Central corneal thickness and vascular risk factors in normal tension glaucoma

Central corneal thickness and vascular risk factors in normal tension glaucoma Aoife Doyle, Ahmed Bensaid and Yves Lachkar L Institut du Glaucome, Fondation Hoˆpital St. Joseph, Paris, France ABSTRACT. Background: Normal tension glaucoma (NTG) has been shown to be associated with reduced central corneal thickness (CCT). The association of NTG with vascular risk factors is well documented. It has been postulated that a subset of NTG patients are misclassified due to incorrect intraocular pressure measurements on thin corneas. The aim of this study was to establish whether corneal thickness in NTG differs between patients with vascular risk factors specific to NTG and those without. Methods: The study comprised a retrospective analysis of 108 eyes of 54 patients with NTG and 54 patients with primary open-angle glaucoma (POAG). Corneal thickness was measured in all patients. Vascular risk factors were recorded. Patients with NTG were divided into two groups depending on the presence (group A) or absence (group B) of vascular risk factors. Results: The mean CCT was 549 ± 34 mm in patients with POAG and 528 ± 31 mm in patients with NTG (p = 0.001). Mean CCT was 512 ± 31 mm in group A (n = 13) and 533 ± 31 mm in group B (n = 41) (p = 0.034). A total of 40.9% of those with thin corneas (n = 22) had vascular risk factors versus only 12.5% of those with CCT within the normal range (n = 32) (p < 0.05). Conclusion: Central corneal thickness in NTG was significantly lower than in POAG and corneas were thinner in NTG patients with vascular risk factors than in those without. Vascular risk factors were significantly more common in patients with thin corneas. The finding of reduced corneal thickness in NTG does not obviate the need to consider vascular risk factors in the pathophysiology of the disease. Key words: corneal thickness normal tension glaucoma vascular risk factors Acta Ophthalmol. Scand. 2005: 83: 191 195 Copyright # Acta Ophthalmol Scand 2005. doi: 10.1111/j.1600-0420.2005.00436.x Introduction The influence of central corneal thickness (CCT) on the accuracy of intraocular pressure (IOP) measurements was acknowledged in the first description of the Goldman tonometer almost 50 years ago (Goldman & Schmidt 1957). The availability of optical pachymetry led to the discovery that erroneous readings due to thick or thin corneas are more common than was initially believed to be the case (Hansen & Ehlers 1971). It has been shown that patients with ocular hypertension (OHT) tend to have thicker corneas than those with primary open-angle glaucoma (POAG) (Argus 1995; Gordon et al. 2002).Conversely, patients with normal tension glaucoma (NTG) have a lower mean CCT than the general population, on average 30 mm below the mean populationlevelof550 mm(ehlers& Hansen1974; Morad et al. 1998; Copt et al. 1999). However, not all patients with NTG have thin corneas. The effect of specific vascular risk factors in this disease is also well known, although such factors are not present in all patients. Normal tension glaucoma may consist of a spectrum of diseases in which glaucomatous optic neuropathy and IOP <22 mmhg are common factors. The literature on corneal thickness in NTG suggests that the disease category of NTG encompasses misdiagnosed POAG in patients with thin central corneas (Morad et al. 1998; Copt et al. 1999; Shah 2000; Brandt 2001). It is suggested that this might provide an explanation for the group of NTG patients who have no other known risk factors for the disease. There is no report to date, to our knowledge, of a comparison of CCT in NTG patients with and without vascular risk factors. With this in mind we looked at CCT in a group of NTG patients compared to a group of POAG controls and then looked for differences in CCT between those of the NTG patients with and without vascular risk factors. Material and Methods We carried out a retrospective analysis of all patients attending our glaucoma 191

