Int Ophthalmol DOI 10.1007/s10792-014-9899-7
ORIGINAL PAPER
Corneal biomechanical characteristics in children with diabetes mellitus Pınar Nalcacioglu-Yuksekkaya • Emine Sen • Semra Cetinkaya • Veysel Bas • Zehra Aycan Faruk Ozturk
•
Received: 27 September 2013 / Accepted: 4 January 2014 Ó Springer Science+Business Media Dordrecht 2014
Abstract To compare the corneal biomechanical properties in children with type 1 diabetes mellitus (DM) and healthy children. In this cross-sectional study, the study and control groups were composed of 68 children with DM and 74 healthy children, respectively. The corneal hysteresis (CH), corneal resistance factor (CRF), Goldmann-correlated intraocular pressure (IOPg) and corneal-compensated intraocular pressure (IOPcc) were measured with the ocular response analyzer (ORA). Associations between ocular and diabetic parameters were also evaluated. There were no statistically significant differences between the two groups in age or gender distribution. The mean CH was 10.8 ± 1.5 and 10.7 ± 1.7 mmHg while the mean CRF was 10.9 ± 1.9 and 10.5 ± 1.6 mmHg in the diabetic group and control group, respectively. The mean IOPg
P. Nalcacioglu-Yuksekkaya (&) Department of Pediatric Opthalmology, Dr Sami Ulus Children’s Health and Disease Training and Research Hospital, Babur Street No: 44, Altindag, Ankara 06080, Turkey e-mail: [email protected]; [email protected] E. Sen F. Ozturk Ulucanlar Eye Research Hospital, Ankara, Turkey S. Cetinkaya V. Bas Z. Aycan Department of Pediatric Endocrinology, Dr Sami Ulus Children’s Health and Disease Training and Research Hospital, Babur Street No: 44, Altindag, Ankara 06080, Turkey
was 15.9 ± 3.7 and 15.2 ± 3.4 mmHg, and the mean IOPcc was 15.8 ± 3.0 and 15.3 ± 3.4 mmHg in the diabetic and control group, respectively. There were no statistically significant differences between the two groups for CH, CRF, IOPg, and IOPcc measurements (independent t test, p = 0.624, p = 0.207, p = 0.263, p = 0.395, respectively). This study shows that type 1 DM does not have any effect on the corneal biomechanical parameters in childhood. Keywords Child Corneal biomechanics Type 1 diabetes mellitus Diabetic parameters
Introduction Diabetes mellitus (DM) is a common disorder which has a significant effect on the morphological, metabolic, physiological, and clinical aspects of the human cornea [1]. Corneal changes have been observed together with signs of chronic abnormal glucose metabolism in the epithelial, stromal, and endothelial layers in diabetic patients [2–6]. Previous studies reported increased corneal autofluorescence, decreased corneal sensitivity, impaired epithelial barrier function, abnormal corneal wound healing, endothelial pleomorphism and polymegathism and lower endothelial permeability [4, 7–11]. The hyperglycemia associated with DM can result in increased protein glycosylation, creating advanced glycosylation end-products (AGEs) [12]. The
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presence of AGEs in corneal tissues causes collagen cross-linking that result in increased stiffness of the cornea [13–15]. It might also lead to biomechanical changes [16, 17]. The ocular response analyzer (ORA; Reichert Inc., Depew, NY, USA) is used to measure in vivo corneal biomechanical properties, which are presented by two parameters—corneal hysteresis (CH), and the corneal resistance factor (CRF). It also provides measurements of Goldmann-correlated intraocular pressure (IOPg) and corneal compensated IOP (IOPcc) which are independent of the influence of corneal biomechanical properties. There have been several studies about corneal biomechanical properties in diabetic adults [18–21]; however, there is a little information regarding corneal biomechanics in children with DM [22]. The aim of our study was therefore to evaluate whether there was a difference between the corneal biomechanical parameters of diabetic and healthy control children by using ORA and also associating the measurements to DM-related variables including fasting blood glucose, hemoglobin A1c (HbA1c) level, and the duration of DM.
