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Correlation of Serial Scleral and Corneal Pneumatonometry Debbie S. Kuo, MD,1 Yvonne Ou, MD,1 Bennie H. Jeng, MD, MS,2 Robert Bhisitkul, MD, PhD,1 Jay M. Stewart, MD,1 Jacque L. Duncan, MD,1 Ying Han, MD, PhD1 Purpose: To evaluate the usefulness of scleral pneumatonometry as an alternative for corneal measurements of intraocular pressure (IOP) over a broad range of IOPs. Design: Prospective, observational cohort study. Participants: The study was conducted in the University of California, San Francisco, Retina Clinic between August and November 2013 in 33 adult patients (age range, 34e94 years; mean standard deviation, 74.113.4 years) receiving antievascular endothelial growth factor intravitreal injections, which transiently increase IOP. Methods: Corneal pachymetry and serial corneal and temporal scleral pneumatonometry (baseline, immediately after, and 10, 20, and 30 minutes after injection) were collected. One-time baseline corneal and scleral pneumatonometry readings were obtained in the noninjected eye. Main Outcome Measures: Correlation analysis and a Bland-Altman plot were used to evaluate reliability and agreement between scleral and corneal measurements of IOP. A linear mixed model was used to determine the relationship between measurements and to perform covariate analyses. Results: Scleral and corneal pneumatonometry showed nearly 1:1 linear correlation, although scleral pneumatonometry was biased toward higher values (r ¼ 0.94; P < 0.001). Scleral pneumatonometry averaged 9.0 mmHg higher than corneal pneumatonometry (95% limits of agreement, 1.5 to 19.5 mmHg). A linear mixed model resulted in the following equation: corneal IOP ¼ 1.04 scleral IOP 10.37. Age, central corneal thickness, laterality, and glaucoma and lens status did not impact this relationship. The difference between corneal and scleral pneumotonometry was correlated between the two eyes of individual patients (r ¼ 0.75; P < 0.001). Conclusions: Differences between serial scleral measurements reflect differences between serial corneal measurements. Scleral pneumatonometry should be considered as an alternative to corneal pneumatonometry for following patients in whom corneal measurements are unreliable or unobtainable. Ophthalmology 2015;122:17711776 ª 2015 by the American Academy of Ophthalmology. Intraocular pressure (IOP) normally is measured over the cornea. However, for patients with significant corneal pathology, such as scarring, thinning, and edema, or for those who have keratoprosthesis implants, corneal tonometry can be inaccurate or impossible to obtain. However, these corneal diseases are associated commonly with either primary or secondary glaucoma. For example, in the case of keratoprosthesis, difficulty with IOP measurement is a significant problem. Glaucoma has been reported to be a preoperative comorbidity in more than two-thirds of patients and to be newly diagnosed in an additional 13% to 25% of patients after keratoprosthesis implantation.1e3 Furthermore, keratoprostheses are associated with postoperative elevation in IOP and progression of glaucoma, which can become vision limiting.1e3 Scleral pneumatonometry has been proposed as an alternative method for IOP measurement in patients for whom corneal measurements are not possible. In a study performed in cadaveric eyes, we previously showed that serial measurements of scleral pneumotonometry correlate strongly and linearly to IOP when IOP was set from 20 to 50 mmHg by infusion cannula.4 Importantly, this relationship was unchanged after the eyes underwent keratoprosthesis 2015 by the American Academy of Ophthalmology Published by Elsevier Inc. implantation. In patients, a cross-sectional study by Kapamajian et al5 found a positive correlation between one-time corneal and scleral pneumatonometry in healthy adult patients. However, the IOP range was limited by the physiologic pressures of this population (10.5e27 mmHg), and the relationship between changes in corneal and scleral pneumatonometry in patients was not studied. Furthermore, scleral pneumatonometry generally resulted in higher measurements than corneal pneumatonometry, but this difference was highly variable across individuals (mean standard deviation, 8.45.7 mmHg).5 For scleral pneumotonometry to be a useful clinical tool, scleral measurements should correlate to corneal measurements over a wide