Thinking Out of the Box

The Lesson and Promise of Corneal Thickness

James D. Brandt, M.D.

Professor of Ophthalmology & Director, Glaucoma Service

University of California, Davis

Background

Goldmann applanation tonometry (GAT) has been regarded for almost a half century as the “gold standard’ of IOP measurement. Goldmann and Schmidt acknowledged that their design assumptions were based on a central corneal thickness (CCT) of 500 µm and that the accuracy of their device would vary if CCT deviated from this value. ¹ Given the paucity of published data at the time, 500 µm seemed a reasonable assumption for the ‘average’ patient. We now know CCT varies greatly among the general population, to a degree that impacts the accuracy of GAT in daily practice.

In 1975, Ehlers cannulated 29 otherwise normal eyes undergoing cataract surgery and correlated corneal thickness with errors in GAT. ² He 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 under-estimation of IOP by as much as 7 mmHg per 100 µm. Numerous investigators have since demonstrated that CCT varies far more among otherwise normal individuals than Goldmann and Schmidt ever dreamed; ^3-6 differences in CCT are seen among different racial and ethnic groups, ^{7, 8} can lead to mis-classification of patients with normal tension glaucoma ^9-11 and ocular hypertension. ^{9, 12-14} The importance of CCT in the management of glaucoma patients, particularly those with ocular hypertension, was recently driven home by findings from the Ocular Hypertension Treatment Study (OHTS). ^15-17

In the OHTS, patients were recruited who had untreated GAT measurements in one eye between 24 and 32 mmHg on two separate occasions (the other had to be between 21 and 32 mmHg), with no secondary cause of elevated IOP. The patients all had normal visual fields and optic nerves. CCT was measured approximately two years after enrollment was completed. Among the OHTS participants, 25% had CCT values above 600 µm. ¹⁵   If one uses Ehler’s correction of 7 mmHg/100 µM deviation from the nominal value of 520 µM, then as many as 50% of OHTS subjects had ‘corrected’ IOP values upon entry below 21 mmHg! In a multivariate model of baseline characteristics predictive of which subjects would develop glaucoma, CCT proved to be the most potent. ¹⁷

The OHTS results demonstrate that many patients are being mis-classified in terms of glaucoma risk on the basis of erroneous IOP estimates by GAT. Clearly, many individuals with elevated GAT measurements but no other findings suggestive of glaucoma probably have normal ‘true’ IOPs and do not need treatment or even increased glaucoma surveillance.

What about patients with established glaucoma? Can CCT provide the clinician with data to help refine target pressures? Some have argued that we don’t yet know enough about CCT to use pachymetry in daily practice. Should pachymetry become a routine aspect of glaucoma care? Is this just the beginning of a re-assessment of tonometry and the underlying assumptions in glaucoma management?

The EMGT versus the OHTS

An argument against the use of CCT in the management of glaucoma patients is that although the OHTS found a strong predictive relationship between CCT and glaucoma conversion, the Early Manifest Glaucoma Trial (EMGT) did not find such a relationship in patients already diagnosed with glaucoma ^{18, 19} . To understand the disparity in the findings, it is important to recognize the following:

1)   The OHTS used IOP as its primary entry criterion (at least from the  standpoint of recruitment/screening), with normality of VFs and nerves confirmed afterwards. If CCT’s influence as a predictive factor is primarily as a confounder of IOP measurement, then the entry criteria for OHTS and the study design is perfectly set up to demonstrate that CCT causes a mis-classification of risk - thus the powerful effect CCT had in predicting who went on to get glaucoma.

2)  In contrast, in the EMGT, patients were recruited based on the presence of damage, regardless of IOP and the recruitment bias an IOP cutoff would cause; in fact, a large portion of the patients were those whom many would consider classifying as having normal tension glaucoma. Thus at the outset, the EMGT started with patients who had demonstrated the propensity to sustain damage at whatever their ‘true’ IOP might be – errors in IOP measurement become less important in such a situation. It may be that if and when we have a correction algorithm and apply it to the EMGT data, we may see a better dose-response relationship between ‘true’ IOP and progression. Finally, the EMGT was a relatively small sample (at least compared to the OHTS) and may not have the statistical power to find such a relationship. The EMGT investigators have published few details on the range and distribution of CCTs they measured in their racially homogeneous population – it is quite possible it was far narrower than what was found in the OHTS. If there is an effect of CCT on progression rates in established disease, the EMGT might be too small, and the range of IOPs and CCTs too narrow, to pick it up.