Materials and methods This study involved 68 eyes of 68 patients with type 1 DM who were referred from the Endocrinology and Metabolism Clinic to the Ophthalmology Department and 74 age- and sex-matched control children who had presented at the Ophthalmology Department for a routine ocular examination. The study group consisted of patients \18 years diagnosed with type 1 DM; the patients were evaluated prospectively and their past medical histories were also recorded. For this study, a patient was defined as diabetic if he or she had a referring physician diagnosis of diabetes and was taking insulin. This study was approved by the Ethical Committee of Ankara University School of Medicine, and written informed consent was obtained from all the parents of each participant after the nature and intent of the study had been fully explained. The study protocol was consistent with the tenets of the Declaration of Helsinki. The exclusion criteria in the study group were the presence of any type of known corneal disease, glaucoma or elevated IOP, contact lens use, chronic
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use of topical ocular medications, any type of ocular surgery, ocular trauma and aphakia. The control group consisted of healthy children who did not have a history of any systemic disease, family history of glaucoma or ocular problems other than refractive error. All of the patients in both the study and the control groups underwent detailed ophthalmologic examinations including best-corrected visual acuity with Snellen charts, cycloplegic refraction, and anterior segment and posterior segment examination using a slit-lamp and a 78 diopter (D) lens. Cycloplegic refraction measurement was performed by means of a hand-held autorefractometer (Welch Allyn Sure Sight, software version 2.16 and 2.20; Welch Allyn Medical Products, Skaneateles Falls, NY, USA) in both eyes 30 min after instillation of cyclopentolate 1 % eye drops three times with 10 min intervals. All participants underwent assessment with the ORA that included measurement of CH, CRF, IOPg and IOPcc by the same experienced physician (ES) between 09.00 and 11.00 a.m. For each patient, three readings of good quality images, defined as having a waveform with two distinct and nearly symmetrical peaks, were used. Examinations with invalid waveforms were not taken into consideration as recommended by the manufacturer. The mean values of each parameter were used for statistical evaluation. The duration of DM, current fasting blood glucose concentration and hemoglobin (HbA1C) level were also recorded in the study group. The effects of these variables on corneal biomechanics were investigated within the study group. A strong correlation was found between right and left eyes, and only right eyes were therefore included in the study. The independent t test and v2 test were used for statistical analysis and statistical significance was set at p \ 0.05. For analysis within the study group, the associations between corneal biomechanical properties and DM-related parameters were examined using Pearson’s correlation coefficient. All statistically analyses were performed using the SPSS software, version 15.
Results The mean age of the 34 (50 %) female and 34 (50 %) male patients (total 68) with DM was 12.7 ± 3.3 years (7–19.5 years) and the mean age of
Int Ophthalmol
the 48 (64.9 %) female and 26 (35.1 %) male (total 74) healthy children was 12.9 ± 2.8 years (8–20 years). There were no statistically significant differences between the two groups in age or gender distribution (p = 0.739, independent t test; p = 0.07, v2 test). Of the 68 children in the diabetic group, 42 (61.7 %) were found to have emmetropia, 14 (20.6 %) had myopia, 6 (8.8 %) had myopic astigmatism, 2 (2.9 %) had hypermetropic astigmatism, 2 (2.9 %) had myopic astigmatism, 1 (1.4 %) had hypermetropia, and 1 (1.3 %) had hypermetropia and hypermetropic astigmatism. Of the 74 patients in the control group, 56 (75.6 %) had emmetropia, 8 (10.8 %) had myopia, 5 (6.7 %) had myopia and myopic astigmatism, 3 (4.1 %) had myopic astigmatism, 1 (1.3 %) had hypermetropia, and 1 (1.3 %) had hypermetropia and hypermetropic astigmatism. The mean myopia was 0.31 D and hypermetropia was 0.08 D, the mean astigmatism was 0.95 D in the control group while the respective values were 0.19 and 0.08 and 1.15 D for the study group. Baseline characteristics for each group are presented in Table 1 and the corneal biomechanical parameters of the groups are summarized in Table 2. There were no significant differences in CH, CRF, IOPg and IOPcc values between the two groups (p = 0.624, p = 0.207, p = 0.263, p = 0.395, respectively). Diabetic retinopathy was not detected in any diabetic patient. Evaluating the effects of age, duration of DM, current fasting blood glucose, and current HbA1C Table 1 The clinical characteristics of the children with diabetes mellitus (DM) and healthy subjects
levels on corneal biomechanical parameters showed no statistically significant difference (p \ 0.05). The results are summarized in Tables 3 and 4.
