The corneal screening method of anterior segment optical coherence tomography (AS-OCT) provides accurate assessment of structural1–3 and topographic changes in eyes with various corneal disorders, such as ectasia and keratoconus,4 as well as compensates for intraocular pressure5 and calculates the risk for progression to glaucoma in patients with ocular hypertension.6 A distinguishing corneal pachymetric feature in keratoconus is asymmetry and focal thinning manifested inferotemporally; quantification of this characteristic pattern may be useful in keratoconus diagnosis and ectasia risk assessment.7,8 Four quantitative parameters calculated by AS-OCT pachymetry have been proposed for keratoconus diagnosis.9 Specifically, these indices are (1) superior–inferior (S–I), which is the mean superior octant thickness minus the mean inferior thickness; (2) superonasal–inferotemporal (SN–IT), which is the mean superior–nasal octant thickness minus the mean of the inferior–temporal thickness; (3) Min–Med focal thinning, defined as the minimum corneal thickness minus the median corneal thickness; and (4) Min–Max, which is the thickness range, or global thinning, and is defined as the minimum corneal thickness minus the maximum corneal thickness.
This study aimed to identify the normal values and distribution of the AS-OCT–derived corneal asymmetry and focal thinning parameters in a large pool of healthy patients and to evaluate sex and age specifics with a clinical AS-OCT system. These data will help establish normative data that can be used as clinical reference benchmarks in screening keratoconus patients and refractive surgery candidates.
Patients and methods
This prospective series study received approval by the Ethics Committee overseeing the institution’s research projects and adhered to the tenets of the Declaration of Helsinki. Informed written consent was obtained from each patient at the time of the first clinical visit. In cases of minors/children (<18 years), the consent was obtained from the next of kin or legal guardians accompanying the patient during the clinical visit, according to the institute’s established protocol.
Patient Groups: Inclusion and Exclusion Criteria
The study group consisted of consecutive cases of unoperated healthy eyes as confirmed by a complete ophthalmologic evaluation. One eye of each patient was randomly selected. Patients were eligible for the study if they met the following criteria: willing and able to understand and sign an informed consent form (for minors provided by the accompanying person), minimum age 8 years at the time of the study, and spherical equivalent between −6.0 diopters (D) and +3.5 D.
Patients with current or past ocular pathology (other than refractive error) in either eye, corneal ulcer, previous surgery, present irritation or dry-eye disorder, and recent contact lens wear were excluded from the study. Soft contact lenses had to be discontinued for 2 weeks, rigid gas-permeable contact lenses for 3 weeks, and hard poly(methyl methacrylate) contact lenses for 4 weeks. Patients with an ocular disease or condition that, by clinical judgment, could interfere significantly or compromise study results were also excluded.
Two sets of subgroups were formed to study sex and age specifics. The sex-specific Group M consisted of eyes of men, whereas Group F consisted of eyes of women. Age specifics were assessed in Group Y (patients 42 years old and younger) and Group O (patients older than 42 years). The age point of 42 was selected on the basis of life expectancy values and trends in Greece.
Optical Coherence Tomography Pachymetry Imaging
The RTVue-100 Fourier-domain AS-OCT system (Optovue, Inc.), running analysis and report software version A6 (9.0.27), was used in the study. The settings were as follows: L-Cam lens, 8 meridional B-scans per acquisition, and 1024 A-scans, each with an axial resolution of 5 μm. The main analysis pachymetry report provided by the system displayed 3-dimensional (3-D) corneal thickness maps covering a 6.0 mm diameter area produced by interpolation from the 8 meridional B-scan data. Automated data processing also produced values for the SN–IT, S–I, Min–Med, and Min–Max indices, measured in microns, which were collected for this study from both groups. The SN–IT and S–I were calculated between the 2.0 mm to 5.0 mm annulus area, while Min–Med and Min–Max were calculated over a 5.0 mm diameter area. Figure 1 shows examples of the data.
In all cases, to minimize testing variations, OCT imaging was performed by the same trained investigator and preceded the clinical ocular examination. Four consecutive individual acquisitions were obtained in each case to determine repeatability and data validity. The 4 measurements were used to assess the intraindividual repeatability for the specific corneal thickness asymmetry and focal thinning indices by calculating the standard deviation (SD) of the 4 consecutive values in each case. In each case, the mean of the 4 replicate measurements per index was used.
