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The Role of the Cornea in Managing Glaucoma

Leon W. Herndon Jr, MD

In routine clinical practice, intraocular pressure (IOP) represents one of several important parameters used not only in the diagnosis of glaucoma but also for following the progression of this disease and its response to treatment. Certainly, its value as a diagnostic tool hinges upon the reliability of measurements taken. The technique used most commonly for this purpose is Goldmann (Haag-Streit) applanation tonometry (GAT; Figure 71-1). In first describing their applanation tonometer, Goldmann and Schmidt discussed the effect of central corneal thickness (CCT) on IOP as measured by the new device.¹ They felt that variations in corneal thickness occurred rarely in the absence of corneal disease and assumed a CCT of 520 μm, but acknowledged that, at least theoretically, CCT might influence applanation readings. They started from the hypothesis that the cornea might be considered as a sheath covered by 2 membranes between which almost nonshifting water is located. It has since become apparent that CCT is more variable among clinically normal patients than Goldmann and Schmidt¹ ever realized. Studies by Von Bahr^2,3 showed that there were large variations in CCT within a normal population, and studies by Ehlers and colleagues^4–6 demonstrated that this variation in CCT had an effect on applanation-measured IOP. Many studies have since looked at the influence of CCT on IOP measurement with most agreeing that there is an increase in measured IOP with increasing CCT. However, CCT alone accounts for only a small proportion of the interindividual variation in measured IOP. In a manometric study,⁶ Ehlers and colleagues cannulated 29 otherwise normal eyes undergoing cataract surgery and correlated corneal thickness with errors in GAT. They found that GAT most accurately reflected true intracameral IOP when CCT was 520 μm and that deviations from this value resulted in an over- or underestimation of IOP by as much as 7 mm Hg per 100 μm. Johnson and colleagues⁷ reported a patient with a CCT of 900 μm with a manometric IOP of 11 mm Hg, but when measured by applanation, the IOP had ranged from 30 to 40 mm Hg while the patient was receiving maximum medical therapy! In a manometric study with the Perkins tonometer (Haag-Streit), Whitacre and colleagues⁸ demonstrated an underestimation of IOP by as much as 4.9 mm Hg in thin corneas, with thick corneas producing an overestimation by as much as 6.8 mm Hg. This corresponded to a calculated range of 0.18 to 0.49 mm Hg of change in IOP for a 10-μm change in CCT from the mean CCT.

The Goldmann tonometer measures the force required to applanate the eye to 3.06-mm diameter. The force required is a combination of opposition to IOP plus the force needed to bend the cornea (less a small attraction due to surface tension). Therefore, simply stated, the thicker the cornea, the higher the force needed to bend, and the thinner the cornea, the lower the force needed to bend. Hence, deviation from normal CCT results in a potentially incorrect indication of IOP.

DISEASE IMPLICATIONS

A number of studies have looked at the distribution of CCT according to diagnosis in primary open-angle glaucoma (POAG), normal-tension glaucoma (NTG), and ocular hypertension (OHT). There was found to be a significant difference in the mean CCT of these 3 groups. In a study by Shah and colleagues,⁹ normal eyes had a mean CCT of 554 μm. The POAG eyes had a mean CCT of 550 μm, the NTG eyes had a mean CCT of 514 μm, and the OHT eyes had a mean CCT of 580 μm. Similarly, Copt and colleagues10 measured the CCT among patients classified as having POAG, NTG, and OHT. In addition to confirming that patients with OHT had thicker corneas than their control and POAG counterparts, they likewise found that patients classified as having NTG had thinner corneas.

CCT has been recognized as a significant risk factor for progression of ocular hypertensive patients to POAG in the Ocular Hypertension Treatment Study (OHTS).¹¹ This study was the first to prospectively demonstrate that a decreased CCT predicts the development of POAG. Participants with a CCT of 555 μm or less had a 3-fold greater risk of developing POAG compared with participants who had a CCT of more than 588 μm. This inverse relationship was found across the ranges of baseline IOP and baseline vertical cup-to-disc ratios. Medeiros and colleagues¹² studied 98 eyes of 98 patients with preperimetric glaucomatous optic neuropathy. The diagnosis of glaucomatous optic neuropathy was based on masked assessment of optic disc stereo photographs. All patients had normal standard automated perimetry visual fields at baseline. Thirty-four patients developed repeatable visual field abnormality during follow-up. A thinner central cornea predicted the development of visual field conversion in both univariate and multivariate models. Mean CCT was significantly lower in converters than in nonconverters. Medeiros and colleagues also found that a CCT value of 545 μm was the best dividing point to separate patients who developed visual field conversion from the patients who did not. At 4-year follow-up, the cumulative probability of developing visual field conversion was 46% in patients with CCT less than 545 μm compared to 11% in patients with CCT of 545 μm or more. Herndon and colleagues¹³ retrospectively examined the initial visit of consecutive POAG patients over a 5-year period. They found that a lower CCT was a powerful clinical factor associated with a worsened Advanced Glaucoma Intervention Study score, worsened mean deviation of visual field, increased vertical and horizontal cup-to-disc ratios, and increased number of glaucoma medications.