Discussion The CH reflects the viscous damping of the cornea which may define the corneal response to applanation forces during ocular tonometry [23] whereas the CRF has been strongly associated with corneal stiffness [24]. Corneal changes have been observed together with signs of chronic abnormal glucose metabolism in Table 2 Corneal biomechanical parameters of the children with diabetes mellitus (DM), healthy subjects and their statistical distribution DM group
Control group
p* value
CH (mmHg)
10.8 ± 1.5
10.7 ± 1.7
0.624
(min–max)
(6.9–16.1)
(7.5–14.6)
CRF (mmHg)
10.9 ± 1.9
10.5 ± 1.6
(min–max)
(7.3–16.4)
(7.0–13.8)
IOPcc (mmHg) (min–max)
15.8 ± 3.0 (8.9–26.4)
15.3 ± 3.4 (8.1–23.7)
0.395
IOPg (mmHg)
15.9 ± 3.7
15.2 ± 3.4
0.263
(min–max)
(7.8–29.3)
(7.0–21.5)
0.207
* Independent t test CH corneal hysteresis, CRF corneal resistance factor, IOPcc corneal compensated intraocular pressure, IOPg Goldmann correlated IOP
DM group
Control group
Eyes (n)
68
74
Mean age ± SD (years)
12.7 ± 3.3
12.9 ± 2.8
(min–max)
(7–19.5 years)
(8–20 years)
Male (n/%)
34/50 %
26/35.1 %
Female (n/%)
34/50 %
48/64.9 %
p value
0.739* 0.073**
The duration of DM Mean ± SD (year) (min–max) Mean HbA1c Mean ± SD (%) 2
* Independent t test, ** v test
DM diabetes mellitus, HbA1C hemoglobin A1C, FBG fasting blood glucose
(min–max)
4.9 ± 2.8 (1–13 years) 8.3 ± 2.0 (5.4–15.4 %)
Mean FBG Mean ± SD (mg/dl) (min–max)
145.6 ± 80.4 (46–407 mg/dl)
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Int Ophthalmol Table 3 Pearson correlation coefficient showing the effects of diabetes on corneal hysteresis and corneal resistance factor
Age (years)
CH (mmHg)
CRF (mmHg)
r value
p value
r value
p value 0.216
-0.225
0.065
-0.152
Duration of DM (year)
0.076
0.538
0.057
0.643
HbA1c (%)
0.021
0.866
0.016
0.900
-0.089
0.474
-0.143
0.247
FBG (mg/dl)
CH corneal hysteresis, CRF corneal resistance factor, r regression coefficient, DM diabetes mellitus, FBG fasting blood glucose
Table 4 Pearson correlation coefficient showing the effects of diabetes on corneal-compensated intraocular pressure and Goldmann-correlated intraocular pressure IOPcc (mmHg)
IOPg (mmHg)
r value
r value
p value
p* value
Age (years)
0.170
0.166
0.041
0.738
Duration of DM (year) HbA1c (%)
0.017
0.889
0.042
0.736
FBG (mg/dl)
0.001
0.994
0.05
0.970
-0.136
0.273
-0.150
0.227
* Pearson correlation test IOPcc corneal-compensated intraocular pressure, IOPg Goldmann-correlated intraocular pressure, r regression coefficient, DM diabetes mellitus, FBG fasting blood glucose
the epithelial, stromal, and endothelial layers in diabetic patients [2–6]. Collagen has been reported to be modified by glycation in the diabetic patient’s cornea [16]. Higher concentrations of glycated endproducts in the laminin of basal membranes develop and might affect CH [17, 18]. Similar collagen crosslinking by the accumulation of non-enzymatic glycation end-products seems to occur with aging and in older corneas [25, 26]. Corneal biomechanics in diabetic adults has been investigated by other studies [18–22]. Kotecha et al. [19] showed that CRF was significantly higher in patients with diabetes than healthy controls while CH was slightly higher and not statistically significant. They concluded that CH and CRF were significantly higher in type 1 diabetic eyes than in type 2 diabetic and non-diabetic eyes. They explained the differences between type 1 and type 2 diabetic patients regarding the corneal biomechanics
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with the fact that patients with type 1 DM were younger than those with type 2 (41.9 ± 11.3 and 61.6 ± 10.6 years, respectively). Similarly, Goldich et al. [20] showed that CH and CRF were significantly higher in the DM group than the healthy group. Furthermore, Hager et al. [18] concluded that CH was significantly higher in diabetic eyes after correcting for age, IOP and central corneal thickness (CCT) values. Their study group predominantly consisted of type 2 DM patients. They also showed that CH decreased significantly with increasing age in the diabetic group as well as the non-diabetic group. In contrast to those reports, Sahin et al. [21] found significantly lower CH in diabetic patients than the healthy group. The diabetic subjects were adults in all these studies. In our study, the participants in the study group had type 1 DM, and the mean age was only 12.7 ± 3.3 years. We found no difference in corneal biomechanical parameters between the study group and the control group. The different results may be explained by the young age group in our study. To date, only one study has investigated the corneal biomechanical properties in diabetic children. They measured CH, CRF parameters in 46 diabetic children and 50 healthy subjects [22]. In concordance with our study, they suggested that that DM did not affect corneal biomechanical parameters. We found no correlation between the