Graefes Arch Clin Exp Ophthalmol DOI 10.1007/s00417-014-2653-z
GLAUCOMA
Corneal biomechanical properties measured by the ocular response analyzer in acromegalic patients Emine Sen & Yasemin Tutuncu & Melike Balikoglu-Yilmaz & Ufuk Elgin & Dilek Berker & Faruk Ozturk & Serdar Guler
Received: 26 January 2014 / Revised: 15 April 2014 / Accepted: 19 April 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose To investigate the effect of acromegaly on corneal biomechanical parameters. Methods This cross-sectional, comparative clinical study included 34 acromegalic patients and 30 age-matched and sexmatched healthy controls. Corneal hysteresis (CH), corneal resistance factor (CRF), Goldmann-correlated and cornealcompensated intraocular pressure (IOPg and IOPcc, respectively) were measured using the Ocular Response Analyzer. Central corneal thickness (CCT) was determined with the ultrasonic pachymeter. Results The mean duration of disease for the acromegalic patients was 5.3 years. There was no significant difference between the groups regarding mean CH, CRF, IOPg and IOPcc values. The respective mean values in patients with acromegaly and controls were 10.3±2.2 and 9.5±1.5 mmHg (p=0.13) for CH; 10.5±2.4 and 9.7±1.7 mmHg (p=0.16) for CRF, 16.1±3.6 and 15.5±2.9 mmHg (p=0.49) for IOPg, 16.8 ±3.4 and 17.0±2.8 mmHg (p=0.82) for IOPcc, and 544.8± 32.2 and 530.7±22.9 μm (p=0.05) for CCT. A significant moderate correlation was detected between the duration of acromegaly and IOPg OD (r=0.430, p=0.01). There was no significant correlation between other ocular parameters and levels of GH and IGF-1 at the time of diagnosis, the status of
E. Sen (*) : U. Elgin : F. Ozturk Ulucanlar Eye Education and Research Hospital, Altındag, Ankara, Turkey e-mail: [email protected] Y. Tutuncu : D. Berker : S. Guler Endocrinology and Metabolism Clinic, Numune Education and Research Hospital, Ankara, Turkey M. Balikoglu-Yilmaz Department of Ophthalmology, Dr. Behçet Uz Children’s Disease and Surgery Education and Research Hospital, Izmir, Turkey
control, adenoma type, radiotherapy treatment, and drug usage. Conclusions In acromegalic patients, the duration of disease was correlated with IOPg OD level. Corneal biomechanical parameters and CCT values were not significantly different than those in age-matched and sex-matched healthy individuals. Keywords Acromegaly . Corneal biomechanics . Corneal hysteresis . Corneal resistance factor . Intraocular pressure . Ocular response analyzer
Introduction Acromegaly is a rare disease caused by excessive growth hormone (GH) secretion from a pituitary GH-secreting adenoma. The prevalence and an annual incidence of acromegaly are estimated as 40 to 70 per million and three to four new cases per million, respectively [1]. High levels of GH and insulin-like growth factor-1 (IGF-1) are responsible for the disease’s signs and symptoms, including cardiovascular system and pulmonary system manifestations, metabolic disorders, acral and soft tissue overgrowth, tooth decay, prognathism and joint damage [2]. Possible ocular findings in these patients are bitemporal hemianopia and visual loss due to a mass effect of the pituitary adenoma. Mass effect-independent signs such as diabetic retinopathy, increased intraocular pressure (IOP) and central corneal thickness (CCT) have also been observed [3, 4]. Biomechanical properties of the cornea might be changed by ocular pathologies and systemic diseases and thus affect many ocular measurements, possibly altering the diagnosis and treatment. The ocular response analyzer (ORA; Reichert Ophthalmic Instruments, Depew, NY, USA) is a new device to measure the corneal viscoelastic and resistance properties
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in vivo and IOP, free from the effect of corneal biomechanical factors [5]. The ORA is a revised version of non-contact tonometry and fires a metered air pulse at the cornea. The machine reflects the corneal response to the air pressure as two measurements. These measurements are recorded by the electro-optical infrared detector system. Energy absorption takes place during inward and outward applanation events, leading to two different applanation pressure values. The first, inward applanation pressure (P1), occurs when the released air pressure increases. The second, outward applanation pressure (P2), occurs when the air pressure drops. The second outward applanation pressure is always lower than the first inward applanation pressure. Four different parameters are available according to the applanation pressure results. The first parameter, corneal hysteresis (CH), is the difference between P1 and P2 and the response of the corneal tissue to dynamic deformation, and is a good indicator of the viscoelastic properties of the cornea [6]. Another parameter, the corneal resistance factor (CRF), is the sum of P1 and P2 and reflects the elastic properties of the cornea better. It refers to the overall “resistance” of the cornea [7]. Corneal compensated IOP (IOPcc) is the sum of P1 and P2 and an IOP estimation that uses a mathematical correction to minimize its corneal dependence. The Goldmanncorrelated IOP (IOPg) is the average value of P1 and P2 and analogous to standard noncontact tonometry IOP measurement [8]. Our hypothesis was that there could be some changes in corneal biomechanics in acromegaly patients. The purpose of this study was to evaluate corneal biomechanical parameters measured by ORA in patients with acromegaly and compare them with normal individuals.
Patients who had refractive errors (>3D spheric and/ or >1D cylindric), systemic or ocular disease (including a history of ocular trauma or surgery), used contact lenses or systemic/ophthalmic drugs, and women who were pregnant, planning pregnancy, or lactating were excluded from the study. Examination protocol and measurements A detailed ophthalmologic examination was performed by a single specialist (E.S.) who was masked to the group assignments. Visual acuity was assessed with a Snellen chart and examination of the anterior and posterior segment was performed with the slit-lamp. Corneal biomechanical parameters, including CH, CRF, IOPg and IOPcc, were measured using the ORA (Reichert Ophthalmic Instruments, Depew, NY, USA). CCT was determined with the ORA-attached handheld ultrasonic pachymeter after instillation of topical proparacaine HCl 0.5 % (Alcaine; Alcon Laboratories, UK). The patients were seated next to the ORA tool and asked to fixate on the target in the instrument (red blinking light). After the area of the central cornea was scanned with a non-contact probe, air pressure was released from the machine to the corneal surface. The corneal response to this pressure was measured by the machine and the CH, CRF, IOPg and IOPcc values were displayed on the computer screen attached to the ORA. Three measurements were taken for each eye and the mean values were used for statistical analysis. Unreliable atypical signals were ignored. Laboratory analyses
Materials and methods Study population and design The study protocol adhered to the tenets of the Declaration of Helsinki and was approved by the Institutional Review Board of Ankara University, School of Medicine (14 March 2011, No. 26–533). This prospective, cross-sectional, comparative study included 34 acromegalic patients (controlled n=26, uncontrolled n=8) referred from Ankara Numune Education and Research Hospital’s Department of Endocrinology and Metabolism, and 30 healthy age-matched and gender-matched individuals who presented at the Ulucanlar Eye Education and Research Hospital for a routine eye examination. Informed consent was obtained from all patients. The GH level less than1 ng/mL on the OGTT-GH suppression test and the IGF-1 level within the normal range for age and gender were accepted as control criteria.