Descriptive statistics, linear regression, and analysis of variance (ANOVA) to look for possible correlations and ANOVA between subgroups were performed using Minitab software (version 16.2.3, Minitab, Ltd.) and Origin Lab software (version 9, Originlab Corp.). Paired analysis P values less than 0.05 were considered statistically significant.
The study evaluated 561 eyes. The mean age of the patients was 45.70 years ± 21.20 (SD) (range 8.0 to 86.0 years). The mean spherical error was −1.6 ± 1.8 D (range −6.0 to +3.5 D). There were 296 right eyes and 265 left eyes.
The mean intraindividual repeatability was 4.67 ± 3.54 μm for the SN–IT index, 4.88 ± 3.21 μm for the S–I index, 1.75 ± 1.51 μm for the Min–Med index, and 4.22 ± 2.57 μm for the Min–Max index. These values correspond to 18% of the mean SN–IT index, 19% of the mean S–I index, 8% of the mean Min–Med index, and 7% of the mean Min–Max index, respectively.
Focal Thinning Optical Coherence Tomography Indices
Table 1 shows the descriptive statistics for central corneal thickness (CCT), minimum corneal thickness, and the focal indices of SN–IT, S–I, Min–Med, and Min–Max obtained with the AS-OCT system; Figure 2 shows boxplots of these data. The negative signs for the Min–Med and Min–Max parameters were the result of the definition adopted by the AS-OCT software, which was preserved in this study for conformity. Figure 3 shows histogram plots of the distribution of these indices in the entire cohort.
Sex and Age Dependence
Group F comprised 315 women and Group M, 246 men. In Group F, the mean values were CCT, 536.71 ± 28.61 μm (range 463.0 to 596.0 μm); minimum corneal thickness, 528.83 ± 27.44 μm (range 454.0 to 583.0 μm); SN–IT, 26.34 ± 14.55 μm (range −6.0 to 97.0 μm); S–I, 25.36 ± 14.90 μm (range −8.0 to 93.0 μm); Min–Med, −20.27 ± 5.82 μm (range −7.0 to −50.0 μm); and Min–Max, −58.98 ± 16.29 μm (range −156.0 to −27.0 μm).
In Group M, the mean values were CCT, 537.77 ± 33.85 μm (range 447.0 to 654.0 μm); minimum corneal thickness, 529.25 ± 33.09 μm (range 435.0 to 644.0 μm); SN–IT, 27.00 ± 14.43 μm (range −2.0 to 72.0 μm); S–I, 26.67 ± 15.95 μm (range −8.0 to 70.0 μm); Min–Med, −21.25 ± 6.16 μm (range −9.0 to −46.0 μm); and Min–Max, −60.82 ± 16.86 μm (range −124.0 to −23.0 μm).
There was no statistically significant difference in the focal thinning indices between Group F and Group M. The 2-sample t test P values comparing Group F and Group M were 0.37 for SN–IT, 1.08 for S–I, 0.06 for Min–Med, and 0.20 for Min–Max.
Group Y comprised 259 eyes and Group O, 302 eyes. Table 1 shows the values for the indices in these 2 subgroups. The differences in the corneal asymmetry and focal thinning indices were statistically significant between Group Y and Group O as follows: SN–IT, P=.0020; S–I, P=.0012; Min–Med, P=.0025; and Min–Max, P=.0026 (all 2-sample t test).
Bases on the above results, a regression analysis of the OCT-derived corneal asymmetry and focal thinning indices against age as the independent variable was performed. Specifically, the regression slope, correlation coefficient (r2), and statistical significance (P) of the regression correlation for the indices were as follows: SN–IT, slope 0.591 ± 0.02, r2 = 0.584, P<.001; S–I, slope 0.588 ± 0.02, r2 = 0.5031, P<.001; Min–Med, slope −0.256 ± 0.01, r2 = 0.604, P<.001; Min–Max, slope −0.508 ± 0.03, r2 = 0.425, P<.001.