Stratifying Risk among Glaucoma Patients

Another argument against the routine use of pachymetry data in the management of glaucoma patients is that patients already carrying the diagnosis of glaucoma have demonstrated a propensity to sustain damage at the IOPs they presented with. While this may be true, the setting of target pressures can be refined by the use of pachymetry data.

Weizer and co-workers recently performed a retrospective review of all newly-referred glaucoma patients over several years. ²⁰ In both univariate and multivariate analyses, CCT had a stronger (inverse) relationship to the degree of glaucoma damage than anything else, including IOP! The implication of this finding is that patients with thin corneas have higher IOPs than are appreciated by the clinicians caring for them – in a patient with advanced disease and a CCT of 480 µm, perhaps the clinician should not consider a GAT measurement of 15 mmHg as acceptable. Thus the knowledge of a patient’s CCT will allow the appropriate titration of therapy to suit the individual.

How to use CCT data

A third argument against the routine use of pachymetry data in the management of glaucoma patients is that there is wide disagreement among investigators as to whether there is an adequately validated ‘correction algorithm’; without a validated algorithm, the argument goes, clinicians can’t use the data.

The question of whether such an algorithm exists is, in my opinion, not particularly important in daily practice. The clinician should be cautious in extrapolating Ehlers’ findings to general clinical practice. His study was based on a small number of eyes (29) that included a relatively narrow range of CCTs (450 to 590 µm). ² The interested reader is referred to a detailed exploration of the mechanical characteristics of the cornea and the role of CCT in GAT error by Orssengo and Pye ²¹ in which a mathematical and engineering model closely approximates Ehlers’ and other published cannulation data. Based on this and the OHTS findings it is my opinion that Ehlers’ estimate is probably close to the magnitude of error that occurs in real life. If there is one thing I’ve learned over the past few years of performing pachymetry on most of my patients is that one can take far better care of patients simply by categorizing corneas as ‘thin, average or thick’, just as it is important to recognize that optic discs come in ‘small, medium and large’, allowing the clinician to interpret disc configurations accordingly.

CCT’s Effect on Response to Treatment

We have recognized for years that individual patients respond to identical treatment with enormous variability. This has been attributed to a variety of factors, including patient compliance, differing disease stage, underlying pharmacokinetics pharmacologic responsiveness and pharmacophysiology. Might variations in CCT explain a significant portion of this variability? The answer is probably yes. In the OHTS, patients underwent a monocular treatment trial at the initiation of the study in 1994-1996; most were treated with a non-selective ß-blocker. This dataset provides a unique opportunity to explore the relationship between CCT and treatment response. The OHTS dataset is being analyzed for this relationship right now, but a preliminary look (ARVO 2001) at a subset of the data demonstrated that OHTS participants with CCTs in the upper (thicker) quartile responded about 1.5 to 2.0 mmHg less than those in the lowest (thinnest) quartile. A virtually identical finding was observed in the bimatoprost Phase III clinical trial. In other words, in a given cohort of patients receiving identical therapy, patients with ‘thin’ corneas appear to respond than those with ‘thick’ corneas. Probably the best way to understand this observation is to imagine a balloon and a basketball of similar size; at any given pressure, the basketball will always feel ‘firmer’ than the balloon, even though the internal pressures might be identical. The bottom line is that we will need CCT data to better understand efficacy data when evaluating IOP-lowering therapies.

LASIK-Induced Normal Tension Glaucoma

A million LASIK procedures are performed each year among mostly young to middle-aged myopes. Myopia is a strong risk factor for the development of glaucoma ²² , and perhaps as many as 5 to 10% of the patients undergoing LASIK today are destined genetically to develop glaucoma in the coming decades. Although we do not yet (and may never) know how to ‘correct’ a GAT measurement made on a LASIK-thinned cornea, it is clear that in many cases GAT will grossly under-estimate IOP. It is easy to predict that ten or fifteen years from now patients will neglect to inform their treating ophthalmologist (or screening optometrist) that they had LASIK back in 2001, and a GAT measurement of 18 mmHg is regarded as ‘normal’ despite a 425 µm cornea. Unless pachymetry becomes a part of the routine glaucoma exam, (or tonometry technologies independent of CCT are developed and widely disseminated) patients like this will fall through the cracks.

