In 1977, Zantos and Holden1 reported that several corneal endothelial cells of an unadapted wearer transiently disappeared from specular reflection during the first 15 to 25 minutes after lens insertion. This phenomenon, known as the bleb response, does not occur in adapted lens wearers and disappears shortly after their removal or once the cornea has adapted. This observation, after the wearing of hydrophilic contact lenses, prompted the industry to develop lenses with increased oxygen transmissibility. The bleb response may also be elicited after exposure of the cornea to a gaseous mixture of 9.8% CO2–20.5% O2 and the remainder of nitrogen gas, or to 100% nitrogen gas, to simulate hypercapnia or anoxia.2 Complete anoxia probably does not occur in goggle experiments with 100% nitrogen unless a corneal lens is worn3: the cornea is still exposed during blinking to oxygen in the vessels of the palpebral conjunctiva, where the partial pressure of oxygen reaches 7%.4
It is believed that the accumulation of lactic acid or carbon dioxide leads to a decrease in pH in the posterior stroma, near the endothelial border. This acidosis is recognized as the common factor between gas exposures and lens wear and was therefore identified as a likely cause of the blebs.2 Observation of the course of time for the bleb response in unadapted wearers led investigators to report a peak response, expressed as a percentage of altered cells (or blebs) over the number of sampled cells, between 10 and 50 minutes after lens insertion, while wearing oxygen-impermeable polymethyl-methacrylate (PMMA)5 or hydrophilic contact lenses.6 Unsurprisingly, there is an inverse correlation between the bleb response and oxygen transmissibility of contact lenses, whether soft or rigid gas permeable. Wearing lenses with increased oxygen transmissibility decreases bleb numbers,7 the relative area of blebs after 20 minutes of eye closure, and the time for blebs to disappear during open eye wear.8 Interestingly, the corneas of Asian subjects develop a more pronounced bleb response compared with those of non-Asian subjects.9,10
The nature of blebs has puzzled investigators for years. Early on, it was observed that during the occurrence of blebs some endothelial cells were edematous in the nuclear area, so much so that their posterior endothelial surface bulged into the anterior chamber.11 The light reflected from edematous cells then shifts to a different direction from that of the observer's eye, causing the dark appearance of blebs in the specular image of the endothelium. However, the reason why only some cells present blebs remains elusive, as endothelial edema is expected to be generalized and affect all cells. The occurrence of blebs has been reported in the literature with the wear of soft hydrophilic,1,2,6–13 silicone,2 and rigid gas-permeable7,8 or gas-impermeable5,7 corneal lens, but not with scleral lenses.
Because of their comfort14 and the improved vision provided to wearers, scleral lenses are now increasingly selected to correct the refractive errors of patients with normal eyes.15 Made of a material that is highly oxygen permeable, these lenses are generally considered safe to be fitted and worn, especially compared with older generations of scleral lenses made of PMMA. However, to consider only the transmissibility coefficient of the scleral lens is not sufficient, as this neglects resistance to the diffusion of oxygen in the liquid reservoir beneath the scleral lens. In several studies, the relative partial pressure of oxygen was estimated at the epithelial surface under various thicknesses and corneal clearances of both scleral lens and post–lens tear film.16–19 Based on the Harvitt-Bonanno20 threshold, all of these studies concluded that thicker lenses fitted with greater apical clearance may generate significant hypoxic stress.
However, these theoretical models do not take into account the limited tear exchange and slow tear mixing underneath scleral lenses.21 Notwithstanding the potential contributions of these elements, the partial pressure of oxygen on the corneal surface under scleral lenses fitted with a clearance of 200 or 400 μm is lower than the theoretical values needed to prevent hypoxia during lens wear (≥9.9%). The relative partial pressure of oxygen at the corneal surface was estimated after 5 minutes of wear at 9.07 ± 0.86 and 6.19 ± 0.87% for identical scleral lenses fitted with apical clearances of 200 and 400 μm, respectively.22 Such levels of partial pressure of oxygen are therefore expected to induce corneal edema.
The purpose of this study is to observe whether or not the corneal endothelium develops blebs during the wear of scleral lenses and if the bleb response is more pronounced with scleral lenses fitted with a greater corneal clearance. A secondary goal is to compare the average areas of cells and blebs.
