Abstract
Purpose
To evaluate the utility of scleral pneumatonometry as an alternative for corneal measurements of intraocular pressure (IOP) over a broad range of IOPs.
Design
A prospective, observational cohort study.
Subjects
The study was conducted in the UCSF Retina Clinic between August and November 2013 in 33 adult patients (ages 34 to 94, mean 74.1 ± 13.4) receiving anti-VEGF intravitreal injections, which transiently increase IOP.
Methods
Corneal pachymetry and serial corneal and temporal scleral pneumatonometry (baseline, immediately and 10, 20 and 30 minutes post-injection) were collected. One-time baseline corneal and scleral pneumatonometry were obtained in the non-injected 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 perform covariate analyses.
Results
Scleral and corneal pneumatonometry showed nearly 1:1 linear correlation, though scleral pneumatonometry was biased toward higher values (r: 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 = 1.04 × scleral IOP – 10.37. Age, central corneal thickness, laterality, glaucoma and lens status did not impact this relationship. The difference between corneal and scleral pneumatonometry was correlated between the two eyes of individual patients (r: 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.
Intraocular pressure (IOP) is normally 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 commonly associated 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 pre-operative co-morbidity in more than two-thirds of patients and to be newly diagnosed in an additional 13-25% of patients after keratoprosthesis implantation.1-3 Furthermore, keratoprostheses are associated with post-operative elevation in IOP and progression of glaucoma, which can become vision limiting. 1-3
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 have previously showed that serial measurements of scleral pneumatonometry correlate strongly and linearly to IOP when it was set from 20 to 50 mmHg by infusion cannula.4 Importantly, this relationship was unchanged after the eyes underwent keratoprosthesis implantation. In patients, a cross-sectional study by Kapamajian et al. found a positive correlation between one-time corneal and scleral pneumatonometry in healthy adult patients.5 However, the IOP range was limited by the physiologic pressures of this population (10.5-27 mmHg) and the relationship between changes in corneal and scleral pneumatonometry in patients was not studied. Furthermore, scleral pneumatonometry generally measured higher than corneal pneumatonometry, but this difference was highly variable across individuals (mean: 8.4 ± 5.7).5
For scleral pneumatonometry 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 two 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 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 if the difference between corneal and scleral measurements was correlated between the two 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 was compliant with HIPAA regulations and adhered to the tenets of the Declaration of Helsinki.
Adult patients receiving anti-VEGF intravitreal injections in the UCSF Retina Clinic 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 al.) with an alpha of 0.05 in an a priori sample size calculation.5 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 which would prevent accurate measurement of intraocular pressure 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 taken on 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 around 3.5 mm posterior to the limbus. Corneal and temporal scleral pneumatonometry measurements (abbreviated as ‘corneal IOP’ and ‘scleral IOP,’ respectively) were taken at baseline in both eyes prior to injection, and then serial measurement were taken in the treated eye immediately after injection, and 10, 20 and 30 minutes after injection. All measurements were taken with patients sitting up. For each pair of measurements, we checked the corneal IOP prior to 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 – 40 mmHg and less than 1.5 mmHg for IOPs above 40 mmHg. The waveform was examined for good quality in all measurements with IOPs less than 40 mmHg, where it was within the limits of the paper printout. We measured central corneal thickness (CCT) by pachymetry (DGH-550 Pachette 2, DGH Technology, Inc., Exton, PA), averaging 5 measurements, at the time of the baseline measurements.
STATISTICS: Pearson correlation coefficient is reported. For paired data with more than one time point for each study subject, an ordinary 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 “within subjects” 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 was 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, iterative resampling of the data. Co-variate analysis was performed using the linear mixed model and likelihood ratio test with p<0.05 considered statistically significant.
Results
Thirty-three patients, ages ranging from 34 to 94, 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 (one subject missed one 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 two eyes of individual patients was significantly correlated (r: 0.75, p<0.001) (Figure 1).
Table 1.
Baseline Characteristics
| Patients Enrolled | 33 |
| Age (Mean ± SD) | 74.1 ± 13.4 |
| Eye | Right = 20 |
| Left = 13 | |
| CCT (Mean ± SD) | 552.4 ± 37.0 |
| Lens Status | Phakic = 16 |
| Pseudophakic = 17 | |
| Glaucoma | 5 (2 POAG, 1 steroid-induced, 2 NOS) |
CCT = central corneal thickness
POAG = primary open angle glaucoma
NOS = not otherwise specified
Figure 1.
Scatterplot of Baseline Differences in Scleral and Corneal Pneumatonometry in the Two Eyes of Each Patient. The value for the eye scheduled to undergo treatment with an anti-VEGF agent is plotted on the x-axis and for the contralateral eye on the y-axis. Pearson correlation coefficient is shown. Reference values x=y are shown as a dotted line.