Serum GH levels were measured using commercially available immunoradiometric assay (IRMA) kits (hGH - IRMA CT; RADIM, Rome, Italy). Assay sensitivity was 0.04 ng/mL. The calibrator had been calibrated against the WHO 80/505 International Standard preparation (1 ng hGH=2 μIU). The GH reference ranges were 0–16 ng/mL and 0–8 ng/mL for women and men, respectively. Serum IGF-1 was measured with the IMMULITE 1000 System using a solid-phase, enzyme-labeled chemiluminescent immunometric assay (Immulite IGF-I, Siemens Medical Solutions Diagnostics, UK). Our IGF-I reference ranges for the 21–25, 26–30, 31– 35, 36–50, 51–60, 61–70, and over 70 years age groups are 116–358, 117–329,115–307, 94–284, 81–238, 69–212, and 55–188 ng/mL, respectively. The assay analytical sensitivity was 20 ng/mL. Calibration was up to 1,600 ng/mL (WHO NIBSC 1st IRR 87/518). For the standard curve low, medium and high points, the within-run coefficients of variation were 3.1, 4.3 and 3.5 % and the total coefficients of variation were 6.1, 6.9, and 5.8 %, respectively.
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Statistical analysis
Corneal biomechanical parameters
The sample size was calculated as 33 for each group, with a power of 80 % and a p value of 0.05, d (effect size) 0.70. Statistical analysis was performed by using the IBM SPSS 20.0 software (SPSS Inc, Chicago, IL, USA). For the purposes of this analysis, qualitative variables were categorized, while quantitative data were presented as mean ± standard deviation. The t-test and chi-square test were used in the analysis of the differences regarding corneal parameters and demographic characteristics between the acromegaly and control groups. For the continuous variables, the data were tested for normality by using the Kolmogorov-Smirnov test, histograms and p-p plots for both groups. As the status of adenoma, radiotherapy, and drug usage in the patient group were not consistent with normal distribution, Spearman rank correlation was used to determine the correlation between these variables and corneal biomechanical properties. Pearson’s correlation coefficient was used for correlation of associations between normally distributed variables. P≤0.05 was considered statistically significant.
The corneal biomechanical parameters in the acromegaly and control groups are summarized in Table 2. There was no statistically significant difference between the groups regarding the mean values of CH, CRF, IOPg, IOPcc, and CCT (p>0.05). Correlation of duration of disease, serum GH and IGF-1 levels, the status of adenoma, previous treatments including radiotherapy or medical agents with ocular parameters of acromegalic patients A significant moderate correlation was found between the duration of acromegaly and IOPg OD (Pearson correlation test; r=0.430, p=0.01) (Fig. 1). The radiotherapy treatment also correlated with CH OD, with a Spearman’s correlation of 0.340 (p=0.049). On the other hand, no correlation was found between levels of GH and IGF-1 at the time of diagnosis, the status of control, adenoma type, radiotherapy treatment, and drug usage with any other ocular parameters (Spearman and Pearson correlation tests, p>0.05).
Discussion
Results Demographic characteristics The mean age of the 22 (64.7 %) female and 12 (35.3 %) male acromegalic patients was 44.4± 11.4 years and the mean age of the 17 (56.7 %) female and 13 (43.3 %) male control group subjects was 42.5±12.5 years. There was no statistically significant difference between the acromegaly and control groups in terms of age or gender (p > 0.05, Table 1).
Acromegaly is a chronic endocrine disorder causing disproportionate skeletal, tissue, and organ growth and is associated with significant morbidity and mortality. As reported in previous studies, ocular tissues seem to be a target organ in patients with acromegaly [9–11]. Growth factors including GH and IGF-1 might play a role in regulating ocular tissue growth and differentiation by affecting the synthesis of the scleral extracellular matrix [12]. Intraocular pressure was first stated to be higher in acromegaly patients in 1955 [13]. In 1961, Kraus reported a case of acromegaly and glaucoma where the IOP returned to normal after resection of the tumor [14]. Growth effects of GH in other ocular tissues might also
Table 1 Demographic characteristic of the subjects Acromegaly (n: 34)
Controls (n: 30)
P value
Age (years) Male, n (%) Female, n (%)
44.4±11.4 12 (35.3) 22 (64.7)
42.5±12.5 13 (43.3) 17 (56.7)
0.53† 0.51‡
Acromegaly duration (years) Control status* (controlled vs. uncontrolled), n (%) Adenoma type (macro. vs. micro.), n (%) History of radiotherapy administration, n (%) Drug usage (octreotide vs. lantreotide vs. unmedicated), n (%)
5.3±2.8 26 (76.5) vs. 8 (23.5) 31 (91.2) vs. 3 (8.8) 9 (26.5) 14 (41.2) vs. 11 (32.4) vs. 9 (26.5)
– – – – –
– – – – –
Values are indicated as mean ± SD or number (percentage) *Control status means control of growth hormone and insulin-like growth factor-1 after treatment †
t-test, ‡ chi-square test
Graefes Arch Clin Exp Ophthalmol Table 2 Ocular response analyzer measurements of acromegaly patients and controls Variable
Acromegaly (n: 34)
Controls (n: 30)
P value
CH OD, mmHg CH OS, mmHg CRF OD, mmHg CRF OS, mmHg
10.3±2.2 10.1±2.0 10.5±2.4 10.2±2.3
9.5±1.5 10.3±1.5 9.7±1.7 10.4±1.6
0.13† 0.75† 0.16† 0.68†
IOPg OD, mmHg IOPg OS, mmHg IOPcc OD, mmHg IOPcc OS, mmHg CCT OD, μm CCT OS, μm
16.1±3.6 15.4±3.3 16.8±3.4 16.3±2.8 544.8±32.2 541.1±32.9
15.5±2.9 15.3±3.1 17.0±2.8 15.8±2.7 530.7±22.9 525.4±21.3
0.49† 0.82† 0.82† 0.48† 0.052† 0.09†
CH: Corneal hysteresis, CRF: corneal resistance factor, IOPg: Goldmanncorrelated intraocular pressure, IOPcc: corneal-compensated intraocular pressure, CCT: central corneal thickness Values are indicated as mean ± SD †
t-test
be seen in the cornea, and CCT values have been found to be higher in patients with acromegaly [9, 10]. However, Ciresi et al. and Bramsen et al. detected similar IOP levels in the acromegaly and control groups when IOP was corrected for the CCT difference [9, 10]. It is well known that IOP measurements are corrected for CCT according to Doughty’s meta-analysis [15]. The importance of corneal biomechanics and accurate IOP measurements in various systemic and ocular pathologies has been recognized. Corneal pathologies altering the viscoelastic structure of the cornea might prevent us Fig. 1 A significant moderate correlation between time (the duration of disease, years) and Goldmann-correlated intraocular pressure OD (IOPg OD, mmHg) (Pearson correlation test; r= 0.430, p=0.01) in acromegalic patients
