The Role of Cornea in Glaucoma Management: Central Corneal Thickness and Corneal Hysteresis
- 1 The Role of Corneal Hysteresis in Glaucoma Management
- 1.1 Introduction
- 1.2 Corneal Structure
- 1.3 Corneal Biomechanics
- 1.4 Ocular Response Analyzer
- 1.5 Corneal Hysteresis
- 1.6 Impact of Corneal Thickness and Intraocular Pressure on Corneal Hysteresis
- 1.7 Impact of Age, Gender, and Race on Corneal Hysteresis
- 1.8 Corneal Hysteresis in Primary Open Angle Glaucoma
- 1.9 Corneal Hysteresis and Structural Changes in Glaucoma
- 1.10 Corneal Hysteresis and Functional Changes in Glaucoma
- 1.11 Corneal Hysteresis and Response to Glaucoma Therapy
- 1.12 Clinical Application of Corneal Hysteresis in Glaucoma Management
- 2 References
The Role of Corneal Hysteresis in Glaucoma Management
Syed Amal Hussnain, MD and Christopher C. Teng, MD
Department of Ophthalmology and Visual Science, Yale School of Medicine, New Haven, CT, USA
Corneal biomechanics, especially corneal hysteresis (CH), has emerged as a topic of great interest in the field of glaucoma. This is mainly due to two reasons: (i) corneal biomechanics may play an important role in accurate measurement of intraocular pressure (IOP), the only modifiable risk factor in glaucoma and (ii) corneal biomechanics may be a surrogate for the overall globe biomechanics and therefore may be an indicator of optic nerve head susceptibility to damage from elevated IOP.
Given the rise in the number of ophthalmic procedures that alter corneal biomechanics, such as LASIK, PRK, and collagen cross-linking, a basic understanding of corneal biomechanics is useful for eye care providers who manage glaucoma.
Corneal hysteresis (CH) is the only widely used in vivo measureable biomechanical property. CH reflects the viscous damping ability of the cornea. It is measured by the Ocular Response Analyzer (Reichert, Corp., Depew, NY, USA) and has been shown in several studies to predict the progression as well as response to therapy in primary open angle glaucoma (POAG). The aim of this article is to review the role of CH in the management of POAG.
The human cornea consists of five layers: epithelium, Bowman layer, stroma, Descemet membrane, and endothelium (Figure 1). Of these corneal layers, stroma constitutes 90% of the total cornea.
Whereas corneal thickness is a static physical property, corneal biomechanics refers to the dynamic behavior of the cornea. The clinically relevant biomechanics of the cornea can be understood by two material properties, i.e. elasticity and viscosity. Both elasticity and viscosity are mechanical properties that describe how a material deforms (“strain”) in response to an external load (“stress”). An elastic material, such as a spring, regains its original position by following the exact pathway of its initial displacement after removal of the external force. The slope of the stress-strain plot defines the elasticity modulus, or Young’s modulus, of a material. Conversely, a viscous material does not follow the exact path of deformation to regain its original shape upon removal of the stress.
The cornea exhibits both elastic and viscous properties that can be explained by the two constituents of its stroma: collagen fibers and the ground substance. Collagen fibers are the main load-bearing substance and provide elasticity whereas the ground substance, composed of glycosaminoglycans (GAGs) and proteoglycans (PGs), offers viscosity. Given its viscoelastic nature, the cornea absorbs and dissipates energy as heat during a stress-strain cycle.
When attempting to measure corneal biomechanical properties, it is important to note that the cornea is a dynamic, viscoelastic, and structurally heterogeneous material. Therefore, any measurement of corneal biomechanics will be affected by the amount and the rate at which the stress is applied, the location of the cornea where the measurement is made, the IOP, as well as the age.