We used correlation to analyze the linear association between serial scleral and corneal IOP by pneumatonometry, and found that they were significantly correlated (r: 0.94, p<0.001) for the injected eyes (Figure 2). The data was fit using a linear mixed model, which takes into account longitudinal measurements over time. This analysis resulted in the following equation: scleral IOP = 0.97 × corneal IOP + 10.0. The standard deviation of the residuals, an error measurement for the entire model, was 2.78 mmHg. The slope (mean ± SD: 0.97 ± 0.21) 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 (Figure 3A). Similarly, the intercept (mean ± SD: 10.0 ± 5.83) was statistically significant (p < 0.001), but demonstrated greater variability among patients (Figure 3B).
Figure 2.
Scatterplot of Scleral versus Corneal Pneumatonometry. Data points from all measurements were plotted. The within subjects Pearson correlation coefficient, evaluating the relationship between scleral and corneal 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 = 0.97 × corneal IOP + 10.0).
Figure 3.
Estimated (A) slope and (B) intercept for individual patients from linear mixed model with random slope and random intercept. Slope represents the change in scleral 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 = 0.87 to 1.06, intercept = 7.55 too 12.50) derived from bootstrap analysis, using repetitive data resampling to get a normal distribution of values for a collection of samples. The random effect 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.
A Bland-Altman plot was created to examine the agreement of scleral IOP and corneal IOP over a range of IOP using data from serial IOP measurements (Figure 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.
Figure 4.
Difference Plot of Scleral and Corneal Pneumatonometry versus the Mean of Scleral and Corneal Pneumatonometry. Agreement between scleral and corneal IOP was analyzed using a Bland-Altman plot with correction for multiple measurements per subject. Data from each subject is 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 to corneal IOP, averaging 9.0 mmHg (95% limits of agreement: −1.5 to 19.5 mmHg).
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 pneumatonometry, we added these co-variates to the linear mixed model and evaluated them with a likelihood ratio test. None of these factors were statistically significant (Table 2).
Table 2.
Co-Variates Do Not Impact Relationship between Scleral and Corneal Pneumatonometry
| Factor | p-value |
|---|---|
| Age | 0.36 |
| Eye | 0.41 |
| CCT | 0.48 |
| Lens Status | 0.60 |
| Glaucoma | 0.92 |
Discussion
This study was designed to evaluate the relationship between serial corneal and scleral pneumatonometry over a wide range of physiologic and pathological levels of IOP. We found that scleral pneumatonometry was significantly correlated to corneal pneumatonometry, but was biased toward higher values. While we did not compare scleral pneumatonometry directly to Goldmann applanation, the relationship between Goldmann applanation and corneal pneumatonometry has been well described (Ta = Tpn -1.2) and corneal pneumatonometry has been reported to be age-independent and correlate best with manometric IOP compared to applanation and TonoPen in patients. 8
Scleral pneumatonometry has previously been found to be increased compared to 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 anterior-posterior location within an individual.9, 10 We chose to take measurements over the sclera temporally in primary gaze since 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 would be required to determine the optimal location for scleral pneumatonometry in patients.
Table 3.
Studies on Scleral Pneumatonometry
| Study | Correlation | Mean Difference | Equation |
|---|---|---|---|
| Kuo et al. | r: 0.94 | 9.0 mmHg compared to corneal IOP | Corneal IOP = 1.04 × Scleral IOP – 10.37 |
| Lin et al. 4 | -- | 13.2 mmHg compared to assigned IOP* | Assigned IOP = 1.01 × Scleral IOP – 14.14 |
| Kapamajian et al. 5 | r: 0.57 | 8.08 mmHg compared to corneal IOP | Corneal IOP = 0.32 × Scleral IOP – 0.05 × Age + 11.90 |
assigned IOP > corneal IOP by 3.78
Our results showed a significant correlation (r: 0.94) between scleral and corneal pneumatonometry in patients using a different approach from Kapamajian et al. (r: 0.57).5 Kapamajian et al. took one-time measurements of scleral and corneal pneumatonometry in patients, which can give variable results for the relationship between corneal and scleral measurements due to 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 of time, 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.
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 would be useful clinically, since differences in scleral tonometry 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 = 1.04 × scleral IOP – 10.37. This formula is remarkably similar to the one we found in our study cadaveric eyes (Table 3). 4 The standard 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 0-40 mmHg and 3.5 mmHg between 40-80 mmHg) (Model 30 Pneumatonometer ™User's Guide, Reichert Technologies, 16030-101 Rev. F, September 4, 2014).
On average, we found scleral pneumatonometry was about 10 mmHg higher than corneal pneumatonometry in our model. This value was close to that obtained 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 less than 40 mmHg, more than 80% of measurements were within 5 mmHg of the average difference between scleral and corneal IOP (Figure 4).