from identifying the correct IOP. Therefore, we evaluated corrected IOP and corneal biomechanical parameters measured by ORA that was not affected by CCT [6, 16] in our acromegalic patients. Corneal biomechanical properties include corneal viscosity, elasticity, and hydration, and connective tissue composition [17]. Congdon et al. was the first to report a relationship between CH and glaucomatous damage [18]. Corneal hysteresis has been used in the classification of corneal diseases and refractive surgery and the diagnosis of glaucoma, especially for determining glaucoma treatment [19]. Reduced CH and increased CRF have been shown to be strongly associated with glaucoma [5, 20, 21]. De Moraes et al. [21] also reported a relationship between low CH and rapid progression of glaucomatous visual field defects. CH is unaffected by age [22] and is independent of intraocular pressure [23]. CH and CRF were also demonstrated to be lower than those of normal subjects in keratoconus, post-LASIK and pseudophakic eyes, Fuchs’ corneal dystrophy, primary open angle glaucoma (POAG) and normal-tension glaucoma (NTG) [24–26]. The CH value was variable and ranged from 1.8 to 14.6 mmHg [19]. In a study on 498 eyes of 258 patients, Touboul et al. compared normal eyes with eyes suffering from glaucoma, keratoconus, and post-LASIK and photorefractive keratectomy surgery, and found the lowest CH values in keratoconus (8.3 mmHg) and the post-LASIK group (8.9 mmHg) [23]. In a study on 48 eyes, the mean CH value was reported as 8.8 mmHg in patients with glaucoma [27], while it was detected as 10.2 mmHg in another study [28]. Kirwan et al. reported lower CH values in eyes with congenital glaucoma compared to normal eyes (6.3 mmHg vs. 12.5 mmHg). CH
Graefes Arch Clin Exp Ophthalmol
values were lowest in buphthalmic eyes, especially when associated with Haab striae [22]. Shah et al. compared CH and CRF values in NTG, POAG, and ocular hypertension (OHT) patients. Eyes suffering from OHT had the highest CH and CRF values. The mean CH was 9, 9.9 and 10.2 mmHg and the mean CRF was 9.1, 10.6 and 12 mmHg, respectively, in eyes suffering from NTG, POAG, and OHT [29]. Shah et al. [30] reviewed the records of 207 eyes of 105 volunteers. They found CRF values ranging from 5.7 to 17.1 mmHg (mean 10.3 mmHg). Oncel et al. [31] evaluated diurnal variation of corneal biomechanics of 62 healthy volunteers and they reported that measurements of CH, CRF, IOPg, IOPcc, and CCT at 8:00 AM, 11:00 AM, 2:00 PM and 5:00 PM did not show remarkable alteration. Ozkok et al. evaluated corneal biomechanical properties of 24 controlled and 22 uncontrolled acromegaly patients [32]. They reported significantly higher CH and CRF values in acromegalic patients (12.1 and 12.3 mmHg, respectively) as compared to healthy individuals (11.0 and 10.8 mmHg, respectively) [32]. In our study, the CH and CRF values were higher in the acromegaly group than the control group (10.3 vs. 9.5 mmHg and 10.5 vs. 9.7 mmHg, respectively). However, the difference in CH and CRF values between the groups was not statistically significant. Lower CH and CRF values in our study than those in the study by Ozkok et al. might be due to greater number of uncontrolled acromegalic patients in the previous study [32]. Corneal-compensated IOP has been proposed as the most accurate IOP measurement [33]. Hager et al. found the mean value for IOPcc to be 17.9 mmHg in glaucomatous eyes [28]. Shah et al. reported IOP by ORA to be 16.9, 20.5 and 20.0 mmHg in patients with NTG, POAG, and OHT, respectively, in another study [29]. There are three studies on IOP in acromegaly patients in the literature, and the IOP measurements in these studies were measured by Goldmann applanation tonometry [9–11]. Bramsen et al. [9] stated that the CCT and IOP were higher in patients with pituitary adenomas plus acromegaly than in controls with only pituitary adenomas (561 vs. 526 μm and 16.9 mmHg vs. 14.7 mmHg). Similarly, Ciresi et al. [10] detected greater CCT values in acromegalic patients when compared to healthy controls (567 vs. 528.5 μm), without concomitant differences in corrected IOP (17.3 vs. 17 mmHg). Polat et al. showed similar mean CCT levels in acromegaly patients and controls (529 vs. 537 μm) and higher mean IOP in acromegaly patients (16 vs. 13 mmHg) [11]. Ozkok et al. [32] reported higher IOPg and similar IOPcc and CCT levels (17.1 mmHg, 15.5 mmHg, and 545.4 μm, respectively) in acromegalic patients than those of controls (15.1 and 15.1 mmHg, 555.1 μm, respectively). Although there was no significant difference in CCT and IOP values in the groups of our study, CCT was observed to be higher in acromegaly patients than in healthy controls (545 vs. 531 μm). Additionally, mean IOPg and IOPcc
measured by ORA were 16.1 and 16.8 mmHg, respectively, in patients with acromegaly. A positive correlation between IGF-1 level and CCT in uncontrolled acromegalic patients was emphasized by Ozkok et al. [32]. However, they did not find any correlation in all or controlled acromegalic patients. They thought that this finding might indirectly demonstrate corneal thickness that was under the effect of prolonged IGF-1 excess, although they detected similar CCT values in acromegalic patients and healthy individuals [32]. Unlike the study by Ozkok et al. [32], the correlation of CCT with acromegaly duration and IGF-1 level was not detected in our study. There was a significant correlation between acromegaly duration and IOPg and also between history of radiotherapy administration and CH in our acromegalic patients. The current study evaluated corneal biomechanical changes in acromegaly patients and the effect of duration of disease, serum GH and IGF-1 levels, the status of adenoma, and previous treatments such as radiotherapy or medical agents on corneal biomechanical changes in these patients. There are some potential limitations in the present study. Firstly, variables including concurrent systemic diseases could not be normalized between the groups. Secondly, there were fewer uncontrolled than controlled acromegalic patients. Finally, measurements of GH or IGF-1 levels in subretinal fluid and aqueous humor to assess their correlation with intraocular pressure measured by ORA, corneal hysteresis and elasticity values could not be performed, as these are interventional procedures. Taking these measurements during routine ophthalmic surgery may shed light on future studies. In conclusion, the present study demonstrated that Goldmann-correlated and corneal-compensated IOPs, corneal elasticity and viscosity measured by ORA and the CCT values of patients with acromegaly are similar to those of healthy subjects. The duration of acromegaly also correlated with the presence of abnormal IOPg OD finding. Ocular characteristics of acromegaly should be well known so that a potential complication is not missed. Acromegaly effects on corneal biomechanical parameters might continue over time, and longitudinal studies are therefore warranted in acromegalic patients.
Conflicts of interest The authors declare that the manuscript has not been published previously, and they have no conflict of interest. No financial support was received for this project.