range of both physiologic and pathological pressures and have a predictable relationship over multiple measurements when used to follow patients clinically. Therefore, in the current study, we measured serial scleral and corneal pneumatonometry in patients receiving intravitreal injections, which transiently increase IOP, to evaluate the relationship between these 2 measurements over a broad range of IOPs. Since the baseline difference between scleral and corneal pneumatonometry in an eye with corneal disease may be unknown, in the case of http://dx.doi.org/10.1016/j.ophtha.2015.05.033 ISSN 0161-6420/15 1771 Ophthalmology Volume 122, Number 9, September 2015 unilateral or asymmetric disease, we hypothesized that one could use the contralateral eye as a surrogate for the baseline difference in the eye of interest. Thus, we also evaluated whether the difference between corneal and scleral measurements was correlated between the 2 eyes of individual patients. Methods Study Design The Institutional Review Board/Ethics Committee at University of California, San Francisco, approved this prospective observational study. This study complied with Health Insurance Portability and Accountability Act regulations and adhered to the tenets of the Declaration of Helsinki. Adult patients receiving antievascular endothelial growth factor intravitreal injections in the Retina Clinic of the University of California, San Francisco, were recruited between August and November 2013. We had a minimum target enrollment of 28 patients, which was predicted to have a 90% power to detect a correlation coefficient of 0.57 (based on the results from Kapamajian et al5) with an a of 0.05 in an a priori sample size calculation. Patients with previous incisional glaucoma surgery, scleral buckle, strabismus surgery, refractive cornea surgery, scleral pathology such as thinning or scarring, or significant corneal pathology such as scarring or edema that would prevent accurate measurement of IOP over the cornea were excluded. The risks and benefits of participation were discussed with each participant and informed consent was obtained. We collected patient information on demographics, diagnosis of glaucoma, and lens status (phakia or pseudophakia) by chart review. Measurements A single observer (D.S.K.) obtained all measurements. Eyes were anesthetized with 1% proparacaine. At each time point, IOP measurements were obtained from the central cornea and temporal sclera with the edge of the pneumatonometer probe (Model 30 Classic; Reichert Ophthalmic Instruments, Depew, NY) placed directly temporal 1 mm from the limbus with the patient in primary gaze, which centered the probe approximately 3.5 mm posterior to the limbus. Corneal and temporal scleral pneumotonometry measurements (abbreviated as corneal IOP and scleral IOP, respectively) were obtained at baseline in both eyes before injection, and then serial measurement were obtained in the treated eye immediately after injection and 10, 20, and 30 minutes after injection. All measurements were obtained with patients sitting up. For each pair of measurements, we checked the corneal IOP before the scleral IOP. All corneal measurements had a standard deviation of less than 0.5 mmHg and all scleral measurements had a standard deviation of less than 1 mmHg for IOPs between 0 and 40 mmHg and a standard deviation of less than 1.5 mmHg for IOPs of more than 40 mmHg. The waveform was examined for good quality in all measurements with IOPs of less than 40 mmHg, where it was within the limits of the paper printout. We measured central corneal thickness by pachymetry (DGH-550 Pachette 2; DGH Technology, Inc, Exton, PA), averaging 5 measurements, at the time of the baseline measurements. correlation coefficient is not appropriate because it does not take into account the lack of independence between repeated measurements for the same subject.6 Instead, we calculated a withinsubjects correlation coefficient, which removes the variation between subjects to examine whether an increase in a variable within the same subject is associated with an increase in another variable.6 Similarly, agreement between scleral and corneal IOP was analyzed using a Bland-Altman plot with correction for multiple measurements per subject using MedCalc Statistical Software (MedCalc Software, Ostend, Belgium).7 The data were fit with a linear mixed model with random slope and intercept