Subjects and Scleral Lenses
This clinical study adheres to the tenets of the Declaration of Helsinki. It was approved by the institutional review board for experimentation on humans. Participants were recruited at the Clinique Universitaire de la Vision, Université de Montréal, via posters and through social networks. Written consent was obtained from the 21 subjects recruited after they were informed of the goals and procedures of the experiment. All subjects were at least 18 years old. Participants were free of any systemic or ocular diseases, had never had eye surgery, had good fixation, and had normal corneas. Most subjects had never worn contact lenses regularly. Four subjects with a history of silicone hydrogel corneal lens wear were asked to stop wearing lenses 72 hours before the beginning of the study. Subjects were on average 25.0 ± 2.0 years old, and the sample was composed of 6 men and 15 women. Participants were required to be available for two testing sessions during which they were fitted with scleral lenses from a previously described diagnostic set (Laboratoires Blanchard, Sherbrooke, Québec, Canada),22 to obtain central corneal clearances of 200 and 400 μm. The scleral lenses with such clearances are referred to as SL200 and SL400. If the lens fit was not correct or did not achieve desired clearance, another lens was inserted to reach these targets.
Selected lenses were worn for only 25 minutes to track bleb responses, known to occur shortly after lens insertion. No lens was dispensed in this project. All lenses used in this study were made of Boston XO2 (Bausch & Lomb, Rochester, NY), a gas-permeable material with a nominal permeability (Dk) of 141 × 10−11 (cm2/s; mL O2/mL × mmHg).23 Scleral lenses were 18 mm in diameter. They had equal central thicknesses (320 μm) and plano powers and were equipped with a standard profile for intermediate and peripheral curves. Lenses were not designed to closely align with every quadrant, with toric haptics, allowing for the possibility for tear exchange, especially during the period of lens settling. Diagnostic lenses were initially selected according to the sagittal height of the eye obtained with the Eaglet Eye Surface Profiler (Eye Eaglet BV, Houten, the Netherlands) and following the manufacturer's fitting guide.24 The desired clearance of 200 or 400 μm beneath each scleral lens was obtained with the sagitta of 4.6 for most participants who had a standard corneal diameter and keratometry readings of between 42 and 50 D. The second lens was then easily determined to obtain the second required clearance, a lens with the sagitta of either 4.4 or 4.8. Therefore, the surface profiler was only used at the beginning.
Diagnostic lenses were filled with a nonpreserved sterile 0.9% inhalation saline solution (hydraSense toGo; Merck Canada, Kirkland, Québec, Canada) placed on the sclera and left in place for 25 minutes. Five minutes before lens removal, the actual clearance was measured using an anterior segment optical coherence tomograph (OptoVue, Clarion, TX) to evaluate the thickness of the tear fluid beneath the lens, as previously reported.22 After each use, lenses were cleaned and disinfected in hydrogen peroxide solution (Clear Care, Alcon, TX) following the manufacturer's recommendations and processed as previously described.22
Because preliminary attempts to achieve a clear endothelial image through the scleral lenses using the noncontact specular microscope (NIDEK model CEM-530, San Jose, CA) were unsuccessful, all post-wear specular microscopy images were obtained shortly after lens removal. According to the manufacturer, this instrument samples endothelial areas of 225 × 550 μm.25 All specular images were obtained while subjects looked at the central fixation point of the microscope. The observer saved the detailed analysis screen displaying the endothelial field along with the automatically calculated morphometric characteristics of the endothelium in a JPG image format. Endothelial field images were saved in a bitmap format for further processing with ImageJ (Laboratory for Optical and Computational Instrumentation, UW-Madison, Madison, WI). A total of eight bitmap images for each subject were required for the two visits. Central endothelial images of the experimental and control eyes were captured at t0 and t1, just before and after lens wear on the experimental eye. Each lens (SL200 or SL400) was worn on the experimental eye during one of the visits. Table 1 indicates the sequence of control and tested eyes over the two visits and the number of occurrences for each. One hundred sixty-eight endothelial images (21 subjects × 2 eyes × 2 times × 2 lenses) were analyzed. Forty-two of these images were taken after scleral lens wear at t1, whereas 126 images, either from the control eye at t0 and t1 or from the experimental eye at t0, were captured without any prior lens wear during that visit.
Subject Visits and Analysis of Specular Images
The two visits with each subject were scheduled at least 2 hours after waking to eliminate physiological corneal edema. There was a minimum of 72 hours between the two visits. During each visit, the following procedures were carried out on each eye: biomicroscopy of the anterior segment with fluorescein, profilometry with the Eaglet ESP Profiler (initially), and examination of the central position of both eyes with specular microscopy with image capture at baseline (t0). The optimal scleral lens, as previously determined, was then inserted in one eye and worn for 25 minutes. After the removal of the lens, participants were asked to keep their eyes closed while they were guided to the specular microscope, to minimize exposure to the oxygen in ambient air. Endothelial analysis and image capture began on the eyes that had worn a lens at t1, shortly after lens wear in the experimental eye. Two observers took the measurements (JRa, JRo). After a participant completed both visits, both observers stored the eight bitmap images, which were coded to hide specific details for blind analysis by the second observer. Once the data collection phase was completed, each observer made the coded files available to her colleague for analysis. Therefore, each observer analyzed the masked images of participants examined by her colleague.