Ocular Response Analyzer
The in vivo measurement of corneal biomechanics was first made possible in 2005 with the advent of the Ocular Response Analyzer. The ORA is based on bi-directional noncontact applanation pneumotonometry (Figure 2A). An accelerating air pulse is generated by the ORA to slightly indent the cornea. Two pressure measurements, P1 and P2, are recorded within 20 milliseconds using an electro-optical system that detects infrared light reflected from the cornea while applanated during its inward and outward movement (Figure 2B). P1 and P2 are not the same due to the viscoelastic properties of the corneal stroma. The average ((P1+P2)/2) and the difference (P1-P2) of these two measurements are recorded as Goldman-correlated IOP (IOPg) and corneal hysteresis (CH), respectively. CH is a reflection of viscous damping (see Corneal Biomechanics above) within the corneal stroma that is providedo by glycosaminoglycans and proteoglycans.
Two other parameters obtained during an ORA measurement are corneal-compensated IOP (IOPcc) and corneal resistance factor (CRF). IOPcc is derived from an algorithm based on pre- and post-LASIK data and is considered to be less affected by the cornea. CRF is a measure of the cornea’s overall resistance related to elastic properties of the cornea and is not associated with CH. The precise meaning and application of IOPcc and CRF is not completely understood.
ORA measurements have been shown to be repeatable and highly consistent. The ORA software generates a reliability indicator called “waveform score” for each measurement. This should be taken into account when interpreting ORA data, with a waveform score of <3.5 suggesting an unreliable measurement. A normal tear film is important for a proper reflected light signal and accurate ORA measurement.
Corneal hysteresis (CH) is a biomechanical property that reflects the viscous damping ability of the cornea. Hysteresis, from Greek meaning “lagging behind”, is the difference between how a material deforms and reforms during loading and unloading from an applied force. It is a property of materials that combine elasticity and viscosity. Two analogies that can be used to understand viscoelastic materials as well as hysteresis are memory foams and automotive suspension systems. Both have coils that provide elasticity as well as shock absorbers to provide viscosity. Unlike simple spring that would respond in a linear fashion during a stress-strain cycle, these products have an initial resistance during loading and a delay during unloading.
Similarly, corneal stroma consisting of glycosaminoglycans and proteoglycans is viscoelastic and has hysteresis. This allows the cornea to absorb and dissipate energy during a stress-strain cycle when a force is applied. CH is not an inherent property of the cornea, but rather reflects how the cornea reacts to an external force.
The average CH in normal eyes has been shown to range from 9.6 to 10.7 mmHg with strong correlation between the two eyes of the same patient, whereas mean values in POAG are lower and range from from 8 to 10 mmHg. 
Impact of Corneal Thickness and Intraocular Pressure on Corneal Hysteresis
Central Corneal Thickness (CCT) and intraocular pressure are two important factors to be considered when assessing corneal hysteresis. In healthy patients, there is a strong positive correlation between CH and CCT. By comparison, there is a positive but much weaker correlation between CH and CCT glaucoma patients. In healthy patients, there is a thicker cornea with healthy stroma and more viscous substance, i.e. GAGs and PGs, which results in a higher viscous damping ability.
IOP is negatively correlated with CH such that the higher the IOP, the lower the CH. La Place’s law, which states that wall tension is a function of internal pressure, can help understand this concept. As IOP increases, the cornea becomes stiffer and its damping ability reduces. It is therefore important to account for CCT and IOP to isolate the effect of CH, both in clinical settings as well as in research studies.
Impact of Age, Gender, and Race on Corneal Hysteresis
Viscous substances responsible for corneal hysteresis (CH) decrease with age resulting in lowering of CH over time. The rate of CH decline over time has been estimated to range from 0.24 to 0.7 mmHg/decade in normal eyes. Though some studies demonstrated CH to be lower in African Americans compared to Caucasians, others have not found a statistically significant difference between these two populations independent of CCT. Gender, axial length, spherical equivalent, and myopia have no significant effects on ORA measurements.