using R (R Foundation for Statistical Computing, Vienna, Austria). Confidence intervals were derived from bootstrap analysis, an iterative resampling of the data. Covariate analysis was performed using the linear mixed model and likelihood ratio test with P < 0.05 considered statistically significant. Results Thirty-three patients ranging in age from 34 to 94 years were included in the study. Baseline characteristics are shown in Table 1. Pseudophakia was present in 52% of patients and glaucoma was present in 15% of patients. A total of 164 serial paired measurements of corneal and scleral IOP were obtained in the treated eye (1 subject missed 1 time point). Corneal IOPs ranged from 9 to 61.5 mmHg and scleral IOPs ranged from 13.5 to 74 mmHg. Thirty-two patients had baseline measurements of scleral and corneal pneumatonometry in the contralateral untreated eye. At baseline, the difference between scleral and corneal pneumatonometry measurements in the 2 eyes of individual patients was correlated significantly (r ¼ 0.75; P < 0.001; Fig 1). We used correlation to analyze the linear association between serial scleral and corneal IOP by pneumatonometry and found that they were significantly correlated (r ¼ 0.94; P < 0.001) for the injected eyes (Fig 2). The data were fit using a linear mixed model, which takes into account longitudinal measurements over time. This analysis resulted in the following equation: scleral IOP ¼ 0.97 corneal IOP þ 10.0. The standard deviation of the residuals, an error measurement for the entire model, was 2.78 mmHg. The slope (mean standard deviation, 0.970.21 mmHg) was statistically significant (P < 0.001) and showed a nearly 1:1 relationship between changes in scleral and corneal IOP on average with some variability between individual patients (Fig 3A). Similarly, the intercept (mean standard deviation, 10.05.83 mmHg) was statistically significant (P < 0.001), but demonstrated greater variability among patients (Fig 3B). A Bland-Altman plot was created to examine the agreement of scleral IOP and corneal IOP over a range of IOP using data from Table 1. Baseline Characteristics No. of patients enrolled Mean age SD (yrs) Eye (no.) Right Left Mean CCT SD (mm) Lens status (no.) Phakic Pseudophakic Glaucoma (no.) 33 74.113.4 20 13 552.437.0 16 17 5 (2 POAG, 1 steroid-induced, 2 NOS) Statistical Analysis The Pearson correlation coefficient is reported herein. For paired data with more than 1 time point for each study subject, an ordinary 1772 CCT ¼ central corneal thickness; NOS ¼ not otherwise specified; POAG ¼ primary open angle glaucoma; SD ¼ standard deviation. Kuo et al Scleral Pneumatonometry serial IOP measurements (Fig 4). Scleral IOP averaged 9.0 mmHg higher than corneal IOP (95% limits of agreement, 1.5 to 19.5 mmHg). Importantly, there was not a trend toward larger differences at higher IOPs, but there were fewer data points and more outliers at higher values. For measurements with a mean of scleral and corneal IOP less than 40 mmHg, which are potentially more clinically relevant, 81.7% of the measurements were within 5 mmHg of the mean difference between scleral and corneal IOP. To test the impact of age, eye laterality, central corneal thickness, lens status (phakia versus pseudophakia), and glaucoma on the relationship between scleral and corneal pneumotonometry, we added these covariates to the linear mixed model and evaluated them with a likelihood ratio test. None of these factors was statistically significant (Table 2). Discussion Figure 1. Scatterplot showing baseline differences in scleral and corneal pneumatonometry in the 2 eyes of each patient. The value for the eye scheduled to undergo treatment with an antievascular endothelial growth factor agent is plotted on the x-axis and for the contralateral eye on the y-axis. Pearson correlation coefficient is shown. Reference values x ¼ y are shown as a dotted line. IOP ¼ intraocular pressure. Figure 2. Scatterplot showing scleral versus corneal pneumatonometry. Data points from all measurements were plotted. The within-subjects Pearson correlation coefficient, evaluating the relationship between scleral and corneal intraocular pressure (IOP) in the same subject over multiple measurements, is shown. The solid line represents line of best fit from a linear mixed model with random slope and intercept (scleral IOP ¼ 0.97 corneal IOP þ 10.0). This study was designed to