The analysis of blebs was initiated by determining whether the endothelial image contained blebs in the observed endothelial field, and if so, how many. The area of cells and blebs (in pixels) was obtained by processing the bmp files using a modification of a previously described routine with ImageJ software.26,27 The original routine was modified in this project to measure the bleb area in the participants instead of the guttae in patients with cornea guttata as previously published.27
Fig. 1 demonstrates this analysis on a smaller area relative to the collected image. In brief, after the observer selects the area of analysis, cell centers are automatically dotted. The cell and bleb contours are drawn by the software but may be corrected by the observer at any stage of this procedure using drawing tools. The observer must then identify cells and blebs. Finally, the software fills in the areas of cells and blebs in light and dark gray shades, respectively. In the image, the surface areas in light and dark gray surrounded by a contour are measured in pixels to provide the surface areas of each cell and bleb. The individual areas of cells and blebs in pixels are saved in the computer's memory.
The mean cell sizes (in micrometers squared) of the right and left eyes were obtained by calculating the multiplicative inverse of endothelial cell density displayed on the JPG image for each of the four measures (two visits × two times) and calculating the average for each eye. All results were considered significant when P < .05. We tested the differences in the median number of blebs in the images of both lenses using the Wilcoxon signed rank test to assess statistical significance. The measured clearance between the subgroup of subjects with and without blebs was also tested for significance using independent t tests carried out separately for the SL200 and SL400. We used a paired t test to compare the difference in surface areas of cells and blebs in pixels. When blebs were present after wearing only one lens, the mean bleb and cell area of that endothelial field were used. When blebs were present under both lenses worn by a subject, the bleb and cell areas under the SL200 and SL400 lenses were separately averaged for that subject. The paired difference between the cell and bleb areas was expressed as a z statistic. Data were normally distributed. We also used a χ2 test to evaluate whether or not the observed frequency of blebs depended on lens type. Sample size was calculated with the shareware G*Power (Allgemeine Psychologie und Arbeitspsychologie, University of Düsseldorf, Düsseldorf, Germany),28 which was directed to detect a significant difference of 10% between bleb and cell areas with paired t tests at the level α of 0.05 with a power of 0.95. Mean cell area and standard deviation from a previous study (330 ± 40 μm2)26 suggested a minimal sample size of 18. These analyses were conducted by the consulting statistical service of the Mathematics and Statistics Department of the Université de Montréal with the SPSS software (IBM Corp., Armonk, NY) and the open-source statistics program JASP (Department of Psychological Methods, University of Amsterdam, Amsterdam, The Netherlands).29
One observer reported the occurrence of blebs in only 1 of the 126 endothelial images without any lens wear (control eyes at t0 and t1, or experimental eyes at t0). In retrospect, this participant had areas of a darker zone over the surface of certain cells. No other bleb was reported for this noncontact lens wearer in this eye or the other after contact lens wear. Because of the near absence of variance in the occurrence of blebs for the control eye at t0 and t1 and for the experimental eye at t0, a statistical analysis of these 126 endothelial images is not a practical option. It is only possible to analyze the 42 endothelial images taken after lens wear, for example, the one shown in Fig. 2B, which shows a subject with blebs after 25 minutes wearing the SL400 lens. Fig. 2A presents the same endothelial field just before scleral lens wear. In the 42 endothelial images taken after scleral lens wear, 9 and 14 subjects had at least one bleb after wearing the SL200 and SL400, respectively. However, χ2 analysis revealed that the different frequencies of subjects with blebs were not significantly correlated with lens type (P = .12). Table 2 shows the mean, median, and maximal and minimal number of blebs observed after wearing the SL200 and SL400. The median numbers of blebs after wearing the SL200 and SL400 were significantly different (SL200, 0.00; SL400, 1.00; P = .02) when tested using the Wilcoxon signed rank test.