Some Predictions and Random Thoughts ‘Outside the Box’ about CCT

CCT is but the tip of the iceberg. GAT estimates IOP by measuring the cornea’s elasticity, as supported by the intraocular pressure. CCT is probably a major (?the major?) component of corneal elasticity, but it is likely not the only component. The mix of collagen types, corneal hydration, packing density of collagen fibrils, the extra-cellular matrix and other factors undoubtedly vary among individuals and in some patients may dwarf the effect of CCT on the accuracy of IOP estimation. In view of this, all bets are off for how LASIK impacts corneal elasticity! We really don’t understand the biomechanical properties of the cornea. This raises some intriguing questions. Might the potent (observed) effect of the hypotensive lipid medications result not only from their impressive effects on outflow but also through an effect on the corneal extracellular matrix (and thus the cornea’s deformability and elastic properties)? No one knows.

The CCT story has caused us all to grudgingly face the fact that our ability to accurately measure IOP is far weaker than we’ve ever imagined – our profession has spent half a century deluding ourselves both that we were good at tonometry and that a one-time measurement told us something about our patients. A failure to question whether our measurement techniques were sufficiently accurate to guide patient care has led us to a propose variety of hypotheses to explain the ‘outliers’ – patients who didn’t seem to fit the mold of a pressure-sensitive disease.  One likely scenario, in my mind, is that as our ability to measure IOP becomes more accurate (and especially once we achieve 24 hour monitoring), a much tighter dose-response relationship between glaucoma damage and IOP will be found. The healthy eye probably regulates IOP within a much tighter range than we can measure

As we refine tonometry, I predict that glaucoma will turn out to be a whole lot more complicated and at the same time a whole lot simpler. We have tended hedge our bets by defining IOP as a ‘risk factor’ rather than as the ‘causative factor’ it really is out of collective discomfort with the ‘messiness’ of the relationship between pressure and disease.

In the end, glaucoma really is a ‘pressure-sensitive’ optic neuropathy.

References

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2.      Ehlers N, Bramsen T, Sperling S. Applanation tonometry and central corneal thickness. Acta Ophthalmol (Copenh) 1975;53(1):34-43.

3.      Alsbirk PH. Corneal thickness. I. Age variation, sex difference and oculometric correlations. Acta Ophthalmol (Copenh) 1978;56(1):95-104.

4.      Wolfs RC, Klaver CC, Vingerling JR, et al. Distribution of central corneal thickness and its association with intraocular pressure: The Rotterdam Study. Am J Ophthalmol 1997;123(6):767-72.

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7.      Foster PJ, Baasanhu J, Alsbirk PH, et al. Central corneal thickness and intraocular pressure in a Mongolian population. Ophthalmology 1998;105(6):969-73.

8.      La Rosa FA, Gross RL, Orengo-Nania S. Central corneal thickness of Caucasians and African Americans in glaucomatous and nonglaucomatous populations. Archives of Ophthalmology 2001;119(1):23-7.

9.      Copt RP, Thomas R, Mermoud A. Corneal thickness in ocular hypertension, primary open-angle glaucoma, and normal tension glaucoma [see comments]. Arch Ophthalmol 1999;117(1):14-6.

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14.    Herndon LW, Choudhri SA, Cox T, et al. Central corneal thickness in normal, glaucomatous, and ocular hypertensive eyes [see comments]. Arch Ophthalmol 1997;115(9):1137-41.

15.    Brandt JD, Beiser JA, Kass MA, Gordon MO. Central Corneal Thickness in the Ocular Hypertension Treatment Study (OHTS). Ophthalmology 2001;108(10):1779-88.

16.    Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular Hypertension Treatment Study: A Randomized Trial Determines That Topical Ocular Hypotensive Medication Delays or Prevents the Onset of Primary Open-Angle Glaucoma. Arch Ophthalmol 2002;120(6):701-13.

17.    Gordon MO, Beiser JA, Brandt JD, et al. The Ocular Hypertension Treatment Study: Baseline Factors That Predict the Onset of Primary Open-Angle Glaucoma. Arch Ophthalmol 2002;120(6):714-20.

18.    Heijl A, Leske MC, Bengtsson B, et al. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol 2002;120(10):1268-79.

19.    Leske MC, Heijl A, Hussein M, et al. Factors for glaucoma progression and the effect of treatment: the early manifest glaucoma trial. Arch Ophthalmol 2003;121(1):48-56.

20.    Weizer J, Stinnett S, Herndon LW. Central corneal thickness as a risk factor for advanced glaucoma damage. Arch Ophthalmol 2003:in press.

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