Corneal Hysteresis in Primary Open Angle Glaucoma
Several cross sectional studies have shown corneal hysteresis (CH) to be lower in eyes with primary open angle glaucoma (POAG) compared to normal eyes, with mean CH values in POAG ranging from 8 to 10 mmHg (Table 1). Similarly, CH has also been shown to be lower in normal tension glaucoma (NTG) when compared to normal eyes, but higher in NTG than POAG eyes. Based on different studies, the difference in CH between POAG and normal eyes ranges anywhere from 1 to 2 mmHg. It has also been reported that CH values can discriminate between normal, POAG, and ocular hypertensive/glaucoma suspect eyes. In addition, CH was recently shown to decline at a faster rate in POAG compared to normal eyes.
Given the cornea’s continuity with the lamina cribrosa, corneal hysteresis (CH) is proposed to be marker of overall globe biomechanics and to predict optic nerve head (ONH) susceptibility to glaucomatous damage. This hypothesis is supported by several studies demonstrating a correlation between CH and ONH structural changes in glaucoma. Higher CH, but not CCT, has been shown to be correlated with more optic nerve surface compliance during artificially induced IOP elevations in the eyes of glaucoma patients. This suggests that eyes with higher CH may be better able to tolerate IOP spikes. Conversely, CH is significantly lower in POAG patients with acquired pit of the optic nerve – a change indicative of glaucomatous damage – than those who do not have such changes. Other structural markers of the optic nerve such as cup-to-disc ratio and Heidelberg Retina Tomograph (HRT) rim area are also associated with CH.
The data suggests that CH may either directly contribute to the pathogenesis of optic nerve damage in glaucoma or may serve as a surrogate marker for overall globe biomechanics. A definitive link between CH and ONH damage, however, is not yet established, with other studies showing no correlation between CH and RNFL thickness or cup-to-disc ratio.
Corneal Hysteresis and Functional Changes in Glaucoma
Corneal hysteresis (CH) has also been shown to be associated with functional changes in glaucoma. Congdon et al. were the first to show that low CH, but not CCT, was associated with progressive visual field loss in glaucoma patients over 5 years. Medeiros et al. recently demonstrated in a prospective study that for each 1 mmHg decrease in baseline CH, there was 0.25% faster rate of visual field index decline over time in glaucoma patients. In addition, in POAG patients with asymmetric visual fields, the worse eye had lower CH.
Corneal Hysteresis and Response to Glaucoma Therapy
Corneal hysteresis (CH) has an inverse relationship with intraocular pressure (IOP), i.e. CH rises as IOP drops, and vice versa. This phenomenon has been demonstrated with various IOP lowering therapies including topical prostaglandin analog, tube shunt, as well as trabeculectomy. Lower CH was shown to result in a higher IOP lowering response in patients being treated with prostaglandins and selective laser trabeculoplasty (SLT).
Clinical Application of Corneal Hysteresis in Glaucoma Management
Corneal hysteresis (CH) is lower in glaucoma and has been shown in various studies to be more strongly associated with structural and functional changes in glaucoma compared to central corneal thickness. In addition, CH has also been shown to predict glaucoma progression and response to glaucoma therapy. For this reason, despite our lack of understanding about the true nature of this variable, it is an important clinical measurement that can help risk stratify and set therapy goals for glaucoma patients.
- Kotecha A. What biomechanical properties of the cornea are relevant for the clinician? Survey of Ophthalmology. 2007; 52(6):109–114.
- Roberts, C. Concepts and misconceptions in corneal Biomechanics. J Cataract Refract Surg. 2014; 40:862–869.
- Terai N, Raiskup F, Haustein M, Pillunat LE, Spoer E. Identification of biomechanical properties of the cornea: the ocular response analyzer. Current Eye Research. 2012;37(7):553–562.
- Elsheikh A, Wang D, Rama P, Campanelli M, Garway-Heath D. Experimental assessment of human corneal hysteresis. Current Eye Research. 2008; 33:205–213.
- Hjortdal JO. On the biomechanical properties of the cornea with particular reference to refractive surgery. Acta Ophthalmol Scand Suppl. 1998;(225):1-23.
- Elsheikh A, Wang D, Brown M, Rama P, Campanelli M,Pye D. Assessment of corneal biomechanical properties and their variation with age. Curr Eye Res. 2007; 32:11–19.