fasting blood glucose levels and corneal biomechanics and this finding was in agreement with Kara et al. [22]. On the other hand, Kotecha et al. [19] investigated the correlation between blood glucose level and CH and CRF. They found a weak positive correlation between CH, CRF and the blood glucose concentration. The mean duration of DM was 4.9 ± 2.8 years in our study. We found that the duration of DM was not associated with corneal biomechanics, agreeing with the findings of previous studies [19, 21, 22]. The study by Hager et al. [18] also found no correlation between these parameters despite a longer duration of disease at 12.6 ± 9.0 years. The mean HbA1c level, reflecting the blood glucose levels in the past 3 months, was 8.3 ± 2.0 % in our study. We found no correlation between the HbA1c level and corneal biomechanical parameters, as also stated by previous studies [19, 21, 22]. There was no significant difference for the mean IOPcc and IOPg values between the diabetic and
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healthy control groups in our study. Comparison between the diabetic group of this study and diabetic patients of large-population studies regarding IOP is inadequate since children (as in this study) have much lower IOP than adults (as in the population studies) [27–30]. Sahin et al. [21] also found the mean values of CCT, IOPg, IOPcc to be significantly higher in diabetic patients than healthy subject groups. The study by Goldich et al. [20] found no difference between diabetic and non-diabetic patients for CCT, IOPcc and IOPg values. We know that higher CCT may cause an overestimation of IOP measurements with certain tonometry methods. This may be the reason Sahin et al. [21] found significantly higher mean IOPg values. In contrast to previous studies in adult diabetic patients, this present study showed that there was no differences between corneal biomechanics in children with DM and healthy subjects. DM-related variables were also not associated with corneal biomechanical properties. Changes in the corneal biomechanical parameters of diabetic eyes is not clearly understood. We believe that the changes in the corneal biomechanics in DM may be dependent on age instead of diabetes-related factors. The differences in stiffness could be related to an increase in cross-linking between fibrils with aging. Further investigations are needed to understand the complex relationship between ocular biomechanics and diabetes.
References 1. Sa´nchez-Thorin JC (1998) The cornea in diabetes mellitus. Int Ophthalmol Clin 38:19–36 2. Azar DT, Spurr-Michaud SJ, Tisdale AS, Gipson IK (1989) Decreased penetration of anchoring fibrils into the diabetic stroma. A morphometric analysis. Arch Ophthalmol 107:1520–1523 3. Azar DT, Spurr-Michaud SJ, Tisdale AS, Gipson IK (1992) Altered epithelial-basement membrane interactions in diabetic corneas. Arch Ophthalmol 110:537–540 4. Siribunkum J, Kosrirukvongs P, Singalavanija A (2001) Corneal abnormalities in diabetes. J Med Assoc Thai 84:1075–1083 5. Saghizadeh M, Brown DJ, Castellon R et al (2001) Overexpression of matrix metalloproteinase-10 and matrix metalloproteinase-3 in human diabetic corneas: a possible mechanism of basement membrane and integrin alterations. Am J Pathol 158:723–734
6. Lee JS, Oum BS, Choi HY, Lee JE, Cho BM (2006) Differences in corneal thickness and corneal endothelium related to duration in diabetes. Eye (Lond) 20:315–318 7. Ozdamar Y, Cankaya B, Ozalp S, Acaroglu G, Karakaya J, Ozkan SS (2010) Is there a correlation between diabetes mellitus and central corneal thickness? J Glaucoma 19:613–616 8. Larsson LI, Bourne WM, Pach JM, Brubaker RF (1996) Structure and function of the corneal endothelium in diabetes mellitus type I and type II. Arch Ophthalmol 114:9–14 9. Weston BC, Bourne WM, Polse KA, Hodge DO (1995) Corneal hydration control in diabetes mellitus. Invest Ophthalmol Vis Sci 36:586–595 10. Ljubimov AV, Huang ZS, Huang GH et al (1998) Human corneal epithelial basement membrane and integrin alterations in diabetes and diabetic retinopathy. J Histochem Cytochem 46:1033–1041 11. Roszkowska AM, Tringali CG, Colosi P, Squeri CA, Ferreri G (1999) Corneal endothelium evaluation in type I and type II diabetes mellitus. Ophthalmologica 213:258–261 12. Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414:813–820 13. Reddy GK (2003) Glucose-mediated in vitro glycation modulates biomechanical integrity of the soft tissues but not hard tissues. J Orthop Res 21:738–743 14. Wollensak G, Spoerl E, Seiler T (2003) Stress-strain measurements of human and porcine corneas after riboflavinultraviolet-A-induced cross-linking. J Cataract Refract Surg 29:1780–1785 15. Dupps WJ Jr, Netto MV, Herekar S, Krueger RR (2007) Surface wave elastometry of the cornea in porcine and human donor eyes. J Refract Surg 23:66–75 16. Sady C, Khosrof S, Nagaraj R (1995) Advanced Maillard reaction and crosslinking of corneal collagen in diabetes. Biochem Biophys Res Commun 214:793–797 17. Kaji Y, Usui T, Oshika T et al (2000) Advanced glycation end products in diabetic corneas. Invest Ophthalmol Vis Sci 41:362–368 18. Hager A, Wegscheider K, Wiegand W (2009) Changes of extracellular matrix of the cornea in diabetes mellitus. Graefes Arch Clin Exp Ophthalmol 247:1369–1374 19. Kotecha A, Oddone F, Sinapis C et al (2010) Corneal biomechanical characteristics in patients with diabetes mellitus. J Cataract Refract Surg 36:1822–1828 20. Goldich Y, Barkana Y, Gerber Y et al (2009) Effect of diabetes mellitus on biomechanical parameters of the cornea. J Cataract Refract Surg 35:715–719 21. Sahin A, Bayer A, Ozge G, Mumcuog˘lu T (2009) Corneal biomechanical changes in diabetes mellitus and their influence on intraocular pressure measurements. Invest Ophthalmol Vis Sci 50:4597–4604 22. Kara N, Yildirim Y, Univar T, Kontbay T (2012) Corneal biomechanical properties in children with diabetes mellitus. Eur J Ophthalmol. doi:10.5301/ejo.5000196 23. Broman AT, Congdon NG, Bandeen-Roche K, Quigley HA (2007) Influence of corneal structure, corneal responsiveness, and other ocular parameters on tonometric measurement of intraocular pressure. J Glaucoma 16:581–588 24. Kotecha A (2007) What biomechanical properties of the cornea are relevant for the clinician? Surv Ophthalmol 52(Suppl 2):109–114
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Int Ophthalmol 25. Elsheikh A, Wang D, Brown M, Rama P, Campanelli M, Pye D (2007) Assessment of corneal biomechanical properties and their variation with age. Curr Eye Res 32:11–19 26. Luce DA (2005) Determining in vivo biomechanical properties of the cornea with an ocular response analyzer. J Cataract Refract Surg 31:156–162 27. Tielsch JM, Katz J, Quigley HA, Javitt JC, Sommer A (1995) Diabetes, intraocular pressure, and primary openangle glaucoma in the Baltimore Eye Survey. Ophthalmology 102:48–53 28. Klein BE, Klein R, Jensen SC (1994) Open-angle glaucoma and older-onset diabetes. The Beaver Dam Eye Study. Ophthalmology 101:1173–1177
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29. Hennis A, Wu SY, Nemesure B, Leske MC, Barbados Eye Studies Group (2003) Hypertension, diabetes, and longitudinal changes in intraocular pressure. Ophthalmology 110:908–914 30. Dielemans I, de Jong PT, Stolk R, Vingerling JR, Grobbee DE, Hofman A (1996) Primary open-angle glaucoma, intraocular pressure, and diabetes mellitus in the general elderly population. The Rotterdam Study. Ophthalmology 103:1271–1275
ORIGINAL PAPER
Corneal biomechanical characteristics in children with diabetes mellitus Pınar Nalcacioglu-Yuksekkaya • Emine Sen • Semra Cetinkaya • Veysel Bas • Zehra Aycan Faruk Ozturk
•
Received: 27 September 2013 / Accepted: 4 January 2014 Ó Springer Science+Business Media Dordrecht 2014
Abstract To compare the corneal biomechanical properties in children with type 1 diabetes mellitus (DM) and healthy children. In this cross-sectional study, the study and control groups were composed of 68 children with DM and 74 healthy children, respectively. The corneal hysteresis (CH), corneal resistance factor (CRF), Goldmann-correlated intraocular pressure (IOPg) and corneal-compensated intraocular pressure (IOPcc) were measured with the ocular response analyzer (ORA). Associations between ocular and diabetic parameters were also evaluated. There were no statistically significant differences between the two groups in age or gender distribution. The mean CH was 10.8 ± 1.5 and 10.7 ± 1.7 mmHg while the mean CRF was 10.9 ± 1.9 and 10.5 ± 1.6 mmHg in the diabetic group and control group, respectively. The mean IOPg
P. Nalcacioglu-Yuksekkaya (&) Department of Pediatric Opthalmology, Dr Sami Ulus Children’s Health and Disease Training and Research Hospital, Babur Street No: 44, Altindag, Ankara 06080, Turkey e-mail: [email protected]; [email protected] E. Sen F. Ozturk Ulucanlar Eye Research Hospital, Ankara, Turkey S. Cetinkaya V. Bas Z. Aycan Department of Pediatric Endocrinology, Dr Sami Ulus Children’s Health and Disease Training and Research Hospital, Babur Street No: 44, Altindag, Ankara 06080, Turkey
was 15.9 ± 3.7 and 15.2 ± 3.4 mmHg, and the mean IOPcc was 15.8 ± 3.0 and 15.3 ± 3.4 mmHg in the diabetic and control group, respectively. There were no statistically significant differences between the two groups for CH, CRF, IOPg, and IOPcc measurements (independent t test, p = 0.624, p = 0.207, p = 0.263, p = 0.395, respectively). This study shows that type 1 DM does not have any effect on the corneal biomechanical parameters in childhood. Keywords Child Corneal biomechanics Type 1 diabetes mellitus Diabetic parameters
