central corneal thickness and vascular risk factors in normal tension glaucoma

Central corneal thickness andvascular risk factors in normaltension glaucoma

Aoife Doyle, Ahmed Bensaid and Yves Lachkar

L’Institut du Glaucome, Fondation Hopital 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 measure-

ments 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± 31mm 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: 191–195Copyright # Acta Ophthalmol Scand 2005.

doi: 10.1111/j.1600-0420.2005.00436.x

Introduction

The influence of central corneal thick-ness (CCT) on the accuracy of intra-ocular pressure (IOP) measurementswas acknowledged in the first descrip-tion of the Goldman tonometer almost50 years ago (Goldman & Schmidt1957). The availability of optical pachy-

metry led to the discovery that erro-neous readings due to thick or thincorneas are more common than wasinitially believed to be the case (Hansen& Ehlers 1971). It has been shown thatpatients 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 normaltension glaucoma (NTG) have a lowermean CCT than the general population,on average 30mmbelow themean popula-tionlevelof550mm(Ehlers&Hansen1974;Morad et al. 1998; Copt et al. 1999).

However, not all patients with NTGhave thin corneas. The effect of specificvascular risk factors in this disease isalso well known, although such factorsare not present in all patients. Normaltension glaucoma may consist of aspectrum of diseases in which glauco-matous optic neuropathy and IOP<22mmHg are common factors. Theliterature on corneal thickness in NTGsuggests that the disease category ofNTG encompasses misdiagnosedPOAG in patients with thin central cor-neas (Morad et al. 1998; Copt et al.1999; Shah 2000; Brandt 2001). It issuggested that this might provide anexplanation for the group of NTGpatients who have no other knownrisk factors for the disease. There is noreport to date, to our knowledge, of acomparison of CCT in NTG patientswith and without vascular risk factors.

With this in mind we looked at CCTin a group of NTG patients comparedto a group of POAG controls and thenlooked for differences in CCT betweenthose of the NTG patients with andwithout vascular risk factors.

Material and Methods

We carried out a retrospective analysisof all patients attending our glaucoma

ACTA OPHTHALMOLOGICA SCANDINAVICA 2005

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service with a diagnosis of NTG, over a6-year period. The diagnosis of NTGwas based on adherence to the guide-lines of the European GlaucomaSociety, which include peak IOP<22mmHg (with no treatment), opticnerve head damage typical of glaucomawith cup : disc ratio >0.6 and corres-ponding glaucomatous visual fielddefects, open-angle on indentationgonioscopy and no history or signs ofother eye disease or steroid use. DiurnalIOP measurements using the Goldmantonometer were taken in all patients.Intraocular pressure without treatmentwas measured at 06.00, 09.00, 12.00,15.00, 18.00, 21.00 and 00.00 hours.The IOP recorded for analysis was themaximum diurnal IOP measurement.Indentation gonioscopy and disc evalu-ation under mydriasis were documen-ted in all patients. Central cornealthickness was measured at the slit-lamp to ensure centration, using anultrasound pachymeter. An average ofthree readings was recorded. All visualfields were performed using automatedperimetry (Humphrey or Octopus). Aglaucomatous field defect was definedas a cluster of at least three adjacenttest points �5 dB lower than in age-matched controls, one of which was>10 dB lower, in a distribution charac-teristic of glaucoma. The presence orabsence of vascular risk factors wasdetermined using a standardized ques-tionnaire in all patients. This question-naire appears on the chart of eachglaucoma patient attending our unitand is completed at the first consulta-tion. Information was gathered fromthe patient, the referring doctor’s letter,and the results of investigations (Caro-tid Doppler/24-hour blood pressuremonitoring) either provided by thepatients or carried out at our request.To satisfy a diagnosis of migraine,patients had to have headaches asso-ciated with one or more of the follow-ing: visual effects, photophobia, nauseaor positive response to antimigrainoustherapy. The diagnosis of Raynaud’ssyndrome was made on a history ofcold extremities associated with blanch-ing of the digits in response to condi-tions other than extreme cold.Magnetic resonance imaging (MRI)was carried out if deemed necessary torule out any compressive lesion as acause of the optic neuropathy. Vascularrisk factors were defined based on areview of the literature. Only factors

considered to have a definite associ-ation with NTG were included forthe basis of categorization, such asmigraine (Phelps & Corbett 1985),Raynaud’s syndrome (Broadway &Drance 1998), nocturnal hypotension(Hayreh et al. 1994; Graham et al.1995), history of hypovolaemic shockor severe blood loss (Drance 1972).Carotid stenosis was included only ifvisual field loss was asymmetrical andassociated with >50% occlusion of thelumen of the common carotid artery.

