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

at increased risk for glaucoma [28], the effect of these procedures on glaucoma management

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

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 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‐

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

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‐

subepithelial keratomileusis seem to have a postoperative decrease in CH [52,53].

the flap and the stromal bed, with fluid accumulating in the flap interface [55].

lieved to be the site at which the neural damage induced by glaucoma occurs.

related with the vulnerability of the ONH to sustain glaucomatous damage [63].

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

ONH parameters obtained with retinal tomography.

should be determined.

238 Glaucoma - Basic and Clinical Aspects

Some ocular hypotensive drugs, such as topical carbonic anhydrase inhibitors (CAIs) and F2α-prostaglandin analogs (PGAs), induce changes in the CCT [71].

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 [78] found a mean 6.9-micron CCT decrease after 6 weeks of travoprost treatment. Sen et al. [79] reported 1.9 ± 2.4% and 2.8 ± 1.8% CCT decreases over 24 months with latanoprost and bimatoprost, respectively. Hatanaka et al. [80] also reported that topical PGAs were associat‐ ed with a CCT reduction over at least 8 weeks (the bimatoprost 0.03% group decreased from 544.41 ± 35.4 to 540.35 ± 35.9 µm; the travoprost 0.004% group decreased from 538.47 ± 32.0 to 532.25 ± 30.4 µm; the latanoprost 0.005% group decreased from 548.57 ± 32.4 to 543.88 ± 35.6 µm). Zhong et al. [81] reported CCT reductions in the latanoprost, travoprost, and bi‐ matoprost groups of 14.95 ± 5.04, 15.73 ± 3.25, and 17.00 ± 6.23 mm, respectively, and no sig‐ nificant difference was seen in the CCT reductions between patients with 6 months or shorter treatment and patients with 6 months or longer treatment in the three groups.

ed a slight but significant increase in CCT in eyes treated with brinzolamide, another CAI inhibi‐ tor [90]. Another way to measure the endothelial function in vivo is to measure the intrastromal corneal pressure [91,92], formerly known as corneal intrastromal pressure, which has a negative value under physiologic conditions. The amount of negative pressure in the corneal stroma is likely to be correlated with the endothelial function, and topical dorzolamide significantly re‐ duces the negative pressure in the corneal stroma in rabbits [91], suggesting that the drug affects the endothelial function in healthy rabbit corneas. This finding is consistent with the reported cases of dorzolamide-induced corneal edema in susceptible patients and with the finding that inhibiting CA in the corneal endothelium causes a 50% decrease in the endothelial fluid trans‐

Cornea and Glaucoma

241

http://dx.doi.org/10.5772/53017

There is growing interest in the possible effect of some corneal parameters in glaucoma. There is sufficient evidence to suggest that CCT evaluation predicts the risk of conversion from OHT to glaucoma. The influence of the CCT on the GAT IOP is clear, so true IOP is higher than GAT IOP in patients with thinner corneas and true IOP is lower than GAT IOP in patients with thicker corneas. In addition, some data suggest that CCT may be an inde‐ pendent risk factor for glaucoma development, although there is no clear evidence to sup‐

Of special interest is the fact that GAT is affected by laser excimer refractive surgery, a pop‐ ular procedure that changes some corneal properties that affect accurate IOP measurement. New tonometers with a lower relationship to the corneal thickness and viscoelastic proper‐

Finally, widely used topical antiglaucomatous medications can alter the corneal viscoelastic properties and thus affect the GAT readings. This also needs to be investigated further.

1 Department of Glaucoma, Hospital Universitario Príncipe de Asturias, Alcalá de Henares,

2 Department of Ophthalmology, Hospital Universitario Príncipe de Asturias, University of

, Javier Paz Moreno-Arrones1\* and Miguel A. Teus2

\*Address all correspondence to: javierpazmoreno@gmail.com

port and some corneal swelling [92].

**9. Conclusion**

port this hypothesis.

ties need to be developed.

Alcalá, Alcalá de Henares, Spain

**Author details**

Gema Bolivar1

Spain

The reason for the effect of the PGAs on the CCT is unknown, but it is widely accepted that PGAs seem to induce ECM remodeling due to a FP-receptor-mediated increased synthesis of matrix metalloproteinases (MMPs) [82]. The MMPs are a family of enzymes that degrade several com‐ ponents of the ECM, thus decreasing the levels of collagen types I, II, III, and IV. Published evi‐ dence suggests that the PGA-related activation of the MMPs activity takes place in the ciliary body, the trabecular meshwork [83], the conjunctiva, the sclera, and the zonular fibers-ciliary muscle complex [84]. Further, naturally occurring prostaglandins seem to play a relevant role in physiologic corneal conditions, i.e., repair after corneal injuries, and in pathologic corneal con‐ ditions, i.e., corneal ectasia. In fact, PGA treatment may be related to keratoconus progression [85]. Thus, there is enough evidence to suggest that topical PGAs might induce changes in the ECM of the corneal stroma via up-regulation of MMPs that may slightly change the CCT and perhaps the corneal viscoelastic properties. In fact, CH seems to be significantly lower in PGAtreated eyes [86]. PGAs also seem to increase the keratocyte density in the corneal stroma, which might also result in changes in the ECM [87].

Previous reports have suggested that chronic topical PGA treatment is associated with a slight decrease in the CCT [86,88] and an increase in the CH. We studied the response of CCT to increased IOP in rabbit eyes treated with travoprost for 1 month and in an untreated control group, and found that the decrease in CCT induced by a sudden increase in IOP was greater in the PGA-treated eyes than in the control eyes [88]. The changes in corneal thick‐ ness induced by IOP increases are believed to be a strain response and thus are probably a biomechanical response of the corneal tissue to the IOP changes. Then the differences in the CCT behavior between groups also suggest that PGAs induce changes in the corneal biome‐ chanical properties, at least in rabbits.

Topical dorzolamide induces a 14.4% increase in CCT in patients with corneal guttata [89]. Patients with severe corneal guttata or a highly compromised endothelial function may have a higher risk of corneal decompensation after prolonged topical use of dorzolamide.

Dorzolamide is a potent cytosolic carbonic anhydrase inhibitor (CAI) isoenzyme II, and the cor‐ neal endothelium contains carbonic anhydrase (CA) II and the cytosolic CA I, which plays a ma‐ jor role in keeping the cornea relatively dehydrated. Dorzolamide has a high affinity for CA II and low affinity for CA I, and thus, it has the potential to interfere with the pump function of the corneal endothelium, which could theoretically lead to corneal edema. Changes in CCT have been used as an indirect indicator of the endothelial function. Some investigations have report‐ ed a slight but significant increase in CCT in eyes treated with brinzolamide, another CAI inhibi‐ tor [90]. Another way to measure the endothelial function in vivo is to measure the intrastromal corneal pressure [91,92], formerly known as corneal intrastromal pressure, which has a negative value under physiologic conditions. The amount of negative pressure in the corneal stroma is likely to be correlated with the endothelial function, and topical dorzolamide significantly re‐ duces the negative pressure in the corneal stroma in rabbits [91], suggesting that the drug affects the endothelial function in healthy rabbit corneas. This finding is consistent with the reported cases of dorzolamide-induced corneal edema in susceptible patients and with the finding that inhibiting CA in the corneal endothelium causes a 50% decrease in the endothelial fluid trans‐ port and some corneal swelling [92].