Introduction Diabetes mellitus (DM) is a common disorder which has a significant effect on the morphological, metabolic, physiological, and clinical aspects of the human cornea [1]. Corneal changes have been observed together with signs of chronic abnormal glucose metabolism in the epithelial, stromal, and endothelial layers in diabetic patients [2–6]. Previous studies reported increased corneal autofluorescence, decreased corneal sensitivity, impaired epithelial barrier function, abnormal corneal wound healing, endothelial pleomorphism and polymegathism and lower endothelial permeability [4, 7–11]. The hyperglycemia associated with DM can result in increased protein glycosylation, creating advanced glycosylation end-products (AGEs) [12]. The
123
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presence of AGEs in corneal tissues causes collagen cross-linking that result in increased stiffness of the cornea [13–15]. It might also lead to biomechanical changes [16, 17]. The ocular response analyzer (ORA; Reichert Inc., Depew, NY, USA) is used to measure in vivo corneal biomechanical properties, which are presented by two parameters—corneal hysteresis (CH), and the corneal resistance factor (CRF). It also provides measurements of Goldmann-correlated intraocular pressure (IOPg) and corneal compensated IOP (IOPcc) which are independent of the influence of corneal biomechanical properties. There have been several studies about corneal biomechanical properties in diabetic adults [18–21]; however, there is a little information regarding corneal biomechanics in children with DM [22]. The aim of our study was therefore to evaluate whether there was a difference between the corneal biomechanical parameters of diabetic and healthy control children by using ORA and also associating the measurements to DM-related variables including fasting blood glucose, hemoglobin A1c (HbA1c) level, and the duration of DM.
Materials and methods This study involved 68 eyes of 68 patients with type 1 DM who were referred from the Endocrinology and Metabolism Clinic to the Ophthalmology Department and 74 age- and sex-matched control children who had presented at the Ophthalmology Department for a routine ocular examination. The study group consisted of patients \18 years diagnosed with type 1 DM; the patients were evaluated prospectively and their past medical histories were also recorded. For this study, a patient was defined as diabetic if he or she had a referring physician diagnosis of diabetes and was taking insulin. This study was approved by the Ethical Committee of Ankara University School of Medicine, and written informed consent was obtained from all the parents of each participant after the nature and intent of the study had been fully explained. The study protocol was consistent with the tenets of the Declaration of Helsinki. The exclusion criteria in the study group were the presence of any type of known corneal disease, glaucoma or elevated IOP, contact lens use, chronic
123
use of topical ocular medications, any type of ocular surgery, ocular trauma and aphakia. The control group consisted of healthy children who did not have a history of any systemic disease, family history of glaucoma or ocular problems other than refractive error. All of the patients in both the study and the control groups underwent detailed ophthalmologic examinations including best-corrected visual acuity with Snellen charts, cycloplegic refraction, and anterior segment and posterior segment examination using a slit-lamp and a 78 diopter (D) lens. Cycloplegic refraction measurement was performed by means of a hand-held autorefractometer (Welch Allyn Sure Sight, software version 2.16 and 2.20; Welch Allyn Medical Products, Skaneateles Falls, NY, USA) in both eyes 30 min after instillation of cyclopentolate 1 % eye drops three times with 10 min intervals. All participants underwent assessment with the ORA that included measurement of CH, CRF, IOPg and IOPcc by the same experienced physician (ES) between 09.00 and 11.00 a.m. For each patient, three readings of good quality images, defined as having a waveform with two distinct and nearly symmetrical peaks, were used. Examinations with invalid waveforms were not taken into consideration as recommended by the manufacturer. The mean values of each parameter were used for statistical evaluation. The duration of DM, current fasting blood glucose concentration and hemoglobin (HbA1C) level were also recorded in the study group. The effects of these variables on corneal biomechanics were investigated within the study group. A strong correlation was found between right and left eyes, and only right eyes were therefore included in the study. The independent t test and v2 test were used for statistical analysis and statistical significance was set at p \ 0.05. For analysis within the study group, the associations between corneal biomechanical properties and DM-related parameters were examined using Pearson’s correlation coefficient. All statistically analyses were performed using the SPSS software, version 15.