- Luce DA. Determining in vivo biomechanical properties of the cornea with an ocular response analyzer. J Cataract Refract Surg. 2005; 31:156–162.
- Mandalos A, Anastasopoulos E, Makris L, et al. Inter-examiner reproducibility of ocular response analyzer using the waveform score quality index in healthy subjects. J Glaucoma. 2013; 22:152–155.
- Lam A, Chen D, Tse J. The usefulness of waveform score from the Ocular Response Analyzer. Optomet Vis Sci. 2010;87:195–199.
- Dupps WJ Jr. Hysteresis: new mechanospeak for the ophthalmologist. J Cataract Refract Surg. 2007; 33:1499–1501.
- Hussnain SA, Alsberge JB, Ehrlich JR, et al. Change in corneal hysteresis over time in normal, glaucomatous and diabetic eyes. Acta Ophthalmol. 2015 Apr 28 [Epub aheadof print].
- Shah S, Laiquzzaman M, Bhojwani R, et al. Assessment of the biomechanical properties of the cornea with the ocular response analyzer in normal and keratoconic eyes. Invest Ophthalmol Vis Sci. 2007; 48:3026–3031.
- Carbonaro F, Andrew T, Mackey DA, et al. The heritability of corneal hysteresis and ocular pulse amplitude: a twin study. Ophthalmology. 2008; 115:1545–1549.
- Laiquzzaman M, Bhojwani R, Cunliffe I, et al. Diurnal variation of ocular hysteresis in normal subjects: relevance in clinical context. Clin Experiment Ophthalmol. 2006; 34:114–118.
- Mangouritsas G, Morphis G, Mourtzoukos S, et al. Association between corneal hysteresis and central corneal thickness in glaucomatous and nonglaucomatous eyes. Acta Ophthalmol. 2009; 87:901–905.
- Orssenjo GJ, Pye DC: Determination of the true intraocular pressure and modulus of elasticity of the human cornea in vivo. Bull Math Biol. 1999; 61:551—72.
- Kamiya K, Shimizu K, Ohmoto F. Effect of aging on corneal biomechanical parameters using the ocular response analyzer. J Refract Surg. 2009;25:888–893.
- Kida T, Liu JH, Weinreb RN. Effects of aging on corneal biomechanical properties and their impact on 24-hour measurement of intraocular pressure. Am J Ophthalmol. 2008;146:567–572.
- Shen M, Wang J, Qu J et al. Diurnal variation of ocular hysteresis, corneal thickness, and intraocular pressure. Optom Vis Sci. 2008;85:1185–1192.
- Kotecha A, Elsheikh A, Roberts CR, et al. Corneal thickness- and age-related biomechanical properties of the cornea measured with the ocular response analyzer. Invest Ophthalmol Vis Sci. 2006;47:5337–5347.
- Haseltine SJ, Pae J, Ehrlich JR, et al. Variation in corneal hysteresis and central corneal thickness among Black, Hispanic and White subjects. Acta Ophthalmol. 2012; 90:e626–e631.
- 22. Detry-Morel M, Jamart J, Hautenauven F, et al. Comparison of the corneal biomechanical properties with the ocular response analyzer (R) (ORA) in African and Caucasian normal subjects and patients with glaucoma. Acta Ophthalmol. 2012;90:e118–e124.
- Leite MT, Alencar LM, Gore C, et al. Comparison of corneal biomechanical properties between healthy Blacks and Whites using the ocular response analyzer. Am J Ophthalmol. 2010; 150:163–168.
- Lazreg S, Mesplié N, Praud D, et al. Comparison of corneal thickness and biomechanical properties between North African and French patients. J Cataract Refract Surg. 2013;39(3):425-30.
- Kamiya K, Hagishima M, Fujimura F, et al. Factors affecting corneal hysteresis in normal eyes. Graefes Arch Clin Exp Ophthalmol. 2008;246:1491–1494.
- Lim L, Gazzard G, Chan YH et al. Cornea biomechanical characteristics and their correlates with refractive error in Singaporean children. Invest Ophthalmol Vis Sci.2008;49:3852–3857.