References 1. Chanson P, Salenave S (2008) Acromegaly. Orphanet J Rare Dis 3: 17. doi:10.1186/1750-1172-3-17
Graefes Arch Clin Exp Ophthalmol 2. Chanson P, Salenave S, Kamenicky P, Cazabat L, Young J (2009) Pituitary tumours: acromegaly. Best Pract Res Clin Endocrinol Metab 23:555–574. doi:10.1016/j.beem.2009.05.010 3. Melmed S, Colao A, Barkan A et al (2009) Guidelines for acromegaly management: an update. J Clin Endocrinol Metab 94:1509–1517. doi:10.1210/jc.2008-2421 4. Sönksen PH, Russell-Jones D, Jones RH (1993) Growth hormone and diabetes mellitus. A review of 63 years of medical research and a glimpse into the future? Horm Res 40:68–79 5. ElMallah MK, Asrani SG (2008) New ways to measure intraocular pressure. Curr Opin Ophthalmol 19:122–126. doi:10. 1097/ICU.0b013e3282f391ae 6. Kotecha A (2007) What biomechanical properties of the cornea are relevant for the clinician? Surv Ophthalmol 52(Suppl 2):S109–14 7. Shah S, Laiquzzaman M, Bhojwani R, Mantry S, Cunliffe I (2007) Assessment of the biomechanical properties of the cornea with the ocular response analyzer in normal and keratoconic eyes. Invest Ophthalmol Vis Sci 48:3026–3031 8. Lau W, Pye D (2011) A clinical description of ocular response analyzer measurements. Invest Ophthalmol Vis Sci 52:2911–2916. doi:10.1167/iovs.10-6763 9. Bramsen T, Klauber A, Bjerre P (1980) Central corneal thickness and intraocular tension in patients with acromegaly. Acta Ophthalmol (Copenh) 58:971–974 10. Ciresi A, Amato MC, Morreale D, Lodato G, Galluzzo A, Giordano C (2011) Cornea in acromegalic patients as a possible target of growth hormone action. J Endocrinol Invest 34: e30–5. doi:10.3275/7205 11. Polat SB, Ugurlu N, Ersoy R, Oguz O, Duru N, Cakir B (2013) Evaluation of central corneal and central retinal thicknesses and intraocular pressure in acromegaly patients. Pituitary [Epub ahead of print] 12. Cuthbertson RA, Beck F, Senior PV, Haralambidis J, Penschow JD, Coghlan JP (1989) Insulin-like growth factor II may play a local role in the regulation of ocular size. Development 107:123–130 13. Aren A, Skanse B (1955) On non-inflammatory glaucoma in acromegaly. Acta Ophthalmol (Copenh) 33:295–306 14. Kraus H (1961) Acromegaly and glaucoma. Cesk Oftalmol 17:64–69 15. Doughty MJ, Zaman ML (2000) Human corneal thickness and its impact on intraocular pressure measures: a review and meta-analysis approach. Surv Ophthalmol 44:367–408 16. Chihara E (2008) Assessment of true intraocular pressure: the gap between theory and practical data. Surv Ophthalmol 53:203–218. doi:10.1016/j.survophthal.2008.02.005 17. Liu J, Roberts CJ (2005) Influence of corneal biomechanical properties on intraocular pressure measurement: quantitative analysis. J Cataract Refract Surg 31:146–155 18. Congdon NG, Broman AT, Bandeen-Roche K, Grover D, Quigley HA (2006) Central corneal thickness and corneal hysteresis associated with glaucoma damage. Am J Ophthalmol 141:868–875 19. Luce DA (2005) Determining in vivo biomechanical properties of cornea with an ocular response analyzer. J Cataract Refract Surg 31:156–162
20. Sullivan-Mee M, Billingsley SC, Patel AD, Halverson KD, Alldredge BR, Qualls C (2008) Ocular response analyzer in subjects with and without glaucoma. OptomVis Sci 85:463–470. doi:10. 1097/OPX.0b013e3181784673 21. De Moraes CV, Hill V, Tello C, Liebmann JM, Ritch R (2012) Lower corneal hysteresis is associated with more rapid glaucomatous visual field progression. J Glaucoma 21:209–213. doi:10.1097/IJG. 0b013e3182071b92 22. Kirwan C, O’Keefe M, Lanigan B (2006) Corneal hysteresis and intraocular pressure measurement in children using the reichert ocular response analyzer. Am J Ophthalmol 142:990–992 23. Touboul D, Roberts C, Kérautret J, Garra C, Maurice-Tison S, Saubusse E, Colin J (2008) Correlations between corneal hysteresis, intraocular pressure, and corneal central pachymetry. J Cataract Refract Surg 34:616–622. doi:10.1016/j.jcrs.2007.11.051 24. Ortiz D, Piñero D, Shabayek MH, Arnalich-Montiel F, Alió JL (2007) Corneal biomechanical properties in normal, post-laser in situ keratomileusis, and keratoconic eyes. J Cataract Refract Surg 33:1371–1375 25. Pepose JS, Feigenbaum SK, Qazi MA, Sanderson JP, Roberts CJ (2007) Changes in corneal biomechanics and intraocular pressure following LASIK using static, dynamic, and noncontact tonometry. Am J Ophthalmol 143:39–47 26. Herndon LW (2006) Measuring intraocular pressure-adjustments for corneal thickness and new technologies. Curr Opin Ophthalmol 17: 115–119 27. Martinez-de-la-Casa JM, Garcia-Feijoo J, Fernandez-Vidal A, Mendez-Hernandez C, Garcia-Sanchez J (2006) Ocular response analyzer versus Goldmann applanation tonometry for intraocular pressure measurements. Invest Ophthalmol Vis Sci 47:4410–4414 28. Hager A, Loge K, Schroeder B, Füllhas MO, Wiegand W (2008) Effect of central corneal thickness and corneal hysteresis on tonometry as measured by dynamic contour tonometry, ocular response analyzer, and Goldmann tonometry in glaucomatous eyes. J Glaucoma 17:361–365. doi:10.1097/IJG.0b013e31815c3ad3 29. Shah S, Laiquzzaman M, Mantry S, Cunliffe I (2008) Ocular response analyser to assess hysteresis and corneal resistance factor in low tension, open angle glaucoma and ocular hypertension. Clin Experiment Ophthalmol 36:508–513. doi:10.1111/j.1442-9071.2008.01828.x 30. Shah S, Laiquzzaman M, Cunliffe I, Mantry S (2006) The use of the Reichert ocular response analyser to establish the relationship between ocular hysteresis, corneal resistance factor and central corneal thickness in normal eyes. Contact Lens Anterior Eye 29:257–262 31. Oncel B, Dinc UA, Gorgun E, Yalvaç BI (2009) Diurnal variation of corneal biomechanics and intraocular pressure in normal subjects. Eur J Ophthalmol 19:798–803 32. Ozkok A, Hatipoglu E, Tamcelik N, Balta B, Gundogdu AS, Ozdamar MA, Kadioglu P (2014) Corneal biomechanical properties of patients with acromegaly. Br J Ophthalmol [Epub ahead of print]. doi:10.1136/bjophthalmol-2013-304277 33. Terai N, Raiskup F, Haustein M, Pillunat LE, Spoerl E (2012) Identification of biomechanical properties of the cornea: the ocular response analyzer. Curr Eye Res 37:553–562. doi:10.3109/ 02713683.2012.669007
GLAUCOMA
Corneal biomechanical properties measured by the ocular response analyzer in acromegalic patients Emine Sen & Yasemin Tutuncu & Melike Balikoglu-Yilmaz & Ufuk Elgin & Dilek Berker & Faruk Ozturk & Serdar Guler