Results The mean age of the 34 (50 %) female and 34 (50 %) male patients (total 68) with DM was 12.7 ± 3.3 years (7–19.5 years) and the mean age of
Int Ophthalmol
the 48 (64.9 %) female and 26 (35.1 %) male (total 74) healthy children was 12.9 ± 2.8 years (8–20 years). There were no statistically significant differences between the two groups in age or gender distribution (p = 0.739, independent t test; p = 0.07, v2 test). Of the 68 children in the diabetic group, 42 (61.7 %) were found to have emmetropia, 14 (20.6 %) had myopia, 6 (8.8 %) had myopic astigmatism, 2 (2.9 %) had hypermetropic astigmatism, 2 (2.9 %) had myopic astigmatism, 1 (1.4 %) had hypermetropia, and 1 (1.3 %) had hypermetropia and hypermetropic astigmatism. Of the 74 patients in the control group, 56 (75.6 %) had emmetropia, 8 (10.8 %) had myopia, 5 (6.7 %) had myopia and myopic astigmatism, 3 (4.1 %) had myopic astigmatism, 1 (1.3 %) had hypermetropia, and 1 (1.3 %) had hypermetropia and hypermetropic astigmatism. The mean myopia was 0.31 D and hypermetropia was 0.08 D, the mean astigmatism was 0.95 D in the control group while the respective values were 0.19 and 0.08 and 1.15 D for the study group. Baseline characteristics for each group are presented in Table 1 and the corneal biomechanical parameters of the groups are summarized in Table 2. There were no significant differences in CH, CRF, IOPg and IOPcc values between the two groups (p = 0.624, p = 0.207, p = 0.263, p = 0.395, respectively). Diabetic retinopathy was not detected in any diabetic patient. Evaluating the effects of age, duration of DM, current fasting blood glucose, and current HbA1C Table 1 The clinical characteristics of the children with diabetes mellitus (DM) and healthy subjects
levels on corneal biomechanical parameters showed no statistically significant difference (p \ 0.05). The results are summarized in Tables 3 and 4.
Discussion The CH reflects the viscous damping of the cornea which may define the corneal response to applanation forces during ocular tonometry [23] whereas the CRF has been strongly associated with corneal stiffness [24]. Corneal changes have been observed together with signs of chronic abnormal glucose metabolism in Table 2 Corneal biomechanical parameters of the children with diabetes mellitus (DM), healthy subjects and their statistical distribution DM group
Control group
p* value
CH (mmHg)
10.8 ± 1.5
10.7 ± 1.7
0.624
(min–max)
(6.9–16.1)
(7.5–14.6)
CRF (mmHg)
10.9 ± 1.9
10.5 ± 1.6
(min–max)
(7.3–16.4)
(7.0–13.8)
IOPcc (mmHg) (min–max)
15.8 ± 3.0 (8.9–26.4)
15.3 ± 3.4 (8.1–23.7)
0.395
IOPg (mmHg)
15.9 ± 3.7
15.2 ± 3.4
0.263
(min–max)
(7.8–29.3)
(7.0–21.5)
0.207
* Independent t test CH corneal hysteresis, CRF corneal resistance factor, IOPcc corneal compensated intraocular pressure, IOPg Goldmann correlated IOP
DM group
Control group
Eyes (n)
68
74
Mean age ± SD (years)
12.7 ± 3.3
12.9 ± 2.8
(min–max)
(7–19.5 years)
(8–20 years)
Male (n/%)
34/50 %
26/35.1 %
Female (n/%)
34/50 %
48/64.9 %
p value
0.739* 0.073**
The duration of DM Mean ± SD (year) (min–max) Mean HbA1c Mean ± SD (%) 2
* Independent t test, ** v test
DM diabetes mellitus, HbA1C hemoglobin A1C, FBG fasting blood glucose
(min–max)
4.9 ± 2.8 (1–13 years) 8.3 ± 2.0 (5.4–15.4 %)
Mean FBG Mean ± SD (mg/dl) (min–max)
145.6 ± 80.4 (46–407 mg/dl)
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Int Ophthalmol Table 3 Pearson correlation coefficient showing the effects of diabetes on corneal hysteresis and corneal resistance factor
Age (years)
CH (mmHg)
CRF (mmHg)
r value
p value
r value
p value 0.216
-0.225
0.065
-0.152
Duration of DM (year)
0.076
0.538
0.057
0.643
HbA1c (%)
0.021
0.866
0.016
0.900
-0.089
0.474
-0.143
0.247
FBG (mg/dl)
CH corneal hysteresis, CRF corneal resistance factor, r regression coefficient, DM diabetes mellitus, FBG fasting blood glucose
Table 4 Pearson correlation coefficient showing the effects of diabetes on corneal-compensated intraocular pressure and Goldmann-correlated intraocular pressure IOPcc (mmHg)
IOPg (mmHg)
r value
r value
p value
p* value
Age (years)
0.170
0.166
0.041
0.738
Duration of DM (year) HbA1c (%)
0.017
0.889
0.042
0.736
FBG (mg/dl)
0.001
0.994
0.05
0.970
-0.136
0.273
-0.150
0.227
* Pearson correlation test IOPcc corneal-compensated intraocular pressure, IOPg Goldmann-correlated intraocular pressure, r regression coefficient, DM diabetes mellitus, FBG fasting blood glucose