service with a diagnosis of NTG, over a 6-year period. The diagnosis of NTG was based on adherence to the guidelines of the European Glaucoma Society, which include peak IOP <22 mmhg (with no treatment), optic nerve head damage typical of glaucoma with cup : disc ratio >0.6 and corresponding glaucomatous visual field defects, open-angle on indentation gonioscopy and no history or signs of other eye disease or steroid use. Diurnal IOP measurements using the Goldman tonometer were taken in all patients. Intraocular pressure without treatment was measured at 06.00, 09.00, 12.00, 15.00, 18.00, 21.00 and 00.00 hours. The IOP recorded for analysis was the maximum diurnal IOP measurement. Indentation gonioscopy and disc evaluation under mydriasis were documented in all patients. Central corneal thickness was measured at the slitlamp to ensure centration, using an ultrasound pachymeter. An average of three readings was recorded. All visual fields were performed using automated perimetry (Humphrey or Octopus). A glaucomatous field defect was defined as a cluster of at least three adjacent test points 5 db lower than in agematched controls, one of which was >10 db lower, in a distribution characteristic of glaucoma. The presence or absence of vascular risk factors was determined using a standardized questionnaire in all patients. This questionnaire appears on the chart of each glaucoma patient attending our unit and is completed at the first consultation. Information was gathered from the patient, the referring doctor s letter, and the results of investigations (Carotid Doppler/24-hour blood pressure monitoring) either provided by the patients or carried out at our request. To satisfy a diagnosis of migraine, patients had to have headaches associated with one or more of the following: visual effects, photophobia, nausea or positive response to antimigrainous therapy. The diagnosis of Raynaud s syndrome was made on a history of cold extremities associated with blanching of the digits in response to conditions other than extreme cold. Magnetic resonance imaging (MRI) was carried out if deemed necessary to rule out any compressive lesion as a cause of the optic neuropathy. Vascular risk factors were defined based on a review of the literature. Only factors considered to have a definite association with NTG were included for the basis of categorization, such as migraine (Phelps & Corbett 1985), Raynaud s syndrome (Broadway & Drance 1998), nocturnal hypotension (Hayreh et al. 1994; Graham et al. 1995), history of hypovolaemic shock or severe blood loss (Drance 1972). Carotid stenosis was included only if visual field loss was asymmetrical and associated with >50% occlusion of the lumen of the common carotid artery. The control group was randomly selected from patients with a diagnosis of POAG attending the clinic over the same time period and was matched for age and race. The diagnosis of POAG was based on the presence of IOP >22 mmhg at the time of diagnosis, open-angle on indentation gonioscopy and glaucomatous damage to the optic nerve with corresponding visual field loss as described above. Patients with a history of previous cataract or filtration surgery were excluded in both groups due to the possible influence of intraocular surgery on corneal thickness, as were patients with any history of corneal disease. The presence or absence of vascular risk factors was recorded as for NTG patients. Patients with NTG were divided into two groups for the purpose of statistical analysis: one group with vascular risk factors and one group without. Either the right or left eye was randomly selected for analysis on each patient. Mean CCTs between and within groups were compared. The difference between CCTs in POAG and NTG was compared using Student s t-test, having verified the normal distribution and similar standard deviations of the two groups. A 95% confidence interval for the difference between the two means was calculated. The difference between NTG patients with and without vascular risk factors was analysed using the Mann Whitney test and 95% CIs calculated for the difference between the means. Further analysis was carried out by looking at the percentages of patients with thin and normal CCTs who also had vascular risk factors and analysed using a chi-squared frequency table for the comparison of two proportions. All cells in the 2 2 table had a value of 5 or more for expected frequency. Finally, maximum diurnal IOP measurements for patients with CCT <520 mm were recalculated using the correction factor derived from a metanalysis of human CCT (Doughty & Zaman 2000) of 0.5 mmhg per 10 mm CCT, in order to determine what percentage of patients could be reclassified as having POAG using these criteria. Results Table 1. Demographic data of patients according to disease category. Number Mean age SD (years) Range Data from 108 eyes of 108 patients (54 eyes with POAG and 54 eyes with