Ideally, to best estimate the corneal IOP from a scleral IOP measurement, a baseline measurement of corneal and scleral pneumatonometry should be taken in the eye of interest prior to the development of significant corneal pathology to know the exact relationship between these measurements. In practice, this may not be feasible and our data supports the use of the contralateral eye to estimate the baseline difference between scleral and corneal IOP in the eye of interest, since the two eyes are significantly correlated within an individual (Figure 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 population-based equation. Since the relationship between Goldmann applanation and pneumatonometry 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, CCT, glaucoma, or lens status. Age has been shown to affect scleral rigidity and was reported to significantly affect the relationship between scleral and corneal pneumatonometry in Kapamajian et al.'s study.5, 13 One possibility for age not significantly affecting our model is that we had an older population of patients. The mean age of our population was 74.1 ± 13.4 years compared to 54.4 ± 17.7 years in Kapamajian et al.'s study. While the range of ages in our patient population did span 34 to 94 years old, we may not have been adequately powered to detect a difference in age on scleral IOP. Furthermore, there may be changes to the sclera related to intravitreal injections or underlying disease, which were not assessed. Additionally, we only evaluated 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 since 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 that the relationship between scleral and corneal pneumatonometry is consistent across the range of physiologic and pathological IOPs for individual patients and that scleral pneumatonometry reflect changes in corneal pneumatonometry.
Précis.
Scleral pneumatonometry was significantly correlated to corneal pneumatonmetry and showed a nearly 1:1 linear relationship over a wide range of physiologic and pathologic pressures.
Acknowledgements
Special thanks to Seth Blumberg, MD, PhD, and Travis Porco, MPH, PhD, for their help and guidance with statistical analysis.
Financial Support:
This work was made possible in part, by NIH-NEI EY02162 - Core Grant for Vision Research, Research to Prevent Blindness, and That Man May See unrestricted grants to the UCSF Department of Ophthalmology. The funding organization had no role in the design or conduct of this research.
Footnotes
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Meeting Presentation:
American Glaucoma Society Annual Meeting, February, 2014.
Association for Research in Vision and Ophthalmology Annual Meeting, May, 2014.
Asia Association for Research in Vision and Ophthalmology Annual Meeting, February, 2015.
Conflict of Interest: No conflicting relationship exists for any author.
References
- 1.Talajic JC, Agoumi Y, Gagné S, et al. Prevalence, progression, and impact of glaucoma on vision after Boston type 1 keratoprosthesissurgery. Am J Ophthalmol. 2012;153:267–274. doi: 10.1016/j.ajo.2011.07.022. [DOI] [PubMed] [Google Scholar]
- 2.Kamyar R, Weizer JS, de Paula FH, et al. Glaucoma associated with Boston type I keratoprosthesis. Cornea. 2012;31:134–9. doi: 10.1097/ICO.0b013e31820f7a32. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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. doi: 10.1097/ICO.0000000000000067. [DOI] [PubMed] [Google Scholar]
- 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. doi: 10.1167/iovs.13-13153. [DOI] [PubMed] [Google Scholar]
- 5.Kapamajian MA, de la Cruz J, Hallak JA, Vajaranant TS. Correlation between corneal and scleral pneumatonometry: an alternative method for intraocular pressure measurement. Am J Ophthalmol. 2013;156:902–6. doi: 10.1016/j.ajo.2013.05.045. [DOI] [PubMed] [Google Scholar]
- 6.Bland JM, Altman DG. Calculating correlation coefficients with repeated observations: Part 1--Correlation within subjects. BMJ. 1995;310:446. doi: 10.1136/bmj.310.6977.446. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Bland JM, Altman DG. Agreement between methods of measurement with multiple observations per individual. J Biopharm Stat. 2007;17:571–82. doi: 10.1080/10543400701329422. [DOI] [PubMed] [Google Scholar]
- 8.Eisenberg DL, Sherman BG, McKeown CA, Schuman JS. Tonometry in Adults and Chidlren. A Manometric Evaluation of Pneumatonometry, Applanation and TonoPen in vitro and in vivo. Ophthalmology. 1998;105:1173–81. doi: 10.1016/S0161-6420(98)97016-6. [DOI] [PubMed] [Google Scholar]
- 9.Friberg TR, Lace JW. A comparison of the elastic properties of human choroid and sclera. Exp Eye Res. 1988;47:429–36. doi: 10.1016/0014-4835(88)90053-x. [DOI] [PubMed] [Google Scholar]
- 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. doi: 10.1111/j.1475-1313.2011.00840.x. [DOI] [PubMed] [Google Scholar]
- 11.Moses RA, Lurie P, Wette R. Horizontal gaze position effect on intraocular pressure. Invest Ophthalmol Vis Sci. 1982;22:551–3. [PubMed] [Google Scholar]
- 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. doi: 10.1007/BF02172708. [DOI] [PubMed] [Google Scholar]
- 13.Pallikaris IG, Kymionis GD, Ginis HS, et al. Ocular rigidity in living human eyes. Invest Ophthalmol Vis Sci. 2005;46:409–14. doi: 10.1167/iovs.04-0162. [DOI] [PubMed] [Google Scholar]