Since the first report of anterior segment imaging by OCT,10 continuous, rapid developments and current high-speed imaging capabilities of AS-OCT11–13 have allowed acquisition of in vivo corneal 3-D pachymetry maps with the reliability and speed required in a clinical setting.14–18 Pachymetry (corneal thickness) measurements with OCT have been shown to have excellent repeatability,6,19 particularly with Fourier-domain OCT systems.20 The detailed pachymetry map analysis by OCT systems may help support crucial diagnostic qualitative data in cases of stromal opacities and scars as well as in highly abnormal anterior cornea cases in which established topography and tomography imaging can be uncertain21 or challenging.22,23
The higher axial resolution, increased accuracy, and finer image processing with spectral-domain OCT24 than with time-domain OCT25 has enabled clinical studies of 2 corneal asymmetry and 2 focal thinning parameters that have been proposed for keratoconus classification.
In this study, we used a spectral-domain AS-OCT system to evaluate these corneal asymmetry and thinning parameters in a large pool of healthy patients in clinical practice. The peer-reviewed literature2,26 contains little data on the distribution and characteristics of corneal asymmetry and focal thinning parameters in a healthy population. Although normal values of corneal-thickness asymmetry alone may lack specificity and sensitivity, they may serve for screening large populations or for screening for abnormalities. Therefore, our study of OCT analysis of the asymmetry and thinning indices in a large healthy population might serve as a reference for future studies comparing such data in eyes with pathologic corneal disorders. One initial observation is that the so-called “normal” corneal thickness range has a wide distribution. The mean CCT in our study ranged from 447.0 to 654.0 μm, with a mean of 537.17 μm and an SD of ±30.99 μm; these findings are in agreement with those in previous studies.5,20 A similar large spread in the minimum corneal thickness was observed.
Our study established the inferior thinning and inferior–nasal thinning of the normal cornea, which was, on average, 25 μm. In a previous study of a healthy population using Scheimpflug imaging,26 a 23.2 μm apical pachymetry difference was reported in less than 5% of the population. The S–I asymmetry reported in our study agrees with findings in other studies showing that the thinnest corneal pachymetry is slightly inferior in normal eyes. These studies used Scheimpflug imaging7 or high-frequency scanning ultrasound.27
The index measurements by AS-OCT as well as the confidence interval (CI) analysis showed that the Min–Med index had the lowest intraindividual SD (1.75 ± 1.51 μm), the smallest CI (0.50 μm), and the highest coefficient of correlation (r2 = 0.604).
There were no statistically significant differences in the corneal asymmetry indices between the sex subgroups; these not significant differences were on the order of ±2.0% of the relative values. However, when comparing the younger age group with the entire sample, the SN–IT index and the S–I index were reduced by −4.44 μm and −4.46 μm, respectively (corresponding to approximately 17%), indicating an overall trend toward a less asymmetric thickness profile in the younger population. The same comparison between the older age group and the entire sample found that the SN–IT index and the S–I index were elevated by +3.81 μm and +3.83 μm, respectively (corresponding to approximately 15%), indicating an overall corneal thickness increase in asymmetry with advancing age. More important, the 2-paired analysis of the same parameters comparing the older group and the younger group showed statistically significant differences. The regression analysis found that the mean correlation coefficient between the corneal asymmetry and focal thinning indices was in the range of 0.5 to 0.6, indicating that age is a possible factor in corneal asymmetry in a healthy population.
A limitation of this study is that at present, the 3-D corneal and epithelial thickness maps from the AS-OCT device we used are limited to the center 6.0 mm corneal area. We anticipate further developments to enable in vivo imaging of the corneal thickness over a larger area (ie, 9.0 mm diameter coverage) and statistics provided over an area of at least 7.0 mm instead of the current 5.0 mm. In addition, it would be valuable to have image acquisition developments that would allow a further increase in lateral resolution, which is currently limited in the AS-OCT system we used because the system produces thickness maps using interpolation data from 8 meridians; it would be important that these developments not compromise the overall acquisition speed, which is a necessity for preventing patient motion error. These advancements would enhance the validity of the 3-D pachymetry imaging and the accuracy of the corneal thickness asymmetry and thinning indices. Nevertheless, we believe these asymmetry indices should be further studied for their applicability in keratoconus classification. They may become automated, reproducible markers for early ectasia detection.