Received: 26 January 2014 / Revised: 15 April 2014 / Accepted: 19 April 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose To investigate the effect of acromegaly on corneal biomechanical parameters. Methods This cross-sectional, comparative clinical study included 34 acromegalic patients and 30 age-matched and sexmatched healthy controls. Corneal hysteresis (CH), corneal resistance factor (CRF), Goldmann-correlated and cornealcompensated intraocular pressure (IOPg and IOPcc, respectively) were measured using the Ocular Response Analyzer. Central corneal thickness (CCT) was determined with the ultrasonic pachymeter. Results The mean duration of disease for the acromegalic patients was 5.3 years. There was no significant difference between the groups regarding mean CH, CRF, IOPg and IOPcc values. The respective mean values in patients with acromegaly and controls were 10.3±2.2 and 9.5±1.5 mmHg (p=0.13) for CH; 10.5±2.4 and 9.7±1.7 mmHg (p=0.16) for CRF, 16.1±3.6 and 15.5±2.9 mmHg (p=0.49) for IOPg, 16.8 ±3.4 and 17.0±2.8 mmHg (p=0.82) for IOPcc, and 544.8± 32.2 and 530.7±22.9 μm (p=0.05) for CCT. A significant moderate correlation was detected between the duration of acromegaly and IOPg OD (r=0.430, p=0.01). There was no significant correlation between other ocular parameters and levels of GH and IGF-1 at the time of diagnosis, the status of
E. Sen (*) : U. Elgin : F. Ozturk Ulucanlar Eye Education and Research Hospital, Altındag, Ankara, Turkey e-mail: [email protected] Y. Tutuncu : D. Berker : S. Guler Endocrinology and Metabolism Clinic, Numune Education and Research Hospital, Ankara, Turkey M. Balikoglu-Yilmaz Department of Ophthalmology, Dr. Behçet Uz Children’s Disease and Surgery Education and Research Hospital, Izmir, Turkey
control, adenoma type, radiotherapy treatment, and drug usage. Conclusions In acromegalic patients, the duration of disease was correlated with IOPg OD level. Corneal biomechanical parameters and CCT values were not significantly different than those in age-matched and sex-matched healthy individuals. Keywords Acromegaly . Corneal biomechanics . Corneal hysteresis . Corneal resistance factor . Intraocular pressure . Ocular response analyzer
Introduction Acromegaly is a rare disease caused by excessive growth hormone (GH) secretion from a pituitary GH-secreting adenoma. The prevalence and an annual incidence of acromegaly are estimated as 40 to 70 per million and three to four new cases per million, respectively [1]. High levels of GH and insulin-like growth factor-1 (IGF-1) are responsible for the disease’s signs and symptoms, including cardiovascular system and pulmonary system manifestations, metabolic disorders, acral and soft tissue overgrowth, tooth decay, prognathism and joint damage [2]. Possible ocular findings in these patients are bitemporal hemianopia and visual loss due to a mass effect of the pituitary adenoma. Mass effect-independent signs such as diabetic retinopathy, increased intraocular pressure (IOP) and central corneal thickness (CCT) have also been observed [3, 4]. Biomechanical properties of the cornea might be changed by ocular pathologies and systemic diseases and thus affect many ocular measurements, possibly altering the diagnosis and treatment. The ocular response analyzer (ORA; Reichert Ophthalmic Instruments, Depew, NY, USA) is a new device to measure the corneal viscoelastic and resistance properties
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in vivo and IOP, free from the effect of corneal biomechanical factors [5]. The ORA is a revised version of non-contact tonometry and fires a metered air pulse at the cornea. The machine reflects the corneal response to the air pressure as two measurements. These measurements are recorded by the electro-optical infrared detector system. Energy absorption takes place during inward and outward applanation events, leading to two different applanation pressure values. The first, inward applanation pressure (P1), occurs when the released air pressure increases. The second, outward applanation pressure (P2), occurs when the air pressure drops. The second outward applanation pressure is always lower than the first inward applanation pressure. Four different parameters are available according to the applanation pressure results. The first parameter, corneal hysteresis (CH), is the difference between P1 and P2 and the response of the corneal tissue to dynamic deformation, and is a good indicator of the viscoelastic properties of the cornea [6]. Another parameter, the corneal resistance factor (CRF), is the sum of P1 and P2 and reflects the elastic properties of the cornea better. It refers to the overall “resistance” of the cornea [7]. Corneal compensated IOP (IOPcc) is the sum of P1 and P2 and an IOP estimation that uses a mathematical correction to minimize its corneal dependence. The Goldmanncorrelated IOP (IOPg) is the average value of P1 and P2 and analogous to standard noncontact tonometry IOP measurement [8]. Our hypothesis was that there could be some changes in corneal biomechanics in acromegaly patients. The purpose of this study was to evaluate corneal biomechanical parameters measured by ORA in patients with acromegaly and compare them with normal individuals.
Patients who had refractive errors (>3D spheric and/ or >1D cylindric), systemic or ocular disease (including a history of ocular trauma or surgery), used contact lenses or systemic/ophthalmic drugs, and women who were pregnant, planning pregnancy, or lactating were excluded from the study. Examination protocol and measurements A detailed ophthalmologic examination was performed by a single specialist (E.S.) who was masked to the group assignments. Visual acuity was assessed with a Snellen chart and examination of the anterior and posterior segment was performed with the slit-lamp. Corneal biomechanical parameters, including CH, CRF, IOPg and IOPcc, were measured using the ORA (Reichert Ophthalmic Instruments, Depew, NY, USA). CCT was determined with the ORA-attached handheld ultrasonic pachymeter after instillation of topical proparacaine HCl 0.5 % (Alcaine; Alcon Laboratories, UK). The patients were seated next to the ORA tool and asked to fixate on the target in the instrument (red blinking light). After the area of the central cornea was scanned with a non-contact probe, air pressure was released from the machine to the corneal surface. The corneal response to this pressure was measured by the machine and the CH, CRF, IOPg and IOPcc values were displayed on the computer screen attached to the ORA. Three measurements were taken for each eye and the mean values were used for statistical analysis. Unreliable atypical signals were ignored. Laboratory analyses
Materials and methods Study population and design The study protocol adhered to the tenets of the Declaration of Helsinki and was approved by the Institutional Review Board of Ankara University, School of Medicine (14 March 2011, No. 26–533). This prospective, cross-sectional, comparative study included 34 acromegalic patients (controlled n=26, uncontrolled n=8) referred from Ankara Numune Education and Research Hospital’s Department of Endocrinology and Metabolism, and 30 healthy age-matched and gender-matched individuals who presented at the Ulucanlar Eye Education and Research Hospital for a routine eye examination. Informed consent was obtained from all patients. The GH level less than1 ng/mL on the OGTT-GH suppression test and the IGF-1 level within the normal range for age and gender were accepted as control criteria.