evaluate the relationship between serial corneal and scleral pneumatonometry over a wide range of physiologic and pathologic levels of IOP. We found that scleral pneumatonometry was significantly correlated to corneal pneumatonometry, but was biased toward higher values. Although we did not compare scleral pneumatonometry directly with Goldmann applanation, the relationship between Goldmann applanation and corneal pneumatonometry has been well described (Tapplanation ¼ Tpneumatonometry 1.2), and corneal pneumatonometry has been reported to be age-independent and to correlate best with manometric IOP measurements compared with applanation and Tono-Pen (Reichert Ophthalmic Instruments, Depew, NY) IOP measurements in patients.8 Scleral pneumatonometry previously was found to be increased compared with both corneal measurements and assigned IOP, and our results are consistent with prior reports (Table 3).4,5 The difference measured between scleral and corneal IOP likely reflects differences in the biomechanical properties between cornea and sclera, which can vary by quadrant and anterioreposterior location within an individual.9,10 We chose to obtain measurements over the sclera temporally in primary gaze because eccentric eye position can change IOP measurement and the temporal region is the most accessible and would be preserved even after glaucoma surgery.11,12 However, more studies are required to determine the optimal location for scleral pneumatonometry in patients. Our results showed a significant correlation (r ¼ 0.94) between scleral and corneal pneumatonometry in patients using a different approach from Kapamajian et al5 (r ¼ 0.57). Kapamajian et al obtained one-time measurements of scleral and corneal pneumatonometry in patients, which can give variable results for the relationship between corneal and scleral measurements because of the individual differences in scleral rigidity. In our study using patients from the retina clinic receiving intraocular injections, we were able to obtain multiple measurements per patient over a short period, spanning a large range of IOPs in each subject. This strategy allowed us to remove the variation among subjects and evaluate whether an increase in scleral pneumatonometry was associated with an increase in corneal pneumatonometry within an individual using a within-subjects Pearson correlation coefficient. 1773 Ophthalmology Volume 122, Number 9, September 2015 Figure 3. Estimated (A) slope and (B) intercept for individual patients from a linear mixed model with random slope and random intercept. Slope represents the change in scleral intraocular pressure (IOP) per unit of change in corneal IOP. Intercept represents a systematic difference in baseline values between scleral and corneal IOP. The solid lines represent the means (slope, 0.97; intercept, 10.0) and the dotted lines show the 95% confidence intervals (slope, 0.87e1.06; intercept, 7.55e12.50) derived from bootstrap analysis, using repetitive data resampling to obtain a normal distribution of values for a collection of samples. The random effect standard deviation (SD) represents an additional variable accounting for stochastic differences between subjects. A histogram with the distribution of values is shown on the right of each graph. In serial IOP measurements, we found close to a 1:1 linear relationship between changes in scleral and corneal pneumatonometry. This finding supports that following scleral pneumatonometry measurements would be useful clinically, because differences in scleral tonometry measurements reflect differences in corneal tonometry even at pathologically elevated levels of IOP. To calculate the predicted corneal IOP from a scleral IOP measurement, our data yielded the following equation: corneal IOP ¼ 1.04 scleral IOP 10.37. This formula is remarkably similar to the one we found in our study of cadaveric eyes (Table 3).4 The standard 1774 deviation of the residuals, which is a measure of the accuracy of predictions made with our model, is 2.8 mmHg. Therefore, measured differences greater than this value are likely to represent true changes in scleral pneumatonometry. This value is similar to the 95% measurement accuracy published for corneal pneumatonometry (1.5 mmHg between 0 and 40 mmHg and 3.5 mmHg between 40 and 80 mmHg).13 On average, we found that scleral pneumatonometry was approximately 10 mmHg higher than corneal pneumatonometry