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Lisbon 2005 Journal of Cataract and Refractive Surgery Symposium Corneal Biomechanics Cheryl Guttman in Lisbon ONCE a subject of scientific curiosity, corneal biomechanics is now the focus of intense research in many areas of clinical ophthalmology. A special symposium of the Journal of Cataract and Refractive Surgery held during the XXIII Congress of the ESCRS spotlighted the most recent developments. Cynthia Roberts PhD, The Ohio State University, chairperson of the symposium, explained that with increased understanding of corneal biomechanics comes the potential to identify sources of error in IOP measurement and therefore to develop more accurate tonometry techniques. A better understanding of corneal biomechanics might also allow for improved predictability of refractive surgery outcomes and could improve the preoperative identification of eyes at risk for developing ectasia after refractive surgery. “Corneal biomechanics can be exploited to manipulate shape and vision, and I see biomechanical customisation as the next generation in refractive surgery,” segments that are drivers to the biomechanical response and doing that reduces the variability associated with variation in biomechanical properties,” noted Dr Roberts. In addition, a contralateral eye study performed by Dr Roberts and colleagues demonstrated the biomechanical response after LASIK could be manipulated by the choice of laser used to perform the ablation.The effect was measured by differences in induced higher order aberrations and could be attributed to between-laser differences in ablation zone sizes. Schematic diagram of the biomechanical response to circumferential severing of corneal lamellae. The anterior peripheral lamellar segments are “relaxed” allowing swelling which leads to central flattening and peripheral steepening. Schematic diagram of the proposed influence of ablation zone size on the biomechanical response. By ablating more of the peripheral lamellar segments, the biomechanical response is reduced, and the variability due to individual biomechanical properties is reduced. “Corneal biomechanics can be exploited to manipulate shape and vision, and I see biomechanical customisation as the next generation in refractive surgery,” Dr Roberts said. She cited various studies to show that the corneal biomechanical response can be manipulated once it is understood. For example, a study by John Marshall PhD, showed refractive predictability after LASIK could be improved by changing from a 5.0 mm to a 6.0 mm optical zone. The explanation for the differences lies in corneal biomechanics. “Adding 1.00 mm to the ablation zone wipes out some of the peripheral lamellar Courtesy of Cynthia Roberts PhD Cynthia Roberts PhD Average tangential curvature maps from a contralateral eye study indicating that the eyes with the smaller ablation zone (right) had significantly greater paracentral steepening and also spherical aberration induction, than the contralateral eyes. Modelling based on structural characterisation William J. Dupps MD, PhD, first described a biomechanical model of corneal response to surgery in 1995. According to that model, the normal cornea is seen as a stacked layer of lamellae and can be analogised to rubber bands with sponges in between. A refractive surgery procedure that circumferentially severs the tension-bearing lamellae can be thought of as removing tension from some of the rubber bands. As a result, they can no longer hold water out of the sponges, and in the midperiphery and periphery, the sponges swell. In the eye, that change is seen as paracentral and peripheral thickening and steepening. However, due to structural interconnections and communication between anterior and posterior layers within the cornea, any procedure that circumferentially severs tension-bearing lamellae also leads to central biomechanical flattening. Biophysicist Keith Meek PhD, and colleagues at Cardiff University have been using X-ray diffraction to analyse the ultrastructure of the corneal stroma in order to shed light on how the cornea responds as a unit to a procedure that affects only one part of it. “Collagen provides mechanical strength to the cornea and it is the orientation and distribution of the fibrils that largely govern how the cornea responds to mechanical stress.That is why it is important to study the distribution and organisation of lamellae in the cornea,” Dr Meek said. The technique being used involves passing an intense beam of x-rays, generated by a synchrotron, through the cornea and measuring how the x-rays are scattered. This provides unique quantitative information about fibril orientation and distribution and allows these parameters to be mapped across the cornea. At present, only two-dimensional maps are produced.Whilst these can help to explain some of the gross biomechanical properties of the cornea, Dr Meek noted that a three-dimensional model would be needed to determine potential implications for refractive surgery. Studies comparing normal eyes and those with keratoconus show that the gross organisation of the stromal lamellae is dramatically disturbed in the keratoconic eyes compared with the normal eyes, particularly in the cone position. In addition, there is variation in the distribution of the collagen fibrillar mass in the keratoconic eyes as compared with the relatively uniform distribution seen in