Serum GH levels were measured using commercially available immunoradiometric assay (IRMA) kits (hGH - IRMA CT; RADIM, Rome, Italy). Assay sensitivity was 0.04 ng/mL. The calibrator had been calibrated against the WHO 80/505 International Standard preparation (1 ng hGH=2 μIU). The GH reference ranges were 0–16 ng/mL and 0–8 ng/mL for women and men, respectively. Serum IGF-1 was measured with the IMMULITE 1000 System using a solid-phase, enzyme-labeled chemiluminescent immunometric assay (Immulite IGF-I, Siemens Medical Solutions Diagnostics, UK). Our IGF-I reference ranges for the 21–25, 26–30, 31– 35, 36–50, 51–60, 61–70, and over 70 years age groups are 116–358, 117–329,115–307, 94–284, 81–238, 69–212, and 55–188 ng/mL, respectively. The assay analytical sensitivity was 20 ng/mL. Calibration was up to 1,600 ng/mL (WHO NIBSC 1st IRR 87/518). For the standard curve low, medium and high points, the within-run coefficients of variation were 3.1, 4.3 and 3.5 % and the total coefficients of variation were 6.1, 6.9, and 5.8 %, respectively.
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Statistical analysis
Corneal biomechanical parameters
The sample size was calculated as 33 for each group, with a power of 80 % and a p value of 0.05, d (effect size) 0.70. Statistical analysis was performed by using the IBM SPSS 20.0 software (SPSS Inc, Chicago, IL, USA). For the purposes of this analysis, qualitative variables were categorized, while quantitative data were presented as mean ± standard deviation. The t-test and chi-square test were used in the analysis of the differences regarding corneal parameters and demographic characteristics between the acromegaly and control groups. For the continuous variables, the data were tested for normality by using the Kolmogorov-Smirnov test, histograms and p-p plots for both groups. As the status of adenoma, radiotherapy, and drug usage in the patient group were not consistent with normal distribution, Spearman rank correlation was used to determine the correlation between these variables and corneal biomechanical properties. Pearson’s correlation coefficient was used for correlation of associations between normally distributed variables. P≤0.05 was considered statistically significant.
The corneal biomechanical parameters in the acromegaly and control groups are summarized in Table 2. There was no statistically significant difference between the groups regarding the mean values of CH, CRF, IOPg, IOPcc, and CCT (p>0.05). Correlation of duration of disease, serum GH and IGF-1 levels, the status of adenoma, previous treatments including radiotherapy or medical agents with ocular parameters of acromegalic patients A significant moderate correlation was found between the duration of acromegaly and IOPg OD (Pearson correlation test; r=0.430, p=0.01) (Fig. 1). The radiotherapy treatment also correlated with CH OD, with a Spearman’s correlation of 0.340 (p=0.049). On the other hand, no correlation was found between levels of GH and IGF-1 at the time of diagnosis, the status of control, adenoma type, radiotherapy treatment, and drug usage with any other ocular parameters (Spearman and Pearson correlation tests, p>0.05).
Discussion
Results Demographic characteristics The mean age of the 22 (64.7 %) female and 12 (35.3 %) male acromegalic patients was 44.4± 11.4 years and the mean age of the 17 (56.7 %) female and 13 (43.3 %) male control group subjects was 42.5±12.5 years. There was no statistically significant difference between the acromegaly and control groups in terms of age or gender (p > 0.05, Table 1).
Acromegaly is a chronic endocrine disorder causing disproportionate skeletal, tissue, and organ growth and is associated with significant morbidity and mortality. As reported in previous studies, ocular tissues seem to be a target organ in patients with acromegaly [9–11]. Growth factors including GH and IGF-1 might play a role in regulating ocular tissue growth and differentiation by affecting the synthesis of the scleral extracellular matrix [12]. Intraocular pressure was first stated to be higher in acromegaly patients in 1955 [13]. In 1961, Kraus reported a case of acromegaly and glaucoma where the IOP returned to normal after resection of the tumor [14]. Growth effects of GH in other ocular tissues might also
Table 1 Demographic characteristic of the subjects Acromegaly (n: 34)
Controls (n: 30)
P value
Age (years) Male, n (%) Female, n (%)
44.4±11.4 12 (35.3) 22 (64.7)
42.5±12.5 13 (43.3) 17 (56.7)
0.53† 0.51‡
Acromegaly duration (years) Control status* (controlled vs. uncontrolled), n (%) Adenoma type (macro. vs. micro.), n (%) History of radiotherapy administration, n (%) Drug usage (octreotide vs. lantreotide vs. unmedicated), n (%)
5.3±2.8 26 (76.5) vs. 8 (23.5) 31 (91.2) vs. 3 (8.8) 9 (26.5) 14 (41.2) vs. 11 (32.4) vs. 9 (26.5)
– – – – –
– – – – –
Values are indicated as mean ± SD or number (percentage) *Control status means control of growth hormone and insulin-like growth factor-1 after treatment †
t-test, ‡ chi-square test
Graefes Arch Clin Exp Ophthalmol Table 2 Ocular response analyzer measurements of acromegaly patients and controls Variable
Acromegaly (n: 34)
Controls (n: 30)
P value
CH OD, mmHg CH OS, mmHg CRF OD, mmHg CRF OS, mmHg
10.3±2.2 10.1±2.0 10.5±2.4 10.2±2.3
9.5±1.5 10.3±1.5 9.7±1.7 10.4±1.6
0.13† 0.75† 0.16† 0.68†
IOPg OD, mmHg IOPg OS, mmHg IOPcc OD, mmHg IOPcc OS, mmHg CCT OD, μm CCT OS, μm
16.1±3.6 15.4±3.3 16.8±3.4 16.3±2.8 544.8±32.2 541.1±32.9
15.5±2.9 15.3±3.1 17.0±2.8 15.8±2.7 530.7±22.9 525.4±21.3
0.49† 0.82† 0.82† 0.48† 0.052† 0.09†
CH: Corneal hysteresis, CRF: corneal resistance factor, IOPg: Goldmanncorrelated intraocular pressure, IOPcc: corneal-compensated intraocular pressure, CCT: central corneal thickness Values are indicated as mean ± SD †
t-test
be seen in the cornea, and CCT values have been found to be higher in patients with acromegaly [9, 10]. However, Ciresi et al. and Bramsen et al. detected similar IOP levels in the acromegaly and control groups when IOP was corrected for the CCT difference [9, 10]. It is well known that IOP measurements are corrected for CCT according to Doughty’s meta-analysis [15]. The importance of corneal biomechanics and accurate IOP measurements in various systemic and ocular pathologies has been recognized. Corneal pathologies altering the viscoelastic structure of the cornea might prevent us Fig. 1 A significant moderate correlation between time (the duration of disease, years) and Goldmann-correlated intraocular pressure OD (IOPg OD, mmHg) (Pearson correlation test; r= 0.430, p=0.01) in acromegalic patients