The control group was randomlyselected from patients with a diagnosisof POAG attending the clinic over thesame time period and was matched forage and race. The diagnosis of POAGwas based on the presence of IOP>22mmHg at the time of diagnosis,open-angle on indentation gonioscopyand glaucomatous damage to the opticnerve with corresponding visual fieldloss as described above. Patients witha history of previous cataract or filtra-tion surgery were excluded in bothgroups due to the possible influence ofintraocular surgery on corneal thick-ness, as were patients with any historyof corneal disease. The presence orabsence of vascular risk factors wasrecorded as for NTG patients.

Patients with NTG were divided intotwo groups for the purpose of statisticalanalysis: one group with vascular riskfactors and one group without. Eitherthe right or left eye was randomlyselected for analysis on each patient.Mean CCTs between and within groupswere compared. The difference betweenCCTs in POAG and NTG was com-pared using Student’s t-test, having veri-fied the normal distribution and similarstandard deviations of the two groups.A 95% confidence interval for the dif-ference between the two means was cal-culated. The difference between NTGpatients with and without vascularrisk factors was analysed using the

Mann–Whitney test and 95% CIs cal-culated for the difference between themeans. Further analysis was carried outby looking at the percentages ofpatients with thin and normal CCTswho also had vascular risk factors andanalysed using a chi-squared frequencytable for the comparison of two pro-portions. All cells in the 2� 2 tablehad a value of 5 or more for expectedfrequency. Finally, maximum diurnalIOP measurements for patients withCCT <520mm were recalculated usingthe correction factor derived from ametanalysis of human CCT (Doughty& Zaman 2000) of 0.5mmHg per 10 mmCCT, in order to determine what per-centage of patients could be reclassifiedas having POAG using these criteria.

Results

Data from 108 eyes of 108 patients (54eyes with POAG and 54 eyes withNTG) were analysed. Normal tensionglaucoma patients were matched interms of age and race, but there was ahigher percentage of females in theNTG group (Tables 1 and 2). Patientswith NTG had a mean CCT of 528mm,significantly lower than the 549mm ofPOAG patients (p¼ 0.001), with a 95%CI for the difference in means of8.4–23.6 mm. The NTG patients weredivided into two groups depending onthe presence or absence of NTG-speci-fic vascular risk factors. Group A hadassociated risk factors for NTG(n¼ 13) and group B did not (n¼ 41).Only two patients had more than onevasospastic risk factor – Raynaud’ssyndrome and migraine (Table 3). Mag-netic resonance imaging (25 patients)was normal in all cases. Corneal thick-ness was significantly lower in group A(512 mm) than in group B (533mm)(p¼ 0.034, Mann–Whitney test; 95% CIfor the difference in means: 1.7–30.3mm).

Table 1. Demographic data of patients according to disease category.

Number Mean age

� SD (years)

Range 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

CCT¼ central corneal thickness; SD¼ standard deviation; POAG¼primary open-angle glauc-

oma; NTG¼normal tension glaucoma; F¼ female.


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A total of 69.2% in group A had CCT<520mm versus only 31.7% in group B(p< 0.05, chi-squared test). The cup : discratio was similar in groups A and Band there was no difference in meanIOP (Table 4).

We reclassified the maximum IOPsbased on a conversion factor of2.5mmHg per 50mm. Only one patientin each of groups A and B would bereclassified on this basis – one to anIOP of 22.75mmHg and the other toan IOP of 23mmHg (Table 5).

Discussion

Central corneal thickness is known to bethinner on average in patients with NTGthan in those with POAG.Many authorshave suggested that some NTG patientsmay, in fact, have POAG, and that theymay be misclassified due to inaccuraciesin Goldman tonometry (Shah 2000;Brandt 2001). A number of studies haveclaimed that a significant percentage (upto 44%) of their NTG patients wouldbe reclassified as having POAG afterthe application of conversion factorssuch as that based on manometric stud-ies by Ehlers et al. (1975); these includeCopt et al. (1999) with 16 NTGpatients, Morad et al. (1998) with 21patients and Shah et al. (1999) with 52eyes. Our findings confirmed a lowCCT of 528mm in our NTG population(54 patients), compared to a mean of549mm in POAG patients. However, aCCT of 528 mm is unlikely to lead to

significant inaccuracies in Goldmantonometry. Furthermore, we appliedthe conversion factor suggested byDoughty & Zaman (2000) and foundthat only two of our NTG patients(with CCTs of 460mm and 505 mm,respectively) would be reclassified andeven these two patients would not haveIOP >24mmHg (Table 5).

We looked at other factors thatmight explain the difference in meanCCT between the two groups. Centralcorneal thickness can be affected byage, sex and race (Alsbirk 1978).There was no significant difference inage between the two groups (p¼ 0.77).Group B included four patients of Afri-can origin, which can be associatedwith thinner corneas (La Rosa et al.2001; Nemesure et al. 2003). However,only one of these patients had a thincornea (499 mm) and as group B hadthe greater mean CCT, the only likelyeffect would be a slight underestima-tion of the difference. There was ahigher percentage of females in groupA, which might affect the differences inCCT. However, results of population-based studies of CCT generally showlittle difference between males andfemales (Wolfs et al. 1997), and Brandtet al. (2001) found that ocular hyper-tensive females tended rather to havethicker corneas than males. Centralcorneal thickness was almost equal inmales (527 mm) and females (528mm) inour NTG group, whereas female CCTwas, in fact, greater than male CCT inour POAG group. Therefore, the high

percentage of females is unlikely toaccount for the low CCT in group A.Cup : disc ratios did not differ betweenthe two groups so the differences inCCT are unlikely to be related to dif-ferences in disease severity.