the normal cornea. “These findings lend further support to the concept that collagen organisation in the cornea is pivotal to the shape of this tissue,” Dr Meek said. New measurement tools Researching corneal biomechanics and the ability to effectively manipulate those properties in clinical practice will depend on the availability of tools that allow noninvasive, in vivo measurement. EuroTimes December 2005 Courtesy of William J. Dupps MD, PhD Jay Pepose different regions of the cornea, yields results that are not confounded by the epithelium, and has a sampling depth range that lies somewhere between 250 and 750 microns. It also performed as predicted in showing an increase in wave velocity following corneal cross-linking and decreases in velocity after relaxing incisions. “Issues that need to be addressed in the clinical setting include sensitivity to surface hydration, IOP and indentation artefacts,” he added. A second instrument that Dr Dupps is creating with collaborators Matthew Ford and Andrew Rollins PhD from Case Western Reserve University is a noncontact system that uses high-speed OCT and sophisticated software to measure and map both the magnitude and direction of strain within different layers of the cornea. Currently, the information is depicted in two formats: 1) as a two-dimensional, cross-sectional map using different colours to represent different levels of strain intensity, and 2) as a vector map that provides information on strain direction and magnitude. The researchers are currently developing software that will provide a threedimensional reconstruction of strain within the cornea. Among the potential applications for this technology, early detection of keratoconus may be most important. The long list of other possible uses includes characterisation of wound healing responses in postkeratoplasty eyes and the prediction of biomechanical responses to refractive surgery. “Ultimately, however, our toolbox for investigating corneal biomechanical properties will need to contain a variety of different instruments, each providing a different view of these complex phenomena. In addition, translation Map based on X-ray diffraction findings showing the orientation of preferentially aligned lamellae at different points across the cornea superimposed on a picture of an eye. The cornea’s collagen is of this information arranged predominantly vertically and horizontally in the central cornea whereas it is essentially into clinical use will tangential at the edge of the cornea. As one moves from the centre of the cornea, there is more require collagen so the plots get larger. The map allows you to see at a glance if a given penetrating multidisciplinary incision would sever the fibrils or cut parallel to most of them. “For years, no one but scientists in the field cared about optical aberrations. However, with the development of wavefront sensors and the ability to measure wavefront errors came new interest and research that led to understanding of how to control that outcome,” Dr Roberts said. William J. Dupps MD, PhD, Cole Eye Institute, described two investigational modalities for measuring corneal biomechanical properties. The first is a handheld ultrasound prototype device dubbed the Sonic Eye, which is being developed by PriaVision, Inc. It measures the “time of flight” or velocity of a wave propagated between two points along a tissue sample. “This instrument provides one modality for characterising corneal stiffness. The propagation speed of a sonic wave is faster in a stiffer cornea,” Dr Dupps explained. In testing a prototype device in porcine and human donor eyes, Dr Dupps and colleagues found that the technology offers good measurement repeatability across Courtesy of Keith M. Meek PhD Kieth Meek EuroTimes December 2005 Jesper Hjortdal collaboration to translate complex biomechanical tissue data into improved diagnostic criteria for ectasia and enhanced surgical outcomes,” said Dr Dupps. “Issues that need to be addressed in the clinical setting include sensitivity to surface hydration, IOP and indentation artefacts,” William J. Dupps MD, PhD Characterising biomechanical responses to corneal procedures Several speakers presented studies investigating the effects of different refractive surgery procedures on the cornea’s biomechanical response. Sunil Shah MD, The Midland Eye Institute, Birmingham, UK, used the currently marketed Ocular Response Analyzer (ORA, Reichert) to measure changes in corneal hysteresis, which is a reflection of corneal viscoelasticity. The study followed a consecutive series of 80 eyes that underwent LASIK or LASEK. Betweengroup differences were expected since LASIK places the ablation deeper in the cornea where the layers are structurally distinct from the more superficial layers. The amount of hysteresis was reduced significantly from 11.5 mm Hg (range 7.9 mmHg to 16.7 mmHg) at baseline to 9.3 mm Hg (range 2.5 mmHg to 13.1 mmHg) for the overall cohort. However, the mean change in hysteresis was not significantly different between the LASIK and LASEK groups. “We were surprised by that finding as we had expected cutting a lamellar flap for Michael Knorz Ioannis Pallikaris LASIK would affect the biomechanical properties of the cornea differently than a LASEK surface ablation,” Dr Shah said. There were other important findings in the study. For example, Dr Shah noted that the mean postoperative hysteresis value of 9.3 mmHg