from identifying the correct IOP. Therefore, we evaluated corrected IOP and corneal biomechanical parameters measured by ORA that was not affected by CCT [6, 16] in our acromegalic patients. Corneal biomechanical properties include corneal viscosity, elasticity, and hydration, and connective tissue composition [17]. Congdon et al. was the first to report a relationship between CH and glaucomatous damage [18]. Corneal hysteresis has been used in the classification of corneal diseases and refractive surgery and the diagnosis of glaucoma, especially for determining glaucoma treatment [19]. Reduced CH and increased CRF have been shown to be strongly associated with glaucoma [5, 20, 21]. De Moraes et al. [21] also reported a relationship between low CH and rapid progression of glaucomatous visual field defects. CH is unaffected by age [22] and is independent of intraocular pressure [23]. CH and CRF were also demonstrated to be lower than those of normal subjects in keratoconus, post-LASIK and pseudophakic eyes, Fuchs’ corneal dystrophy, primary open angle glaucoma (POAG) and normal-tension glaucoma (NTG) [24–26]. The CH value was variable and ranged from 1.8 to 14.6 mmHg [19]. In a study on 498 eyes of 258 patients, Touboul et al. compared normal eyes with eyes suffering from glaucoma, keratoconus, and post-LASIK and photorefractive keratectomy surgery, and found the lowest CH values in keratoconus (8.3 mmHg) and the post-LASIK group (8.9 mmHg) [23]. In a study on 48 eyes, the mean CH value was reported as 8.8 mmHg in patients with glaucoma [27], while it was detected as 10.2 mmHg in another study [28]. Kirwan et al. reported lower CH values in eyes with congenital glaucoma compared to normal eyes (6.3 mmHg vs. 12.5 mmHg). CH
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values were lowest in buphthalmic eyes, especially when associated with Haab striae [22]. Shah et al. compared CH and CRF values in NTG, POAG, and ocular hypertension (OHT) patients. Eyes suffering from OHT had the highest CH and CRF values. The mean CH was 9, 9.9 and 10.2 mmHg and the mean CRF was 9.1, 10.6 and 12 mmHg, respectively, in eyes suffering from NTG, POAG, and OHT [29]. Shah et al. [30] reviewed the records of 207 eyes of 105 volunteers. They found CRF values ranging from 5.7 to 17.1 mmHg (mean 10.3 mmHg). Oncel et al. [31] evaluated diurnal variation of corneal biomechanics of 62 healthy volunteers and they reported that measurements of CH, CRF, IOPg, IOPcc, and CCT at 8:00 AM, 11:00 AM, 2:00 PM and 5:00 PM did not show remarkable alteration. Ozkok et al. evaluated corneal biomechanical properties of 24 controlled and 22 uncontrolled acromegaly patients [32]. They reported significantly higher CH and CRF values in acromegalic patients (12.1 and 12.3 mmHg, respectively) as compared to healthy individuals (11.0 and 10.8 mmHg, respectively) [32]. In our study, the CH and CRF values were higher in the acromegaly group than the control group (10.3 vs. 9.5 mmHg and 10.5 vs. 9.7 mmHg, respectively). However, the difference in CH and CRF values between the groups was not statistically significant. Lower CH and CRF values in our study than those in the study by Ozkok et al. might be due to greater number of uncontrolled acromegalic patients in the previous study [32]. Corneal-compensated IOP has been proposed as the most accurate IOP measurement [33]. Hager et al. found the mean value for IOPcc to be 17.9 mmHg in glaucomatous eyes [28]. Shah et al. reported IOP by ORA to be 16.9, 20.5 and 20.0 mmHg in patients with NTG, POAG, and OHT, respectively, in another study [29]. There are three studies on IOP in acromegaly patients in the literature, and the IOP measurements in these studies were measured by Goldmann applanation tonometry [9–11]. Bramsen et al. [9] stated that the CCT and IOP were higher in patients with pituitary adenomas plus acromegaly than in controls with only pituitary adenomas (561 vs. 526 μm and 16.9 mmHg vs. 14.7 mmHg). Similarly, Ciresi et al. [10] detected greater CCT values in acromegalic patients when compared to healthy controls (567 vs. 528.5 μm), without concomitant differences in corrected IOP (17.3 vs. 17 mmHg). Polat et al. showed similar mean CCT levels in acromegaly patients and controls (529 vs. 537 μm) and higher mean IOP in acromegaly patients (16 vs. 13 mmHg) [11]. Ozkok et al. [32] reported higher IOPg and similar IOPcc and CCT levels (17.1 mmHg, 15.5 mmHg, and 545.4 μm, respectively) in acromegalic patients than those of controls (15.1 and 15.1 mmHg, 555.1 μm, respectively). Although there was no significant difference in CCT and IOP values in the groups of our study, CCT was observed to be higher in acromegaly patients than in healthy controls (545 vs. 531 μm). Additionally, mean IOPg and IOPcc
measured by ORA were 16.1 and 16.8 mmHg, respectively, in patients with acromegaly. A positive correlation between IGF-1 level and CCT in uncontrolled acromegalic patients was emphasized by Ozkok et al. [32]. However, they did not find any correlation in all or controlled acromegalic patients. They thought that this finding might indirectly demonstrate corneal thickness that was under the effect of prolonged IGF-1 excess, although they detected similar CCT values in acromegalic patients and healthy individuals [32]. Unlike the study by Ozkok et al. [32], the correlation of CCT with acromegaly duration and IGF-1 level was not detected in our study. There was a significant correlation between acromegaly duration and IOPg and also between history of radiotherapy administration and CH in our acromegalic patients. The current study evaluated corneal biomechanical changes in acromegaly patients and the effect of duration of disease, serum GH and IGF-1 levels, the status of adenoma, and previous treatments such as radiotherapy or medical agents on corneal biomechanical changes in these patients. There are some potential limitations in the present study. Firstly, variables including concurrent systemic diseases could not be normalized between the groups. Secondly, there were fewer uncontrolled than controlled acromegalic patients. Finally, measurements of GH or IGF-1 levels in subretinal fluid and aqueous humor to assess their correlation with intraocular pressure measured by ORA, corneal hysteresis and elasticity values could not be performed, as these are interventional procedures. Taking these measurements during routine ophthalmic surgery may shed light on future studies. In conclusion, the present study demonstrated that Goldmann-correlated and corneal-compensated IOPs, corneal elasticity and viscosity measured by ORA and the CCT values of patients with acromegaly are similar to those of healthy subjects. The duration of acromegaly also correlated with the presence of abnormal IOPg OD finding. Ocular characteristics of acromegaly should be well known so that a potential complication is not missed. Acromegaly effects on corneal biomechanical parameters might continue over time, and longitudinal studies are therefore warranted in acromegalic patients.
Conflicts of interest The authors declare that the manuscript has not been published previously, and they have no conflict of interest. No financial support was received for this project.