in our model. This value was close to that obtained Kuo et al Scleral Pneumatonometry Table 2. Covariates Do Not Impact Relationship between Scleral and Corneal Pneumotonometry Figure 4. Difference plot of scleral and corneal pneumatonometry versus the mean of scleral and corneal pneumatonometry. Agreement between scleral and corneal intraocular pressure (IOP) was analyzed using a BlandAltman plot with correction for multiple measurements per subject. Data from each subject are plotted with a different symbol. Perfect agreement would show a value of 0 for the difference between scleral IOP and corneal IOP across the range of IOPs. Mean IOP of 40 mmHg is marked as a clinically relevant reference point. Scleral IOP showed a bias toward higher values compared with corneal IOP, averaging 9.0 mmHg (95% limits of agreement, 1.5 to 19.5 mmHg). SD ¼ standard deviation. by analyzing the raw data using a Bland-Altman plot. The Bland-Altman plot also showed that the average difference between scleral and corneal pneumatonometry measurements appeared consistent over the range of IOPs that we tested. Furthermore, at more clinically relevant levels of IOP, such as mean scleral and corneal IOPs of less than 40 mmHg, more than 80% of measurements were within 5 mmHg of the average difference between scleral and corneal IOP (Fig 4). Ideally, to estimate best the corneal IOP from a scleral IOP measurement, a baseline measurement of corneal and scleral pneumatonometry should be obtained in the eye of interest before the development of significant corneal pathology to know the exact relationship between these measurements. In practice, this may not be feasible, and our data support the use of the contralateral eye to estimate the baseline difference between scleral and corneal IOP in the eye of interest, because the 2 eyes are significantly Factor P Value Age Eye Central corneal thickness Lens status Glaucoma 0.36 0.41 0.48 0.60 0.92 correlated within an individual (Fig 1). Using this calculated relationship between scleral and corneal pressure in the contralateral eye of an individual would be more accurate than using an estimate from a populationbased equation. Because the relationship between Goldmann applanation tonometry and pneumotonometry is linear, one could use the baseline difference between Goldmann applanation of the cornea and scleral pneumatonometry in the contralateral eye to estimate the predicted Goldmann applanation value for the eye of interest using scleral pneumatonometry.8 In our patient population, the relationship between scleral and corneal pneumatonometry was not impacted by age, eye laterality, central corneal thickness, glaucoma, or lens status. Age has been shown to affect scleral rigidity and was reported to affect the relationship between scleral and corneal pneumatonometry significantly in the study of Kapamajian et al.5,14 One possibility for age not affecting our model significantly is that we had an older population of patients. The mean age of our population was 74.113.4 years compared with 54.417.7 years in the study by Kapamajian et al. Although the range of ages in our patient population did span 34 to 94 years, we may not have been powered adequately to detect a difference in age on scleral IOP. Furthermore, there may be changes to the sclera related to intravitreal injections or underlying disease that were not assessed. Additionally, we evaluated only adult patients in our study, which limits the generalizability of our results. Additional studies are needed to understand the relationship of scleral IOP to corneal IOP for children because there are significant differences in scleral rigidity between adult and pediatric populations. Accurate and reliable IOP measurements are important for both diagnosing and treating glaucoma. In patients for whom corneal measurements are not possible or are unreliable, scleral pneumatonometry should be considered as a potential alternative. Our results support consistency of the Table 3. Studies of Scleral Pneumatonometry Study Correlation (r) Mean Difference Equation Kuo et al Lin et al4 Kapamajian et al5 0.94 d 0.57 9.0 mmHg compared with corneal IOP 13.2 mmHg compared with assigned IOP* 8.08 mmHg compared with corneal IOP corneal IOP ¼ 1.04 scleral IOP 10.37 assigned IOP ¼ 1.01 scleral IOP 14.14 corneal IOP ¼ 0.32 scleral IOP 0.05 age þ 11.90 IOP ¼ intraocular pressure; d ¼ no data. *Assigned IOP > corneal IOP by 3.78. 