is lower than the mean for the keratoconus population at his clinic. “This observation suggests that refractive surgeons probably do need to be concerned about the biomechanical effects of their procedures on the cornea,” he commented. In addition, a regression analysis of the relationship between change in corneal hysteresis and change in corneal thickness showed only a moderate correlation at best due to very wide spread of the data. “This finding indicates hysteresis does not change by a predictable amount per unit change in corneal thickness, and so refractive surgeons cannot use corneal thickness change to predict which patients will have a huge postoperative reduction in hysteresis and therefore biomechanical property problems. However, it may be prudent to not offer refractive surgery to a patient with a low hysteresis or at least to counsel that individual about potential risk,” Dr Shah said. Courtesy of Sunil Shah MD Cynthia Roberts assessment tests, including laser polarimetry and tonometry, are filtered through the biomechanical properties of the cornea. Research in the area of IOP measurement has revealed that biomechanical properties, rather than corneal thickness or curvature, are likely the largest source of error in IOP measured with Goldmann applanation tonometry (GAT).The Ocular response Analyzer (ORA, Reichert) and the Pascal Dynamic Contour Tonometer (PDCT, SMT Swiss Microtechnology) are two new commercially available tonometry instruments that may reduce errors due to the biomechanical property changes induced by laser ablation refractive surgery. Tangential and axial difference maps (Orbscan II) after laser ablation. Note the peripheral steepening. Jesper Hjortdal MD and colleagues at Aarhus University are also comparing outcomes after surface ablation and intrastromal procedures to determine whether the two surgeries are biomechanically distinct.Their long-term study originally randomised 45 eyes with myopia between -6.0 and -8.0 D to PRK or LASIK. Corneal rigidity was assessed by the apparent IOP value measured with pneumotonometry (Reichert). “There appears to be some interlamellar healing during the first year after LASIK while over the long-term, some re-stiffening appears to occur in eyes that undergo PRK,” Jesper Hjortdal MD The results showed the apparent IOP readings were significantly affected after both surgeries, mainly due to the reductions in corneal thickness. For both groups, apparent IOP was approximately 6.0 to 7.0 mmHg lower after the procedure, and that change could be partly explained by the 70 to 80 micron reductions in central corneal thickness (CCT) associated with the procedures. When the results were analysed with the data divided by follow-up interval, timedependent differences were noted. Between one and 12 months after surgery, there was a large increase in CCT in the PRK eyes but little change in the LASIK group. However, apparent IOP increased significantly in the LASIK eyes. Between one and three years after surgery CCT increased slightly and to a similar extent in both groups, while apparent IOP increased slightly in the PRK eyes and decreased slightly in the LASIK eyes. “These data indicate corneal rigidity is permanently decreased after both LASIK and PRK. However, there appears to be some interlamellar healing during the first year after LASIK while over the long-term, some re-stiffening appears to occur in eyes that undergo PRK,” Dr Hjortdal said. Michael C. Knorz MD, FreeVis LASIK Centre, Mannheim, Germany, evaluated the topographic and wavefront changes occurring when LASIK was performed in a two-step procedure in order to separately characterise the cornea’s biomechanical responses to flap creation and ablation. He obtained measurements from 48 eyes of 24 patients after the flap was cut, lifted, and replaced.Then, patients returned three months later for the ablation, and the topographic and aberrometry measurements were repeated. The topographic evaluations showed the flap creation caused no change in central curvature, although cutting the cornea was associated with a significant increase in paracentral curvature and an even greater increase in peripheral curvature. Consistent with the biomechanical response model introduced by Dr Dupps, the ablation caused a significant decrease in central curvature and was also accompanied by a significant increase in paracentral and peripheral curvature. “These findings underline the importance of understanding corneal biomechanics in order to refine ablation pattern algorithms,” Michael Knorz MD Results from wavefront evaluation showed the flap creation caused a significant increase in spherical aberration that was consistent with the increase in peripheral steepening. Spherical aberration was also increased significantly by the ablation, despite the fact that the procedures were customised. “The results of this study show that both cutting the flap and the laser ablation independently cause an increase in peripheral corneal curvature and thereby spherical aberration, and these findings underline the importance of understanding corneal biomechanics in order to refine ablation pattern algorithms,” Dr Knorz said. Implications for IOP measurement Understanding of corneal biomechanics and the effects of refractive surgery on those properties is also important for determining glaucoma risk because some of the standard “More accurate measures of IOP will require