References 1. Chanson P, Salenave S (2008) Acromegaly. Orphanet J Rare Dis 3: 17. doi:10.1186/1750-1172-3-17
Graefes Arch Clin Exp Ophthalmol 2. Chanson P, Salenave S, Kamenicky P, Cazabat L, Young J (2009) Pituitary tumours: acromegaly. Best Pract Res Clin Endocrinol Metab 23:555–574. doi:10.1016/j.beem.2009.05.010 3. Melmed S, Colao A, Barkan A et al (2009) Guidelines for acromegaly management: an update. J Clin Endocrinol Metab 94:1509–1517. doi:10.1210/jc.2008-2421 4. Sönksen PH, Russell-Jones D, Jones RH (1993) Growth hormone and diabetes mellitus. A review of 63 years of medical research and a glimpse into the future? Horm Res 40:68–79 5. ElMallah MK, Asrani SG (2008) New ways to measure intraocular pressure. Curr Opin Ophthalmol 19:122–126. doi:10. 1097/ICU.0b013e3282f391ae 6. Kotecha A (2007) What biomechanical properties of the cornea are relevant for the clinician? Surv Ophthalmol 52(Suppl 2):S109–14 7. Shah S, Laiquzzaman M, Bhojwani R, Mantry S, Cunliffe I (2007) Assessment of the biomechanical properties of the cornea with the ocular response analyzer in normal and keratoconic eyes. Invest Ophthalmol Vis Sci 48:3026–3031 8. Lau W, Pye D (2011) A clinical description of ocular response analyzer measurements. Invest Ophthalmol Vis Sci 52:2911–2916. doi:10.1167/iovs.10-6763 9. Bramsen T, Klauber A, Bjerre P (1980) Central corneal thickness and intraocular tension in patients with acromegaly. Acta Ophthalmol (Copenh) 58:971–974 10. Ciresi A, Amato MC, Morreale D, Lodato G, Galluzzo A, Giordano C (2011) Cornea in acromegalic patients as a possible target of growth hormone action. J Endocrinol Invest 34: e30–5. doi:10.3275/7205 11. Polat SB, Ugurlu N, Ersoy R, Oguz O, Duru N, Cakir B (2013) Evaluation of central corneal and central retinal thicknesses and intraocular pressure in acromegaly patients. Pituitary [Epub ahead of print] 12. Cuthbertson RA, Beck F, Senior PV, Haralambidis J, Penschow JD, Coghlan JP (1989) Insulin-like growth factor II may play a local role in the regulation of ocular size. Development 107:123–130 13. Aren A, Skanse B (1955) On non-inflammatory glaucoma in acromegaly. Acta Ophthalmol (Copenh) 33:295–306 14. Kraus H (1961) Acromegaly and glaucoma. Cesk Oftalmol 17:64–69 15. Doughty MJ, Zaman ML (2000) Human corneal thickness and its impact on intraocular pressure measures: a review and meta-analysis approach. Surv Ophthalmol 44:367–408 16. Chihara E (2008) Assessment of true intraocular pressure: the gap between theory and practical data. Surv Ophthalmol 53:203–218. doi:10.1016/j.survophthal.2008.02.005 17. Liu J, Roberts CJ (2005) Influence of corneal biomechanical properties on intraocular pressure measurement: quantitative analysis. J Cataract Refract Surg 31:146–155 18. Congdon NG, Broman AT, Bandeen-Roche K, Grover D, Quigley HA (2006) Central corneal thickness and corneal hysteresis associated with glaucoma damage. Am J Ophthalmol 141:868–875 19. Luce DA (2005) Determining in vivo biomechanical properties of cornea with an ocular response analyzer. J Cataract Refract Surg 31:156–162
20. Sullivan-Mee M, Billingsley SC, Patel AD, Halverson KD, Alldredge BR, Qualls C (2008) Ocular response analyzer in subjects with and without glaucoma. OptomVis Sci 85:463–470. doi:10. 1097/OPX.0b013e3181784673 21. De Moraes CV, Hill V, Tello C, Liebmann JM, Ritch R (2012) Lower corneal hysteresis is associated with more rapid glaucomatous visual field progression. J Glaucoma 21:209–213. doi:10.1097/IJG. 0b013e3182071b92 22. Kirwan C, O’Keefe M, Lanigan B (2006) Corneal hysteresis and intraocular pressure measurement in children using the reichert ocular response analyzer. Am J Ophthalmol 142:990–992 23. Touboul D, Roberts C, Kérautret J, Garra C, Maurice-Tison S, Saubusse E, Colin J (2008) Correlations between corneal hysteresis, intraocular pressure, and corneal central pachymetry. J Cataract Refract Surg 34:616–622. doi:10.1016/j.jcrs.2007.11.051 24. Ortiz D, Piñero D, Shabayek MH, Arnalich-Montiel F, Alió JL (2007) Corneal biomechanical properties in normal, post-laser in situ keratomileusis, and keratoconic eyes. J Cataract Refract Surg 33:1371–1375 25. Pepose JS, Feigenbaum SK, Qazi MA, Sanderson JP, Roberts CJ (2007) Changes in corneal biomechanics and intraocular pressure following LASIK using static, dynamic, and noncontact tonometry. Am J Ophthalmol 143:39–47 26. Herndon LW (2006) Measuring intraocular pressure-adjustments for corneal thickness and new technologies. Curr Opin Ophthalmol 17: 115–119 27. Martinez-de-la-Casa JM, Garcia-Feijoo J, Fernandez-Vidal A, Mendez-Hernandez C, Garcia-Sanchez J (2006) Ocular response analyzer versus Goldmann applanation tonometry for intraocular pressure measurements. Invest Ophthalmol Vis Sci 47:4410–4414 28. Hager A, Loge K, Schroeder B, Füllhas MO, Wiegand W (2008) Effect of central corneal thickness and corneal hysteresis on tonometry as measured by dynamic contour tonometry, ocular response analyzer, and Goldmann tonometry in glaucomatous eyes. J Glaucoma 17:361–365. doi:10.1097/IJG.0b013e31815c3ad3 29. Shah S, Laiquzzaman M, Mantry S, Cunliffe I (2008) Ocular response analyser to assess hysteresis and corneal resistance factor in low tension, open angle glaucoma and ocular hypertension. Clin Experiment Ophthalmol 36:508–513. doi:10.1111/j.1442-9071.2008.01828.x 30. Shah S, Laiquzzaman M, Cunliffe I, Mantry S (2006) The use of the Reichert ocular response analyser to establish the relationship between ocular hysteresis, corneal resistance factor and central corneal thickness in normal eyes. Contact Lens Anterior Eye 29:257–262 31. Oncel B, Dinc UA, Gorgun E, Yalvaç BI (2009) Diurnal variation of corneal biomechanics and intraocular pressure in normal subjects. Eur J Ophthalmol 19:798–803 32. Ozkok A, Hatipoglu E, Tamcelik N, Balta B, Gundogdu AS, Ozdamar MA, Kadioglu P (2014) Corneal biomechanical properties of patients with acromegaly. Br J Ophthalmol [Epub ahead of print]. doi:10.1136/bjophthalmol-2013-304277 33. Terai N, Raiskup F, Haustein M, Pillunat LE, Spoerl E (2012) Identification of biomechanical properties of the cornea: the ocular response analyzer. Curr Eye Res 37:553–562. doi:10.3109/ 02713683.2012.669007