NTG) were analysed. Normal tension glaucoma patients were matched in terms of age and race, but there was a higher percentage of females in the NTG group (Tables 1 and 2). Patients with NTG had a mean CCT of 528 mm, significantly lower than the 549 mm of POAG patients (p ¼ 0.001), with a 95% CI for the difference in means of 8.4 23.6 mm. The NTG patients were divided into two groups depending on the presence or absence of NTG-specific vascular risk factors. Group A had associated risk factors for NTG (n ¼ 13) and group B did not (n ¼ 41). Only two patients had more than one vasospastic risk factor Raynaud s syndrome and migraine (Table 3). Magnetic resonance imaging (25 patients) was normal in all cases. Corneal thickness was significantly lower in group A (512 mm) than in group B (533 mm) (p ¼ 0.034, Mann Whitney test; 95% CI for the difference in means: 1.7 30.3 mm). Sex %F Race % white Mean CCT (mm) SD (range) POAG 54 65.7 9.8 39 81 46.3 92.6 549 34 NTG 54 66.5 11 36 89 64.8 92.6 528 32 p 0.71 0.001 CCT ¼ central corneal thickness; SD ¼ standard deviation; POAG ¼ primary open-angle glaucoma; NTG ¼ normal tension glaucoma; F ¼ female. 192

Table 2. Differences in CCT in men and women with POAG and NTG. A total of 69.2% in group A had CCT <520 mm versus only 31.7% in group B (p < 0.05, chi-squared test). The cup : disc ratio was similar in groups A and B and there was no difference in mean IOP (Table 4). We reclassified the maximum IOPs based on a conversion factor of 2.5 mmhg per 50 mm. Only one patient in each of groups A and B would be reclassified on this basis one to an IOP of 22.75 mmhg and the other to an IOP of 23 mmhg (Table 5). Discussion Mean age SD (years) Central corneal thickness is known to be thinner on average in patients with NTG than in those with POAG. Many authors have suggested that some NTG patients may, in fact, have POAG, and that they may be misclassified due to inaccuracies in Goldman tonometry (Shah 2000; Brandt 2001). A number of studies have claimed that a significant percentage (up to 44%) of their NTG patients would be reclassified as having POAG after the application of conversion factors such as that based on manometric studies by Ehlers et al. (1975); these include Copt et al. (1999) with 16 NTG patients, Morad et al. (1998) with 21 patients and Shah et al. (1999) with 52 eyes. Our findings confirmed a low CCT of 528 mm in our NTG population (54 patients), compared to a mean of 549 mm in POAG patients. However, a CCT of 528 mm is unlikely to lead to Mean CCT SD (mm) POAG male (n ¼ 29) 64.4 10.8 540 30 POAG female (n ¼ 25) 67.2 8.4 558 35 (p ¼ 0.05) NTG male (n ¼ 18) 65.6 10 527 41 NTG female (n ¼ 35) 68.2 11.6 528 26 significant inaccuracies in Goldman tonometry. Furthermore, we applied the conversion factor suggested by Doughty & Zaman (2000) and found that only two of our NTG patients (with CCTs of 460 mm and 505 mm, respectively) would be reclassified and even these two patients would not have IOP >24 mmhg (Table 5). We looked at other factors that might explain the difference in mean CCT between the two groups. Central corneal thickness can be affected by age, sex and race (Alsbirk 1978). There was no significant difference in age between the two groups (p ¼ 0.77). Group B included four patients of African origin, which can be associated with thinner corneas (La Rosa et al. 2001; Nemesure et al. 2003). However, only one of these patients had a thin cornea (499 mm) and as group B had the greater mean CCT, the only likely effect would be a slight underestimation of the difference. There was a higher percentage of females in group A, which might affect the differences in CCT. However, results of populationbased studies of CCT generally show little difference between males and females (Wolfs et al. 1997), and Brandt et al. (2001) found that ocular hypertensive females tended rather to have thicker corneas than males. Central corneal thickness was almost equal in males (527 mm) and females (528 mm) in our NTG group, whereas female CCT was, in fact, greater than male CCT in our POAG group. Therefore, the high Table 3. NTG-specific vascular risk factors in patients with NTG and POAG. Vascular risk factors NTG POAG Nocturnal hypotension 2 1 Blood transfusion 0 1 Raynaud s syndrome 7* 1 Migraine 6* 0 Hypovolaemic state (history of) 0 0 * Two patients had both Raynaud s syndrome and migraine. percentage of females is unlikely to account for the low CCT in group A. Cup : disc ratios did