In conclusion, this was a comprehensive study of corneal asymmetry and focal thinning indices performed using AS-OCT in a cohort of consecutive normal eyes in a clinical setting. Our findings indicate that AS-OCT may become an alternative device to screen, diagnose, and follow-up multiple physiologic corneal parameters.
What Was Known
- Corneal thickness asymmetry and focal thinning parameters measured by detailed pachymetry provided by AS-OCT have been proposed for keratoconus and ectasia screening. In studies of healthy populations using Scheimpflug or high-frequency scanning ultrasound imaging, a 23.2 μm apical pachymetry difference was reported to represent less than 5% of the population.
What This Paper Adds
- Inferior thinning and inferior–nasal thinning were, on average, 25 μm (95% CI, 1.2), the Min–Med index was, on average, −21 μm (95% CI, 0.50), and the Min–Max was, on average, −60 μm (95% CI, 1.4).
- There was no statistically significant difference in corneal asymmetry between men and women. Corneal asymmetry was greater in older patients than in younger patients.
- Normal data were quite uniform for both sexes and among younger and middle-aged adults, potentially creating a sensitive benchmark for early ectasia detection.
1. Sandali O, El Sanharawi M, Temstet C, Hamiche T, Galan A, Ghouali W, Goemaere I, Basli E, Borderie V, Laroche L. Fourier-domain optical coherence tomography imaging in keratoconus; a corneal structural classification. Ophthalmology
2. Szalai E, Berta A, Hassan Z, Módis L Jr. Reliability and repeatability of swept-source Fourier-domain optical coherence tomography and Scheimpflug imaging in keratoconus. J Cataract Refract Surg
3. Facuda S, Yamanari M, Lim Y, Hoshi S, Beheregaray S, Oshika T, Yasuno Y. Keratoconus diagnosis using anterior segment polarization-sensitive optical coherence tomography. Invest Ophthalmol Vis Sci. 54, 2013, p. 1384-1391, Available at: http://www.iovs.org/content/54/2/1384.full.pdf
. Accessed May 9, 2014.
4. Nakagawa T, Maeda N, Higashiura R, Hori Y, Inoue T, Nishida K. Corneal topographic analysis in patients with keratoconus using 3-dimensional anterior segment optical coherence tomography. J Cataract Refract Surg
5. Doughty MJ, Zaman ML. Human corneal thickness and its impact on intraocular pressure measures: a review and meta-analysis approach. Surv Ophthalmol
6. Mohamed S, Lee GKY, Rao SK, Wong AL, Cheng ACK, Li EYM, Chi SCC, Lam DSC. Repeatability and reproducibility of pachymetric mapping with Visante anterior segment-optical coherence tomography. Invest Ophthalmol Vis Sci. 48, 2007, p. 5499-5504, Available at: http://www.iovs.org/cgi/reprint/48/12/5499
. Accessed May 9, 2014.
7. Ambrósio R Jr, Caiado ALC, Guerra FP, Louzada R, Sinha Roy A, Luz A, Dupps WJ, Belin MW. Novel pachymetric parameters based on corneal tomography for diagnosing keratoconus. J Refract Surg
8. Branco Ramos JL, Li Y, Huang D. Clinical and research applications of anterior segment optical coherence tomography – a review. Clin Exp Ophthalmol. 37, 2009, p. 81-89, Available at: http://onlinelibrary.wiley.com/doi/10.1111/j.1442-9071.2008.01823.x/pdf
. Accessed May 9, 2014.
9. Li Y, Meisler DM, Tang M, Lu ATH, Thakrar V, Reiser BJ, Huang D. Keratoconus diagnosis with optical coherence tomography pachymetry mapping. Ophthalmology
10. Izatt JA, Hee MR, Swanson EA, Lin CP, Huang D, Schuman JS, Puliafito CA, Fujimoto JG. Micrometer-scale resolution imaging of the anterior eye in vivo with optical coherence tomography. Arch Ophthalmol
11. Potsaid B, Baumann B, Huang D, Barry S, Cable AE, Schuman JS, Duker JS, Fujimoto1 JG. Ultrahigh speed 1050nm swept source/Fourier domain OCT retinal and anterior segment imaging at 100,000 to 400,000 axial scans per second. Opt Express. 18, 2010, p. 20029-20048, Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3136869/pdf/nihms304233.pdf
. Accessed May 9, 2014.