- Sullivan-Mee M, Billingsley SC, Patel AD. Ocular response analyzer in subjects with and without glaucoma. Optom Vis Sci. 2008; 85: 463–470.
- Kaushik S, Pandav SS, Banger A, et al. Relationship between corneal biomechanical properties, central corneal thickness, and intraocular pressure across the spectrum of glaucoma. Am J Ophthalmol. 2012; 153:840–849.
- Abitbol O, Bouden J, Doan S et al. Corneal hysteresis measured with the ocular response analyzer in normal and glaucomatous eyes. Acta Ophthalmol. 2010; 88: 116–119.
- Grise-Dulac A, Saad A, Abitbol O, et al. Assessment of corneal biomechanical properties in normal tension glaucoma and comparison with open-angle glaucoma, ocular hypertension, and normal eyes. J Glaucoma. 2012; 21:486–489.
- 31. Wells AP, Garway-Heath DF, Poostchi A, et al. Corneal hysteresis but not corneal thickness correlates with optic nerve surface compliance in glaucoma patients. Invest Ophthalmol Vis Sci. 2008; 49:3262–3268.
- Bochmann F, Ang GS, Azuara-Blanco A. Lower corneal hysteresis in glaucoma patients with acquired pit of the optic nerve (APON). Graefes Arch Clin Exp Ophthalmol. 2008; 246:735–738.
- Prata TS, Lima VC, Guedes LM, et al. Association between corneal biomechanical properties and optic nerve head morphology in newly diagnosed glaucoma patients. Clin Experiment Ophthalmol. 2012; 40:682–688.
- 34. Khawaja AP, Chan MPY, Broadway DC, et al. Corneal biomechanical properties and glaucoma-related quantitative traits in the EPIC-Norfolk eye. Invest Ophthalmol Visual Sci. 2014; 55:117–124.
- Vu DM, Silva FQ, Haseltine SJ, et al. Relationship between corneal hysteresis and optic nerve parameters measured with spectral domain optical coherence tomography. Graefes Arch Clin Exp Ophthalmol. 2013; 251:1777–1783.
- Carbonaro F, Hysi PG, Fahy SJ, et al. Optic disc planimetry, corneal hysteresis, central corneal thickness, and intraocular pressure as risk factors for glaucoma. Am J Ophthalmol. 2014; 157:441–446.
- 37. Congdon NG, Broman AT, Bandeen-Roche K, et al.Central corneal thickness and corneal hysteresis associated with glaucoma damage. Am J Ophthalmol. 2006;141:868–875.
- Medeiros FA, Meira-Freitas D, Lisboa R, et al. Corneal hysteresis as a risk factor for glaucoma progression: a prospective longitudinal study. Ophthalmology. 2013; 120:1533–1540.
- Anand A, De Moraes CG, Teng CC, et al. Corneal hysteresis and visual field asymmetry in open angle glaucoma. Invest Ophthalmol Vis Sci.2010;51:6514–8.
- Bolivar G, Sanchez-Barahona C, Teus M, et al. Eﬀect of topical prostaglandin analogues on corneal hysteresis. Acta Ophthalmol. 2015;[Epub ahead of print]
- Pakravan M, Afroozifar M, Yazdani S. Corneal biomechanical changes following trabeculectomy, phaco-trabeculectomy, Ahmed glaucoma valve implantation and phacoemulsification. J Ophthalmic Vis Res. 2014; 9:7–13.
- Agarwal DR, Ehrlich JR, Shimmyo M, et al. The relationship between corneal hysteresis and the magnitude of intraocular pressure reduction with topical prostaglandin therapy. Br J Ophthalmol. 2012; 96:254–257.
- Hirneiss C, Sekura K, Brandlhuber U, et al. Corneal biomechanics predict the outcome of selective laser trabeculoplasty in medically uncontrolled glaucoma. Graefes Arch Clin Exp Ophthalmol. 2013; 251:2383–2388.