes in the GAT IOP after corneal refractive surgery have been studied because of the large number of patients who undergo laser refractive procedures. In corneal laser exci‐ mer refractive surgery, the cornea becomes thinner and, therefore, the IOP measurement is affected [47,48]. Because most patients undergoing laser refractive surgery are myopic and at increased risk for glaucoma [28], the effect of these procedures on glaucoma management should be determined.

The correlation between CCT and ONH topographic changes in response to IOP reductions in patients with POAG also has been evaluated [64]. The hypothesis was that thinner CCTs might be associated with greater changes in ONH topography due to a more compliant lam‐ ina cribrosa. Nicolela et al. [65] found that patients with thinner corneas show significantly greater cup shallowing, which is a surrogate marker for lamina cribrosa displacement and compliance in response to IOP reduction. The investigators interrupted the medical treat‐ ment for 4 weeks (with an average increase of IOP of 5.4 mmHg), and when the medical treatment was restarted, the IOPs were remeasured after 4 weeks, and they found that the IOP decreased from a mean of 22.27±4.12 mmHg to a mean of 17.39±2.67 mmHg. This finding may support the hypothesis that eyes with a thinner CCT have an increased risk of developing glaucomatous ONH changes because the lamina cribrosa may be more prone to displacement in response to IOP changes. Nevertheless, the changes of the ONH topogra‐ phy were unconfirmed [65] for relatively moderate IOP changes of about 5 mmHg. In addi‐ tion, the stage of the ONH glaucomatous damage and the disease duration might affect the degree of compliance of the lamina in response to IOP changes, so that for more advanced

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and long-standing damage less compliance of the lamina can be expected.

ness that makes these eyes more vulnerable to glaucomatous damage [67].

**8. Effect of topical hypotensive drugs on the cornea**

F2α-prostaglandin analogs (PGAs), induce changes in the CCT [71].

limited [69, 70].

The differences in laminar thickness have been studied in different glaucoma types. Park et al. [66] reported that NTG was associated with a thinner lamina cribosa than OAG in patients with a similar disease stage; another study showed that patients with pseudoexfoliation syndrome have less stiffness compared with normal controls, which may reflect an inherent tissue weak‐

Researchers generally agree that the lamina cribrosa is important in glaucoma [68]. Never‐ theless, in vivo clinical clues regarding the correlated parameters of the lamina cribrosa are

Some ocular hypotensive drugs, such as topical carbonic anhydrase inhibitors (CAIs) and

The hypotensive effect of PGAs, first-line treatments of glaucoma and OHT, may be affected by some ocular characteristics, such as the axial length [72]. Eyes with a longer axial length have a worse response to PGAs treatment. If a patient had undergone a previous argon laser trabeculoplasty, there is a minimal response to a PGA [73]. In addition to its effectiveness in lowering IOP, PGAs have mild and local side effects that include changes in iris color in up to 70% of patients [74], especially in patients with mixed colors and in the irises of older pa‐ tients [75]. The changes in iris pigmentation are related to increased melanin content of the iris melanocytes [76]. Other side effects are periocular hyperpigmentation and darkening and increased eyelash length. PGAs are highly efficient for lowering IOP, with few local and systemic side effects. Interestingly, most recent studies have shown that PGAs decrease the CCT, and Viestenz et al. [77] reported thinner CCTs in patients treated with topical prosta‐ glandin F2-alpha, compared with topical CAIs. Harasymowycz et al. in a prospective study

After laser ablation, the corneal thickness and shape change, so the mathematical assump‐ tions used in existing models for IOP measurement cannot be satisfied [49]. In lamellar pro‐ cedures, creation of a corneal flap changes the corneal biomechamical stability. The depthdependent tensile strength of the cornea, also have been reported [50,51], with the anterior 40% of stroma having a significantly higher tensile strength than the posterior 60%; there‐ fore, a corneal flap can have viscoelastic properties that differ from the underlying stroma and further affect the GAT IOP readings. Patients who underwent LASIK and laser-assisted subepithelial keratomileusis seem to have a postoperative decrease in CH [52,53].