12. Rocha KM, Perez-Straziota CE, Stulting RD, Randleman JB. SD-OCT analysis of regional epithelial thickness profiles in keratoconus, postoperative corneal ectasia, and normal eyes. J Refract Surg
13. Ge L, Yuan Y, Shen M, Tao A, Wang J, Lu F. The role of axial resolution of optical coherence tomography on the measurement of corneal and epithelial thicknesses. Invest Ophthalmol Vis Sci. 54, 2013, p. 746-755, Available at: http://www.iovs.org/content/54/1/746.full.pdf
. Accessed May 9, 2014.
14. Wojtkowski M, Kaluzny B, Zawadzki RJ. New directions in ophthalmic optical coherence tomography. Optom Vis Sci. 89, 2012, p. 524-542, Available at: http://journals.lww.com/optvissci/Fulltext/2012/05000/New_Directions_in_Ophthalmic_Optical_Coherence.4.aspx
. Accessed May 9, 2014.
15. Khurana RN, Li Y, Tang M, Lai MM, Huang D. High-speed optical coherence tomography of corneal opacities. Ophthalmology
16. Li Y, Shekhar R, Huang D. Corneal pachymetry mapping with high-speed optical coherence tomography. Ophthalmology
17. Dutta D, Rao HL, Addepalli UK, Vaddavalli PK. Corneal thickness in keratoconus; comparing optical, ultrasound, and optical coherence tomography pachymetry. Ophthalmology
18. Pöltner G, Miller K, Berke A, Sickenberger W. Measuring of corneal thickness of contact lens wearers with keratoconus and keratoplasty by means of optical coherence tomography (OCT). Coll Antropol. 37(suppl 1): 2013, p. 165-173, Available at: http://hrcak.srce.hr/file/151425
. Accessed May 9, 2014.
19. Li Y, Tang M, Zhang X, Salaroli CH, Ramos JL, Huang D. Pachymetric mapping with Fourier-domain optical coherence tomography. J Cataract Refract Surg
20. Kanellopoulos AJ, Asimellis G. In vivo three-dimensional corneal epithelium imaging in normal eyes by anterior-segment optical coherence tomography: a clinical reference study. Cornea
21. Kanellopoulos AJ, Asimellis G. Forme fruste keratoconus imaging and validation via novel multi-spot reflection topography. Case Rep Ophthalmol. 4, 2013, p. 199-209, Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3843937/pdf/cop-0004-0199.pdf
. Accessed May 9, 2014.
22. Kanellopoulos AJ, Asimellis G. In vivo 3-dimensional corneal epithelial thickness mapping as as indicator of dry eye: preliminary clinical assessment. Am J Ophthalmol
23. Bald MR, Stoeger C, Galloway J, Tang M, Holiman J, Huang D. Use of Fourier-domain optical coherence tomography to evaluate anterior stromal opacities in donor corneas. J Ophthalmol. 2013, 2013, 397680, Available at: http://downloads.hindawi.com/journals/joph/2013/397680.pdf
. Accessed May 9, 2014.
24. Chen TC, Cense B, Pierce MC, Nassif N, Park BH, Yun SH, WhiteBR Bouma BE, Tearney GJ, de Boer JF. Spectral domain optical coherence tomography: ultra-high speed, ultra-high resolution ophthalmic imaging. Arch Ophthalmol
25. Prakash G, Agarwal A, Jacob S, Kumar DA, Agarwal A, Banerjee R. Comparison of Fourier-domain and time-domain optical coherence tomography for assessment of corneal thickness and intersession repeatability. Am J Ophthalmol
26. Khachikian SS, Belin MW, Ciolino JB. Intrasubject corneal thickness asymmetry. J Refract Surg
27. Reinstein DZ, Archer TJ, Gobbe M, Silverman RH, Coleman DJ. Stromal thickness in the normal cornea: three-dimensional display with Artemis very high-frequency digital ultrasound. J Refract Surg