the epithelial, stromal, and endothelial layers in diabetic patients [2–6]. Collagen has been reported to be modified by glycation in the diabetic patient’s cornea [16]. Higher concentrations of glycated endproducts in the laminin of basal membranes develop and might affect CH [17, 18]. Similar collagen crosslinking by the accumulation of non-enzymatic glycation end-products seems to occur with aging and in older corneas [25, 26]. Corneal biomechanics in diabetic adults has been investigated by other studies [18–22]. Kotecha et al. [19] showed that CRF was significantly higher in patients with diabetes than healthy controls while CH was slightly higher and not statistically significant. They concluded that CH and CRF were significantly higher in type 1 diabetic eyes than in type 2 diabetic and non-diabetic eyes. They explained the differences between type 1 and type 2 diabetic patients regarding the corneal biomechanics
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with the fact that patients with type 1 DM were younger than those with type 2 (41.9 ± 11.3 and 61.6 ± 10.6 years, respectively). Similarly, Goldich et al. [20] showed that CH and CRF were significantly higher in the DM group than the healthy group. Furthermore, Hager et al. [18] concluded that CH was significantly higher in diabetic eyes after correcting for age, IOP and central corneal thickness (CCT) values. Their study group predominantly consisted of type 2 DM patients. They also showed that CH decreased significantly with increasing age in the diabetic group as well as the non-diabetic group. In contrast to those reports, Sahin et al. [21] found significantly lower CH in diabetic patients than the healthy group. The diabetic subjects were adults in all these studies. In our study, the participants in the study group had type 1 DM, and the mean age was only 12.7 ± 3.3 years. We found no difference in corneal biomechanical parameters between the study group and the control group. The different results may be explained by the young age group in our study. To date, only one study has investigated the corneal biomechanical properties in diabetic children. They measured CH, CRF parameters in 46 diabetic children and 50 healthy subjects [22]. In concordance with our study, they suggested that that DM did not affect corneal biomechanical parameters. We found no correlation between the fasting blood glucose levels and corneal biomechanics and this finding was in agreement with Kara et al. [22]. On the other hand, Kotecha et al. [19] investigated the correlation between blood glucose level and CH and CRF. They found a weak positive correlation between CH, CRF and the blood glucose concentration. The mean duration of DM was 4.9 ± 2.8 years in our study. We found that the duration of DM was not associated with corneal biomechanics, agreeing with the findings of previous studies [19, 21, 22]. The study by Hager et al. [18] also found no correlation between these parameters despite a longer duration of disease at 12.6 ± 9.0 years. The mean HbA1c level, reflecting the blood glucose levels in the past 3 months, was 8.3 ± 2.0 % in our study. We found no correlation between the HbA1c level and corneal biomechanical parameters, as also stated by previous studies [19, 21, 22]. There was no significant difference for the mean IOPcc and IOPg values between the diabetic and
Int Ophthalmol
healthy control groups in our study. Comparison between the diabetic group of this study and diabetic patients of large-population studies regarding IOP is inadequate since children (as in this study) have much lower IOP than adults (as in the population studies) [27–30]. Sahin et al. [21] also found the mean values of CCT, IOPg, IOPcc to be significantly higher in diabetic patients than healthy subject groups. The study by Goldich et al. [20] found no difference between diabetic and non-diabetic patients for CCT, IOPcc and IOPg values. We know that higher CCT may cause an overestimation of IOP measurements with certain tonometry methods. This may be the reason Sahin et al. [21] found significantly higher mean IOPg values. In contrast to previous studies in adult diabetic patients, this present study showed that there was no differences between corneal biomechanics in children with DM and healthy subjects. DM-related variables were also not associated with corneal biomechanical properties. Changes in the corneal biomechanical parameters of diabetic eyes is not clearly understood. We believe that the changes in the corneal biomechanics in DM may be dependent on age instead of diabetes-related factors. The differences in stiffness could be related to an increase in cross-linking between fibrils with aging. Further investigations are needed to understand the complex relationship between ocular biomechanics and diabetes.
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