In some cases, LASIK is associated with the interface fluid syndrome (IFS), first described by Rehany et al. [54], that is characterized by fluid collection in the flap interface due to a marked IOP increase. The resultant GAT IOP value is falsely lower [48]. In normal corneas with intact functioning membranes and avascular compact corneal stroma, the stroma bears the acute IOP increases, and the fluid flows from the stroma to the epithelium, which has lower pressure, resulting in epithelial edema. After LASIK, there is a virtual space between the flap and the stromal bed, with fluid accumulating in the flap interface [55].

### **7. Cornea, lamina cribrosa, and glaucoma**

The lamina cribrosa is a sieve-like fenestrated structure in the posterior sclera through which the optic nerve fibers and the retinal vessels enter and exit the eye. The glial segment of the optic nerve and lamina cribrosa derive from the neuroectoderm, and the mesenchyme originates from the neural crest. Because the corneal stroma and the corneal endothelium al‐ so derive from the neural crest, they are related embryologically. The lamina cribrosa is be‐ lieved to be the site at which the neural damage induced by glaucoma occurs.

The CCT may reflect the scleral and lamina cribrosa properties associated with glaucoma‐ tous optic neuropathy. In fact, the CCT is correlated with the anterior scleral thickness in pa‐ tients with POAG [56]. Several studies have assessed the relationship between the CCT and objectively measured optic disc parameters, but they provide inconsistent results. Using the confocal scanning laser ophthalmoscopy (Heidelberg Retina Tomograph, Heidelberg Engi‐ neering, Heidelberg, Germany), several hospital-based studies of patients with glaucoma have suggested that the CCT is correlated with the optic disc area and nasal rim volume [57], while another population-based study [58] did not identify these correlations. In anoth‐ er population-based survey [59], no significant relationship was found between the CCT and ONH parameters obtained with retinal tomography.

Thin corneas also can be associated with weak ONHs and this weakness may be related with a thin lamina cribrosa [60-62]. Further, the development and progression of glaucoma are corre‐ lated with the CCT [62]. Other studies have suggested that CH and not corneal thickness is cor‐ related with the vulnerability of the ONH to sustain glaucomatous damage [63].

The correlation between CCT and ONH topographic changes in response to IOP reductions in patients with POAG also has been evaluated [64]. The hypothesis was that thinner CCTs might be associated with greater changes in ONH topography due to a more compliant lam‐ ina cribrosa. Nicolela et al. [65] found that patients with thinner corneas show significantly greater cup shallowing, which is a surrogate marker for lamina cribrosa displacement and compliance in response to IOP reduction. The investigators interrupted the medical treat‐ ment for 4 weeks (with an average increase of IOP of 5.4 mmHg), and when the medical treatment was restarted, the IOPs were remeasured after 4 weeks, and they found that the IOP decreased from a mean of 22.27±4.12 mmHg to a mean of 17.39±2.67 mmHg. This finding may support the hypothesis that eyes with a thinner CCT have an increased risk of developing glaucomatous ONH changes because the lamina cribrosa may be more prone to displacement in response to IOP changes. Nevertheless, the changes of the ONH topogra‐ phy were unconfirmed [65] for relatively moderate IOP changes of about 5 mmHg. In addi‐ tion, the stage of the ONH glaucomatous damage and the disease duration might affect the degree of compliance of the lamina in response to IOP changes, so that for more advanced and long-standing damage less compliance of the lamina can be expected.

The differences in laminar thickness have been studied in different glaucoma types. Park et al. [66] reported that NTG was associated with a thinner lamina cribosa than OAG in patients with a similar disease stage; another study showed that patients with pseudoexfoliation syndrome have less stiffness compared with normal controls, which may reflect an inherent tissue weak‐ ness that makes these eyes more vulnerable to glaucomatous damage [67].

Researchers generally agree that the lamina cribrosa is important in glaucoma [68]. Never‐ theless, in vivo clinical clues regarding the correlated parameters of the lamina cribrosa are limited [69, 70].