not differ between the two groups so the differences in CCT are unlikely to be related to differences in disease severity. Normal tension glaucoma is known to be a multifactorial disease, with vascular risk factors playing an important role in the aetiology. Certain vasospastic factors such as migraine (Phelps & Corbett 1985) and Raynaud s syndrome (Broadway & Drance 1998) have been shown to be associated with NTG. Other recognized associations are nocturnal hypotension (Hayreh et al. 1994; Graham et al. 1995) and history of hypovolaemic shock or severe blood loss (Drance 1972). There is conflicting evidence as to the role of vaso-occlusive risk factors in NTG and the overlap with POAG is not clear. Hypertension has been associated with NTG by some authors (Goldberg et al. 1981; Hayreh 1999), but the Rotterdam study found an association of hypertension with POAG but not NTG (Wolfs et al. 1997). Although half the patients in the collaborative normal tension glaucoma study (CNTGS) had a history of cardiovascular disease, no definite association with NTG has been proven (Anderson et al. 2003). Furthermore, the CNTGS, patients with cardiovascular risk factors were less likely to develop progressive visual field loss in eyes not treated for IOP, and showed no significant benefit of IOP lowering in treated eyes (Drance et al. 2001; Anderson et al. 2003), but CCT was not measured. We included only vascular risk factors proven to be associated with NTG, as listed above. We were surprised to find that more patients had thin corneas in group A than in group B 69% versus 32% (p < 0.05). This finding has not previously been reported. Bearing in mind CNTGS findings that patients with vasospastic risk factors tend to be both more likely to progress if untreated and more responsive to treatments aimed at lowering the IOP, our finding of thinner corneas in such patients could explain an increased sensitivity to IOP lowering. However, the reclassification based on the aforementioned conversion factor resulted in only a small increase in mean IOP, from 17.8 mmhg to 19.8 mmhg, which certainly did not put these patients into the category of 193

Table 4. Demographic data and CCT from NTG patients with and without vascular risk factors. Group A Group B p-value Mean age (years) SD 65.6 9.8 66.8 11.5 0.77* Range 43 80 36 89 % Female (n) 76.9 (10 of 13) 59 (23 of 39) % White (n) 100 92.4 Mean CCT (mm) SD 512 31 533 31 0.034* Range CCT (mm)* 472 575 460 580 % CCT < 520 mm* 69.2 (9 of 13) 31.7 (13 of 41) p < 0.005 Mean IOP mmhg SD 18.1 2.3 17.8 2.7 Mean C/D ratio 0.73 0.74 Group A ¼ NTG patient with vascular risk factors. Group B ¼ NTG patient without vascular risk factors. CCT ¼ central corneal thickness; mm ¼ microns; SD ¼ standard deviation. * Mann Whitney test. Chi-squared test. IOP is the mean of the maximum diurnal measurements for each patient. Table 5. Maximum IOP adjusted for CCT in patients with NTG. Group CCT < 520 mm Mean IOP (mean value) Mean (max. diurnal) above-normal IOP. There appears to be a role for reduced CCT both in glaucoma progression (Brandt 2001) and severity (Herndon et al. 2004) distinct from any effect on IOP measurements. Thin corneas may be an indicator of other weakened ocular structures and hence of increased susceptibility to IOP-related damage (e.g. a weakened lamina cribrosa and an optic nerve more susceptible to IOP-related stress), but this is speculative and has never been proven. Alternatively, vasospastic disease might have a secondary effect on corneal thickness. Although our findings were significant, the numbers were small. They suggest that any future prospective study of NTG patients should include pachymetry in order to examine the apparent association of vasospastic risk factors and thin corneas shown here. In conclusion, we showed that reduced CCT in NTG was more common in a group of NTG patients with vascular risk factors specific to the disease than in those without, and suggest that the discovery of a low CCT in NTG is only one of a number of risk factors and does not obviate the need to consider the effect of other factors in the pathophysiology of the disease. Future prospective studies of NTG patients ought to include CCT measurements to determine more precisely the contribution of this parameter to the progression and the severity of the condition. References > 22 mmhg converted IOP Group A 496 14 mm (n ¼ 9) 17.8 mmhg 19.9 mmhg 1 Group B 498 17 mm (n ¼ 12) 17.5 mmhg 18.6 mmhg 1 Alsbirk PH (1978): Corneal thickness. I. Age variation, gender difference and oculometric correlations. Acta Ophthalmol Scand 56: 95 104. Anderson DR, Drance SM & Schulzer M (2003): Factors that predict the benefit of lowering intraocular pressure in normal tension glaucoma. Normal Tension Glaucoma Study Group. Am J Ophthalmol 136: 820 829. Argus WA (1995): Ocular hypertension and central corneal thickness. Ophthalmology 102: 1810 1812. Brandt JD (2001): The influence of corneal thickness on the diagnosis and management of glaucoma. J Glaucoma 10: S65 S67. Brandt JD, Beiser JA, Kass MA et al. (2001): Central corneal thickness in the ocular hypertension treatment study. Ophthalmology 108: 1779 1788. Broadway DC & Drance SM (1998): Glaucoma and vasospasm. Br J Ophthalmol 82: 862 870. n Copt RP, Thomas R & Mermoud A (1999): Corneal thickness in ocular hypertension, primary open-angle glaucoma and normal tension glaucoma. Arch Ophthalmol 117: 14 16. Doughty MJ & Zaman ML (2000): Human corneal thickness and its impact on intraocular pressure measures: a review and metaanalysis approach. Surv Ophthalmol 44: 367 408. Drance SM (1972): Some factors in the production of low tension glaucoma. Br J Ophthalmol 56: 229 242. Drance S, Anderson DR & Schulzer M (2001): Risk factors for progression of visual field abnormalities in normal tension glaucoma. Am J Ophthalmol 131: 699 708. Ehlers N, Bramsen T & Sperling S (1975): Applanation tonometry and central corneal thickness. Acta Ophthalmol Scand 53: 1974 1983. Ehlers N & Hansen FK (1974): Central corneal thickness in low tension glaucoma. Acta Ophthalmol Scand 52: 740 746. Fechtner R & Weinreb R (1994): Mechanisms of optic nerve damage in primary openangle glaucoma. Surv Ophthalmol 39: 23 42. Goldberg I, Hollows FC, Kass MA & Becker B (1981): Systemic factors in patients with low tension glaucoma. Br J Ophthalmol 65: 56 62. Goldmann H & Schmidt T (1957): Uber Applanationstonometrie Ophthalmologica. Ophthalmologica 134: 221 242. Gordon MO, Beiser JD, Brandt JD et al. (2002): The Ocular Hypertension Treatment Study: baseline factors that predict the onset of primary open-angle glaucoma. Arch Ophthalmol 120: 714 720. GrahamSL,DranceSM,WijsmanK,DouglasGR & Mikelberg FS (1995): Ambulatory blood pressure monitoring in glaucoma: the nocturnal dip. Ophthalmology 102: 61 69. Hansen FK & Ehlers N (1971): Elevated tonometer readings caused by thick corneas. Acta Ophthalmol Scand 49: 775 778. Hayreh S (1999): The role of age and cardiovascular disease in glaucomatous optic neuropathy. Surv Ophthalmol 43: S27 S42. Hayreh SS, Zimmerman XX, Podhajsky P & Alward WLM (1994): Nocturnal arterial hypotension and its role in optic nerve head and ocular ischaemic disorders. Am J Ophthalmol 117: 603 624. Herndon LW, Weizer JS & Stinnett SS (2004): Central corneal thickness as a risk factor for advanced glaucoma damage. Arch Ophthalmol 122: 17 21. La Rosa F, Gross RL & Orengo-Nania S (2001): Central corneal thickness of Caucasians and African Americans in glaucomatous and non-glaucomatous populations. Arch Ophthalmol 119: 23 27. Morad Y, Sharon E, Hefetz L & Nemet P (1998): Corneal thickness and curvature in normal tension glaucoma. Am J Ophthalmol 125: 164 168. 194

Nemesure B, Wu SY, Hennis A & Leske MC (2003): Corneal thickness and intraocular pressure in the Barbados eye studies. Arch Ophthalmol 121: 240 244. Ong K, Farinelli A, Bilson F et al. (1995): Comparative study of brain magnetic resonance imaging findings in patients with low tension glaucoma and control subjects. Ophthalmology 102: 1632 1638. Phelps CD & Corbett JJ (1985): Migraine and low tension glaucoma. A case control study. Invest Ophthalmol Vis Sci 26: 1105 1108. Shah S, (2000): Accurate intraocular pressure measurement the myth of modern ophthalmology? Ophthalmology 107: 1805 1807. Shah S, Chatterjee A, Mathai M, Kelly SP, Kwartz J, Henson D & McLeod D (1999): Relationship between corneal thickness and measured intraocular pressure in a general ophthalmology clinic. Ophthalmology 106: 2154 2160. Wolfs RCW, Klaver CCW, Vingerling JR et al. (1997): Distribution of central corneal thickness and its association with intraocular pressure. The Rotterdam Study. Am J Ophthalmol 123: 767 772. Received on September 14th, 2004. Accepted on December 22nd, 2004. Correspondence: Aoife Doyle L Institut du Glaucome Fondation Hôpital St. Joseph 185 Rue Raymond Losserand 75764 Paris Cedex 14 France Tel: þ 33144123420 Fax: þ 33144123285 Email: aoife@fusio.net 195