1775 Ophthalmology Volume 122, Number 9, September 2015 relationship between scleral and corneal pneumatonometry across the range of physiologic and pathologic IOPs for individual patients and show that changes in scleral pneumatonometry reflect changes in corneal pneumatonometry. Acknowledgments. The authors thank Seth Blumberg, MD, PhD, and Travis Porco, MPH, PhD, for their guidance with statistical analysis. References 1. Talajic JC, Agoumi Y, Gagné S, et al. Prevalence, progression, and impact of glaucoma on vision after Boston type 1 keratoprosthesis surgery. Am J Ophthalmol 2012;153:267–74. 2. Kamyar R, Weizer JS, de Paula FH, et al. Glaucoma associated with Boston type I keratoprosthesis. Cornea 2012;31:134–9. 3. Crnej A, Paschalis EI, Salvador-Culla B, et al. Glaucoma progression and role of glaucoma surgery in patients with Boston keratoprosthesis. Cornea 2014;33:349–54. 4. Lin CC, Chen A, Jeng BH, et al. Scleral intraocular pressure measurement in cadaver eyes pre- and postkeratoprosthesis implantation. Invest Ophthalmol Vis Sci 2014;55:2244–50. 5. Kapamajian MA, de la Cruz J, Hallak JA, Vajaranant TS. Correlation between corneal and scleral pneumotonometry: an alternative method for intraocular pressure measurement. Am J Ophthalmol 2013;156:902–6. 6. Bland JM, Altman DG. Calculating correlation coefficients with repeated observations: part 1dcorrelation within subjects. BMJ 1995;310:446. 7. Bland JM, Altman DG. Agreement between methods of measurement with multiple observations per individual. J Biopharm Stat 2007;17:571–82. 8. Eisenberg DL, Sherman BG, McKeown CA, Schuman JS. Tonometry in adults and children. A manometric evaluation of pneumotonometry, applanation and Tono-Pen in vitro and in vivo. Ophthalmology 1998;105:1173–81. 9. Friberg TR, Lace JW. A comparison of the elastic properties of human choroid and sclera. Exp Eye Res 1988;47: 429–36. 10. Patel H, Gilmartin B, Cubbidge RP, Logan NS. In vivo measurement of regional variation in anterior scleral resistance to Schiotz indentation. Ophthalmic Physiol Opt 2011;31: 437–43. 11. Moses RA, Lurie P, Wette R. Horizontal gaze position effect on intraocular pressure. Invest Ophthalmol Vis Sci 1982;22: 551–3. 12. Nardi M, Bartolomei MP, Romani A, Barca L. Intraocular pressure changes in secondary positions of gaze in normal subjects and in restrictive ocular motility disorders. Graefes Arch Clin Exp Ophthalmol 1988;226:8–10. 13. Model 30 Pneumatonometer User’s Guide. 16030-101 Rev. F. Depew, NY: Reichert Technologies; 2014:32. 14. Pallikaris IG, Kymionis GD, Ginis HS, et al. Ocular rigidity in living human eyes. Invest Ophthalmol Vis Sci 2005;46: 409–14. Footnotes and Financial Disclosures Originally received: December 22, 2014. Final revision: May 15, 2015. Accepted: May 18, 2015. Available online: July 10, 2015. Manuscript no. 2014-2070. 1 Department of Ophthalmology, University of California, San Francisco, San Francisco, California. 2 That Man May See, San Francisco, California (unrestricted grants to the University of California, San Francisco, Department of Ophthalmology). The funding organization had no role in the design or conduct of this research. Author Contributions: Conception and design: Kuo, Ou, Jeng, Bhisitkul, Stewart, Duncan, Han Department of Ophthalmology and Visual Sciences, University of Maryland School of Medicine, Baltimore, Maryland. Analysis and interpretation: Kuo, Han Presented at: American Glaucoma Society Annual Meeting, February 2014, Washington, DC.; Association for Research in Vision and Ophthalmology Annual Meeting, May 2014, Orlando, FL; and Asia Association for Research in Vision and Ophthalmology Annual Meeting, February 2015, Yokohama, Japan. Obtained funding: none Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Supported in part by the National Eye Institute, National Institutes of Health, Bethesda, Maryland (Core Grant for Vision Research no.: EY02162); Research to Prevent Blindness, Inc, New York, New York; and 1776 Data collection: Kuo, Han Overall responsibility: Kuo, Ou, Jeng, Bhisitkul, Stewart, Duncan, Han Abbreviations and Acronyms: Corneal IOP ¼ corneal pneumatonometry; IOP ¼ intraocular pressure; Scleral IOP ¼ scleral pneumatonometry. Correspondence: Ying Han, MD, PhD, Department of Ophthalmology, University of California, San Francisco, 10 Koret Way K-323, Box 0730, San Francisco, CA 94143. E-mail: [email protected].