As shown in Table 3, the actual clearances of the SL200 and SL400, measured by coherence tomography, were close to the expected values, suggesting that the fitting objectives were met. The clearances of the SL200 and SL400 were 200.4 ± 41.8 μm (median, 198.0 μm) and 417.5 ± 58.6 μm (median, 424.0), respectively, under the SL200 and SL400. However, because the standard deviation of the clearance of the current sample was larger than that observed in a recent study with the same lenses (≈30),22 we wondered if this variability in fluid thickness could be sufficient to observe differences in clearance between those who developed blebs and those who did not. The difference in clearance between the 12 subjects who did not develop blebs after wearing the SL200 (197.3 ± 36.2; 12) and the mean of the 9 participants who had blebs (204.4 ± 50.4) was not significant (P = .71). The 7 subjects who did not develop any blebs with the SL400 had a mean clearance of 382.4 ± 46.4 μm, whereas the 14 participants who presented blebs had a mean clearance of 435.0 ± 57.4 μm. This last difference nearly reached statistical significance but ultimately did not: it is located on the boundary of the limit for differences of statistical significance, but because the interval is open because of the rule of acceptance (P < .05), the boundary value is not included in the confidence interval (P = .05; t = −2.097, df = 19).
None of the four subjects who wore contact lenses at least once a week developed blebs after wearing the SL200, whereas nine nonwearers developed blebs with this lens. Twelve nonwearers developed blebs after 25 minutes of wearing the SL400, whereas two of the aforementioned four subjects wearing contacts once a week or more developed blebs after wearing the SL400. However, the number of participants wearing contact lenses was not sufficient to test for an association between contact lens use and the occurrence of blebs.
Finally, evaluation with the contour detection software allowed for comparison of the areas of blebs and cells in the same subject. The difference between bleb and cell areas (blebs, 181.8 ± 17.5; cells, 229.3 ± 19.7 pixels; n = 14) was highly significant (P < .0001). The mean endothelial cell sizes, as measured with the specular microscope, were 367.3 ± 32.4 μm2 for the right eyes and 370.0 ± 32.0 μm2 for the left eyes. Considering an average cell area of 370 μm2 suggests that the average bleb area is 293 μm2, or 79% of the cell area.
In this project, the rapid occurrence of blebs was monitored after subjects wore scleral lenses with two different targeted clearances. The median number of observed blebs was significantly larger with the SL400 than the SL200 lens. We do not yet know exactly what an endothelial bleb means clinically or whether the observed difference of one in the median number of blebs is clinically significant. However, results from this study indicate that an apical clearance of 400 μm increases the likelihood of developing transitory endothelial edema, or at least one bleb. Increased apical clearance increases resistance to the diffusion of oxygen and carbon dioxide.
It is not surprising to find corneal edema after lens wear, as relative oxygen tension previously reported after 5 minutes of wearing these lenses does not reach the minimum required.20,30,31 There is high intersubject variability in the amount of swelling observed after various contact lenses and various protocols,32,33 and/or anoxia.34 This variability is associated with variable corneal metabolism (oxygen consumption) and endothelial function.35,36 In addition, adaptation in corneal metabolism toward a more effective use of glucose through oxidative phosphorylation seems to occur during adaptation to contact lenses: the corneas of a group of contact lens wearers swell significantly less compared with a group of naive controls wearing the same lenses.36
How does the corneal environment during present-day scleral lens wear compare with that of classical experiments with goggles? Interestingly, in early goggle experiments, a dissociation between endothelial edema and corneal edema was observed. Exposure of the cornea to 100% nitrogen gas or a mixture of 9.8% CO2–20.5% O2 and the remainder of nitrogen gas could induce a bleb response, but corneal edema occurred only in the absence of oxygen.2 To define the environment underneath scleral lenses and determine how it compares with these goggle experiments, the relative partial pressure of oxygen beneath the scleral lenses was calculated with mean lens central thickness and clearance to first estimate the average transmissibility of the system.16,22 Then, from this transmissibility, the expected partial pressure of oxygen was calculated using an equation from Benjamin.37 From this partial pressure of oxygen, we calculated the relative tension in carbon dioxide, based on an equation relating both partial pressures under open-eye conditions.38 As shown in Table 4, the calculated partial pressures of carbon dioxide and oxygen beneath scleral lenses are, respectively, around seven to eight times smaller and two to three times smaller than the nominal levels of carbon dioxide and oxygen present in a gas cylinder containing a mixture of 9.8% CO2–20.5% O2 and the remainder of N2.2
It is not clear why only some cells present blebs. Their transitory appearance may represent an attempt by the cell to regulate its volume42: the edema could activate the endothelial mechanisms of cell volume regulation,43 by which swollen cells first lose ions, causing water efflux from the cell and resolution of the edema. Increases in lactate production by the epithelium and the ensuing lactate overload in endothelial cells are expected to be present in all cells. Here, we show that the onset of blebs is restricted to only a few cells, which seem to have a smaller apical surface. A smaller cell might be more susceptible to deformation of its apical membrane and bulging into the anterior chamber. Interestingly, the apical surface, which faces the aqueous humor, is both the interface on which specular reflection occurs and the last membrane through which membrane transporters act to maintain corneal deturgescence. When the swollen cell's rear surface is lengthened, its image will be reflected in a different direction from that of the observer's eye, and the cell will appear dark.