instrumentation that performs dynamic rather than static applanation measurements and therefore assesses and compensates for corneal biomechanics,” Jay Pepose MD PhD Jay Pepose MD PhD, Pepose Vision Institute and Washington University School of Medicine, reported the results of a prospective study comparing pre- to postLASIK IOP changes measured using GAT, the ORA, and the PDCT in a cohort of 66 eyes with an average MRSE of -5.0 D.Two values were generated with the ORA: the ORA-G, which has been shown to correlate with the GAT value, and an IOP-CC, which is a corneal compensated measure, generated using a new third-generation nomogram. There was a greater mean reduction in post-LASIK IOP when it was measured with the GAT and ORA-G than with PDCT.The IOP reduction measured with the ORA was minimised by the IOP-CC.The GAT and ORA-G values were correlated to pachymetry, while the IOP measurement derived with the PDCT was not. “While there have been proposals to create linear algorithms to modify the GAT data in eyes after laser ablation refractive surgery, there is no scientific basis to support that approach because there is only a weak positive correlation between the GAT IOP and central pachymetry.We know Goldmann IOP generally drops after radial keratotomy and hyperopic LASIK.Those procedures induce little change in central pachymetry but do have a profound effect on corneal rigidity.Therefore, more accurate measures of IOP will require instrumentation that performs dynamic rather than static applanation measurements and therefore assesses and compensates for corneal biomechanics,” Dr Pepose said. EuroTimes December 2005 Courtesy of Jay Pepose MD PhD Courtesy of Jesper Hjortdal MD Courtesy of Michael C. Knorz MD Tangential and axial difference maps (Orbscan II) after LASIK cut without ablation. Note the peripheral steepening. The the Courtesy of Jay Pepose MD PhD 18 globe and how they may modulate characteristics of corneal stress. Dr Pallikaris is investigating relationships between ocular rigidity, which expresses the elastic properties of the entire globe, blood flow, and the The Ocular Response Analyzer (Reichert) (left) is a non-contact device that utilizes a collimated air pulse to applanate the cornea, along with an infrared electro-optical detection system (right). cornea. He explained that the cornea is a living structure that exists under a continuously fluctuating pressure load as a result of the pulsatile blood flow in the choroid. When the cornea is ablated in refractive surgery, the stress localised at the cornea may be increased, despite the fact that the system is continuing to work under the same pressure. That change may cause the cornea to bend outwards, affecting The Pascal Dynamic Contour Tonometer (Zeimer) (left) utilises the “principle of Pascal” that when the contours of its final curvature. the cornea and tonometer match, then the pressure measured at the surface of the eye equals the pressure inside The risk of ectasia the eye (right). may be associated to Adding another dimension the temporal characteristics and Ioannis G. Pallikaris MD PhD, Institute of fluctuation amplitude of the pressure load Vision and Optics, Crete, approaches the on the cornea. subject of the consequences of refractive However, responses elsewhere in the surgery on corneal biomechanics with a globe must also be taken into account, and broader view. Recognising that the cornea in that regard, it is important to consider is just one part of a larger organ, he is the fact that highly myopic eyes may have considering responses elsewhere in the relatively thin scleras. Therefore, it seems EuroTimes December 2005 reasonable that tissue relaxation posteriorly, away from the cornea, may result to reduced corneal stress in those eyes after the cornea is ablated. “According to this model, the localised stress on the cornea may be relatively reduced in highly myopic eyes with thin walls and low rigidity. Perhaps that explains why ectasia is more of a problem in eyes that have been treated for between -6 and -10 D of spherical error than it is for higher myopes. Studies we have performed indicate ocular rigidity is not strongly related to corneal biomechanics. However, ocular rigidity can modulate the characteristics of corneal stress. Its role in keratectasia needs to be investigated,” Dr Pallikaris said. Cynthia Roberts PhD Torrence A. Makley Research Professor Department of Ophthalmology Associate Director, Biomedical Engineering The Ohio State University [email protected] Kieth Meek PhD Structural Biophysics Group School of Optometry and Vision Sciences, Cardiff University, UK [email protected] William J. Dupps MD PhD Cole Eye Institute, Cleveland, Ohio, USA [email protected] “According to this model, the localised stress on the cornea may be relatively reduced in highly myopic eyes with thin walls and low rigidity.” Sunil Shah MD The Midland Eye Institute, Birmingham, UK [email protected] Jay Pepose MD Professor of Clinical Ophthalmology and Visual Sciences Washington University School of Medicine St. Louis, Missouri, USA [email protected] Jesper Hjortdal MD Department of Ophthalmology Århus University Hospital, Denmark [email protected] Ioannis Pallikaris MD PhD Michael C. Knorz MD, FreeVis LASIK Center, University Medical Center Mannheim, Germany [email protected] Ioannis G. Pallikaris MD PhD Institute of Vision and Optics University of Crete, Greece [email protected]