Normal tension glaucoma is knownto be a multifactorial disease, withvascular risk factors playing animportant role in the aetiology. Certainvasospastic factors such as migraine(Phelps & Corbett 1985) and Ray-naud’s syndrome (Broadway & Drance1998) have been shown to be associatedwith NTG. Other recognized associa-tions are nocturnal hypotension(Hayreh et al. 1994; Graham et al.1995) and history of hypovolaemicshock or severe blood loss (Drance1972). There is conflicting evidence asto the role of vaso-occlusive risk factorsin NTG and the overlap with POAG isnot clear. Hypertension has been asso-ciated with NTG by some authors(Goldberg et al. 1981; Hayreh 1999),but the Rotterdam study found anassociation of hypertension with POAGbut not NTG (Wolfs et al. 1997).Although half the patients in thecollaborative normal tension glaucomastudy (CNTGS) had a history ofcardiovascular disease, no definite asso-ciation with NTG has been proven(Anderson et al. 2003). Furthermore,the CNTGS, patients with cardio-vascular risk factors were less likely todevelop progressive visual field loss ineyes not treated for IOP, and showedno significant benefit of IOP loweringin treated eyes (Drance et al. 2001;Anderson et al. 2003), but CCT wasnot measured. We included only vascu-lar risk factors proven to be associatedwith NTG, as listed above. We weresurprised to find that more patientshad thin corneas in group A than ingroup B – 69% versus 32% (p< 0.05).This finding has not previously beenreported. Bearing in mind CNTGSfindings that patients with vasospasticrisk factors tend to be both more likelyto progress if untreated and moreresponsive to treatments aimed atlowering the IOP, our finding of thinnercorneas in such patients could explainan increased sensitivity to IOP lowering.However, the reclassification based onthe aforementioned conversion factorresulted in only a small increase inmean IOP, from 17.8mmHg to19.8mmHg, which certainly did not putthese patients into the category of

Table 2. Differences in CCT in men and women with POAG and NTG.

Mean age

� SD (years)

Mean CCT

� SD (mm)

POAG male (n¼ 29) 64.4� 10.8 540� 30

POAG female (n¼ 25) 67.2� 8.4 558� 35 (p¼ 0.05)

NTG male (n¼ 18) 65.6� 10 527� 41

NTG female (n¼ 35) 68.2� 11.6 528� 26

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.


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above-normal IOP. There appears to bea role for reduced CCT both in glau-coma progression (Brandt 2001) andseverity (Herndon et al. 2004) distinctfrom any effect on IOP measurements.Thin corneas may be an indicator ofother weakened ocular structures andhence of increased susceptibility toIOP-related damage (e.g. a weakenedlamina cribrosa and an optic nervemore susceptible to IOP-related stress),but this is speculative and has never beenproven. Alternatively, vasospastic dis-ease might have a secondary effect oncorneal thickness. Although our findingswere significant, the numbers weresmall. They suggest that any future pro-spective study of NTG patients shouldinclude pachymetry in order to examinethe apparent association of vasospasticrisk factors and thin corneas shown here.

In conclusion, we showed thatreduced CCT in NTG was more com-mon in a group of NTG patients withvascular risk factors specific to thedisease than in those without, andsuggest that the discovery of a lowCCT in NTG is only one of anumber of risk factors and does notobviate the need to consider theeffect of other factors in the patho-

physiology of the disease. Futureprospective studies of NTG patientsought to include CCT measurementsto determine more precisely thecontribution of this parameter to theprogression and the severity of thecondition.

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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< 520mm* 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 A¼NTG patient with vascular risk factors.

Group B¼NTG patient without vascular risk factors.

CCT¼ central corneal thickness; mm¼microns; SD¼ 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< 520mm Mean IOP

(mean value)

Mean

(max. diurnal)

> 22mmHg

converted IOP

n

Group A 496� 14 mm (n¼ 9) 17.8mmHg 19.9mmHg 1

Group B 498� 17 mm (n¼ 12) 17.5mmHg 18.6mmHg 1


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Received on September 14th, 2004.

Accepted on December 22nd, 2004.

Correspondence:

Aoife Doyle

L’Institut du Glaucome

Fondation Hopital St. Joseph

185 Rue Raymond Losserand

75764 Paris Cedex 14

France

Tel:þ 33 1 44 12 34 20

Fax:þ 33 1 44 12 32 85

Email: [email protected]


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central corneal thickness and vascular risk factors in normal tension glaucoma

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