There are a few limitations in the design of this study. First, the eye selected to wear the lens was not always the same eye. Because the two eyes might not have identical scleral topography and response to hypoxia, there is potential for a different peripheral fit and a different extent of tear exchange, which might have influenced tear mixing and corneal edema. Conversely, tear mixing has been reported to be better with scleral lenses with a lower clearance than those with a higher clearance, although this was shown in lenses with a slightly smaller diameter (15.6 mm).21 However, the same fitting procedures were used in this experiment as had been used in a previous article.22 Second, this project is limited by the use of spherical lenses with a variable lacrimal exchange, depending on whether or not the conjunctiva is toroidal. The reduced number of participants is also a limitation of the study that may have contributed to decreasing the power of statistical tests. For example, the difference in clearance between the subjects who did not develop blebs after wearing the SL400 and the mean of those participants who did develop blebs failed to achieve statistical significance but was at exactly the cutoff level. However, as an open interval, the significance level (P = .05) is not included, meaning that the null hypothesis cannot be rejected. Third, the removal of the scleral lens to image the endothelium could have allowed some blebs to disappear. This could have exerted a greater effect, had we not asked participants to keep their eyes closed after lens removal until endothelial capture. Fig. 3 shows the considerable evanescence of blebs. Fig. 3A shows blebs in the endothelial image after wearing of a scleral lens and eye closure. Very soon after, the control eye was photographed (Fig. 3B), but in the time required to switch eyes and align the microscope to capture the experimental eye again, the blebs had almost disappeared from its endothelial field (Fig. 3C). Lastly, these are very short-term experiments based on 25 minutes of wearing each lens type. However, this duration is close to the reported time to obtain the maximal bleb response during the wear of a silicone lens (23.8 minutes) or hydroxyethyl methacrylate lens (28.6 minutes), or during anoxia by exposure to 100% nitrogen (32.4 minutes).2
Despite these limitations, this study shows for the first time that a scleral lens with a larger clearance exerts a larger short-term effect on the endothelial physiology. This is not surprising considering that theoretical calculations16 and empirical measurements of partial pressure of oxygen in the cornea22 predict that oxygen tension will be lower in lenses with a larger clearance. Conversely, carbon dioxide tension would be expected to be higher (Table 4) in lenses with increased clearance.38,39,44
Based on the present study and previous works,16,22 we know that the larger the clearance is, the larger the hypoxic and hypercapnic stresses will be. This may be true for all wearing hours depending on how much the tear film thins beneath the lens, whether the design of the lens favors tear exchange with channels, or whether the lens is fluid ventilated. It has been shown that the clearance under scleral lenses decreases on average by 80 to 100 μm over the course of a full day.45–47 Therefore, this study suggests that a lens with an apical clearance of 200 μm is preferred whenever possible, as compared with a clearance of 400 μm, because the former induces fewer blebs.
Consequently, to avoid chronic hypoxic stress on all corneal layers and minimize hypercapnia, scleral lenses should be fitted with limited clearance because this minimizes bleb response. This may be accomplished notwithstanding the lens diameter, provided that the lens is well supported by all quadrants of the conjunctiva. In that regard, for larger lenses, toric haptics may help achieve an optimal fitting.
Observations of short-term physiological changes—blebs in the corneal endothelium—after wearing Boston XO2 scleral lenses fitted with an apical clearance of 200 and 400 μm indicate that the endothelium of subjects fitted with greater apical clearance presents more blebs. Therefore, the largest clearance used in the present study should be avoided, as it limits oxygen delivery to the cornea by 30% more than those fitted with a clearance of 200 μm.22 Even if it is very likely that these blebs will disappear and not occur again once the wearer has adapted, the principle of nonmaleficence requires avoidance of use of the higher clearance of 400 μm whenever possible.48 We hope that this report on the occurrence of blebs after the wear of scleral lenses will stimulate the industry and practitioners to design improved tear exchange on scleral lenses49 and to fit them with the advised clearances.
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© 2019 American Academy of Optometry
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