RACIAL DIFFERENCES IN CENTRAL CORNEAL THICKNESS

Until recently, most pachymetry studies were performed on predominately White populations. Foster and colleagues,¹⁴ however, studied more than 1000 Mongolian patients in rural China and found that this population had CCT measurements that were 30 to 40 μm lower than the average CCT in surveys found in White populations. Kunert and colleagues¹⁵ measured the CCT of 615 Indian patients who presented for refractive surgery evaluation and found this group to have a mean CCT of approximately 520 μm. Several investigators have provided further evidence that Black individuals, as a group, tend to have thinner corneas than White individuals. LaRosa and colleagues¹⁶ reported thinner CCT values among Black male veterans compared with their White counterparts. Nemesure and colleagues,¹⁷ following a CCT survey of participants in the Barbados Eye Survey, reported that Black participants had thinner corneas (mean thickness 530 μm) than White participants (545 μm). Shimmyo and colleagues¹⁸ performed a retrospective biometric review of patients at a large refractive surgery center, also finding that Black patients had thinner corneas than White patients seeking refractive surgery; they found no difference in CCT among White, Asian, and Hispanic patients in their population. This is in contrast to the findings of the population-based Los Angeles Latino Eye Study¹⁹ that found CCTs among their Hispanic patients intermediate between values reported for Black and White populations. Herndon and colleagues¹³ showed that Black persons with POAG had a significantly lower CCT (537 μm) compared to White persons (556 μm). These racial differences in CCT may in part explain the more advanced progression of glaucomatous disease at a relatively lower measured IOP among some groups.

CORNEAL REFRACTIVE SURGERY AND TONOMETRY

Laser-assisted in situ keratomileusis (LASIK) procedures are performed throughout the world among mostly young to middle-aged persons with myopia. Myopia is a strong risk factor for the development of glaucoma,²⁰ and many of the patients undergoing LASIK today are destined genetically to develop glaucoma in the coming decades. Although we do not yet know how to correct a GAT measurement made on a LASIK-thinned cornea, it is clear that in many cases GAT will grossly underestimate IOP. The problem will arise 10 or 15 years from now when patients neglect to inform their ophthalmologist that they had LASIK years ago, and a GAT measurement of 18 mm Hg is regarded as normal despite a 425-μm cornea.

One promising technology that may prove useful is the Pascal Dynamic Contour Tonometer (DCT; Ziemer Group). This device consists of an electronic strain gauge embedded in a contoured plastic tip. When in contact with the cornea, the tonometer tip creates a tight-fitting shell on the corneal surface without applanation of corneal tissue (Figure 71-2). The assumption is that the tonometer compensates for all forces exerted on the cornea, allowing the strain gauge to measure IOP largely independent of corneal properties. Studies have shown that the IOP measured by DCT is not altered after LASIK, unlike IOP measured by GAT.^21,22 Realini and colleagues²³ evaluated the diurnal IOP of 47 patients with POAG and 38 normal control patients. They found no correlation between GAT and CCT and a weak inverse correlation between DCT and CCT in glaucoma eyes, which was different from the associations seen in normal controls. This finding might suggest that the collagen of the cornea is altered by glaucoma (or its treatment) altering the biomechanical properties of the cornea. DCT also provides a measurement called the ocular pulse amplitude (OPA), which may be a marker for overall ocular rigidity. OPA is the difference in IOP between systole and diastole (Figure 71-3). In studying the clinical utility of the OPA, Weizer and colleagues²⁴ found that an increased OPA was associated with a decreased severity of glaucoma. Kaufmann and colleagues²⁵ measured OPA in 223 healthy eyes and found that these readings were not affected by CCT or corneal curvature. The readings were, however, affected by IOP and axial length.

THE BIOMECHANICS FACTOR

GAT measures IOP by flattening the cornea, which is not neutral in this measurement. Liu and Roberts²⁶ have shown that factors affecting corneal resistance include structural considerations, such as the amount of rigidity produced by the way the collagen beams in the tissue line up. The bendability of corneal tissue can also be affected by short-term factors, such as the presence of corneal edema. The Ocular Response Analyzer (ORA; Reichert Technologies) measures the corneal response to indentation by a rapid air pulse (Figure 71-4). The principles of the ORA are based on those of noncontact tonometry, in which the IOP is determined by the air pressure required to applanate the central cornea. The instrument makes 2 measurements of the corneal response to the pulse of air—the force required to flatten the cornea as the air pressure rises (force-in applanation, P1) and the force at which the cornea becomes flat again as the air pressure falls (force-out applanation, P2). The difference between the 2 pressures is termed corneal hysteresis (CH; Figure 71-5). CH is a direct measure of the cornea’s biomechanical properties and may more completely describe the contribution of corneal resistance to IOP measurements than CCT alone.27 The corneal resistance factor (CRF) is another measurement of corneal biomechanical properties produced by the ORA and is derived from the formula P1 – kP2 where k is a constant. The CRF offers a measurement of corneal resistance and is a parameter that is relatively unaffected by changes in IOP. A feature of the ORA is that the maximum air pressure applied is not constant and is dependent on P1, a value determined by both the true IOP and the structural resistance of each individual eye. Kotecha and colleagues²⁸ recently assessed what effect this feature might have on CH values by measuring eyes before and after pharmacological reduction of IOP. The study found a weak but significant negative correlation between changes in CH and changes in IOP, such that higher values of CH were found at lower levels of IOP. Variations in maximum air pressure applied to the cornea may cause differing amounts of corneal indentation. Further work is needed to determine whether these variations alter the CH measurement.

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