Intraocular scattering changes with age

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Driving at night, you may experience being blinded by the headlights of an oncoming car. This may also happen when looking at a low sun. Inhomogeneities in the ocular media can cause light scattering, resulting in a veil of light, called straylight, projected onto the retinal image. The Commission Internationale de l'Éclairage (CIE) defines straylight as disability glare. Straylight, however, manifests itself with more than glare alone. Contrast and color loss, hazy vision, and difficulty with face recognition against the light are some complaints people with increased straylight may experience. Even in young healthy eyes, a small part of the light entering the eye is scattered. The age-dependence of straylight in a healthy normal population has been extensively studied. It is now known that ageing and various ocular pathological conditions, such as cataract, can elevate straylight. Although straylight does not increase before the age of 40, some pathological conditions, such as congenital (early onset) cataracts, can increase it, sometimes to an extreme degree. Cataract-dependence of straylight has been studied in various cataract types; a significant difference in straylight has been shown to exist between cataract types. While straylight varies among different cataract morphologies, in some cases, strongly elevated straylight can be accompanied by good visual acuity. It is believed that cataract, the clouding of the eye’s crystalline lens, occurs when the proteins that form the lens get damaged or disorganized. As cataract progresses, it can cause a gradual loss of vision and eventually lead to total blindness. Cataract is the most common cause of vision loss and is the leading cause of blindness around the globe. Despite an increasing number of cataract operations worldwide and advancement of measurement techniques and surgical instrumentation, the decision-making process for the indication of cataract surgery has remained traditional, that is ophthalmologists take mainly subjective measures (i.e. patient’s visual complaints, visual acuity, and the clarity of the eye media evaluated using a slit-lamp) into account. This information is then weighted against the visual demands of the patients. However, a more objective assessment of the cataract’s impact on visual function, and the impact of surgery on visual function, may be interesting. For that reason, identifying and employing quantifiable variables and balancing them against the subjective measures seem logical. In this doctoral thesis, we have evaluated several optical functions to be considered as objective measures of the visual effect of cataract. The main interest of this work, however, was to study the change in the amount of scattered light in the ageing eyes, with a focus on cataractous eyes. Potentially, in the future such objective measures may be used for developing an algorithm that could become an apt surrogate for the present cataract decision-making process. Understanding the functional effect of cataract on visual functions is essential. Optical imperfections determine the quality of the retinal image. In practice, this can be assessed by determining the extent of light (coming from a point source) being spread across the retina. This is called the point spread function (PSF) which is accepted as a full description of optical quality. In the absence of any imperfections (i.e. a perfect eye), the response of the optical system is identical to the incident light. However, in the human eye with imperfections in the optical media, the light is spread out and generates a bright spot in the center, losing intensity gradually but continuously towards the periphery. Two aspects of the PSF that belong to different functional domains should be discriminated: a central portion and an outer skirt. The outer skirt with a wide-angle domain (beyond 1°), is affected by light scatter which is known as straylight. Straylight is quantifiable with a commercial straylight meter (C-Quant, Oculus Optikgeräte GmbH, Wetzlar, Germany). The central portion of the PSF, called the small-angle domain (up to 0.3°), on the other hand, is affected by optical aberrations. In clinical practice, it is this small-angle domain that is assessed by visual acuity tests, contrast sensitivity, and with wavefront aberrometry, measuring both lower and higher order aberrations, if we can assume low order aberrations to be zero because of correction. Optical aberrations of the eye limit the quality of the retinal image and constrain spatial vision by decreasing visual acuity and contrast. By assessing ocular wavefront aberrations, important information can be obtained. Ocular aberrometry has been practiced over the past few decades. Primary methods were based on subjective evaluations. However, with the advent of automated aberrometers it has become possible for ophthalmologists to measure higher order aberrations as easy as they measure lower order aberrations with a refractometer. Commercial aberrometers utilize variety of principles, e.g. Shack-Hartmann, ray-tracing, Tscherning. Either way, these aberrometers provide informative aberrometric maps with profuse details. The amount of details contained in such maps can make the interpretation a hard and confusing task. To facilitate the understanding of aberrometric maps, they can be described with Zernike polynomials. Some metrics such as Strehl ratio and root-mean-square (RMS) wavefront error have been used somewhat widely in ophthalmology. Several studies, however, showed that these metrics are not proper predictors of visual performance. There are multiple ways to formulate image quality metrics of the human eye. One publication demonstrated the correlation of 31 single-value image quality metrics with high-contrast visual acuity. The correlations were estimated for a 6-mm pupil where the RMS error was kept constant. This study concluded that the best metric in terms of high correlation with visual acuity, as a measure of visual performance, was a visual Strehl-based image quality metric called the visual Strehl ratio (VSR). This metric is the ratio of the actual intensity of the eye’s PSF in the presence of aberrations at the Gaussian image point to the maximum intensity of a diffraction-limited spot in the absence of any aberrations. What distinguishes this metric from the Strehl ratio metric, is the inclusion of neural components of the visual system. Previously, it was shown that 0.25 μm of aberration over a 6-mm pupil, could shift visual acuity by two lines on a logMAR chart, whereas the total RMS error remained unchanged. It was also shown that the combination of Zernike modes can be more important than the magnitude of each individual mode. The type and the relative proportions of each mode in the combination determine the amount of gain/loss in visual performance, with the RMS error and pupil size remaining constant. The best VSR metric was reported to account for 81% of the variance in high-contrast logMAR acuity in normal (non-cataract) eyes, and was shown by the original authors to be an accurate predictor of visual acuity. Other studies also confirmed that there is a strong correlation between VSR metrics and visual acuity. As mentioned earlier, the goals of this thesis were (1) to study in vivo straylight of ageing eyes with a focus on cataractous eyes; (2) to study the eligibility of certain optical functions and cataract morphology to be considered as reliable discriminators for establishing a surgical decision algorithm in the future. In Chapter 2, we aimed to find out what the pupillary conditions are during straylight measurement, and what potential effect this might have on the measured straylight value. In other words, we investigated whether pupil size and straylight measured under dim room light conditions is the same as pupil size and straylight measured under dark room light conditions. To this end, we designed a study encompassing two parts: (1) The measurement of pupil diameter under various room illuminances; (2) The measurement of ocular straylight under various room illuminances. A group of 21 subjects, 6 of them between 26 and 29, and 15 of them between 50 to 68 years of age, from the staff of Rotterdam Ophthalmic Institute, all with normal pupillary responses, volunteered to participate in this study. Three of the younger subjects were non-Caucasian; the remaining 18 subjects were Caucasian. First part of the measurements were performed on all 21 subjects, however, the second part of the measurements were performed on 20 of them; one subject from the younger group dropped out. First, pupil diameter was measured at three levels of room illuminance, 4, 40, and 400 lux, measured at the table surface. To eliminate the effect of hippus, a fifteen-second adaption time to each level of illumination was given. Measurements were carried out from the lowest to the highest level of illumination. Next, ocular straylight was assessed using the C-Quant straylight meter. The C-Quant works based on the compensation comparison method, which compares the amplitude of a counter-phase flickering light required to compensate the induced flickering light produced by the straylight source. Simultaneously, the change in pupil size of the fellow eye was registered by a camera mounted against the shaft of the straylight meter. The results showed that the pupil size decreased with room illuminance and with age (both p < 0.05). The dependency of pupil size on age, decreased as room illuminance increased (0.018 mm/year at 4 lux, 0.014 mm/year at 40 lux, and 0.008 mm/year at 400 lux illuminances). However, during straylight measurement, pupil sizes hardly differed between 4 and 40 lux illuminances. Respective pupil sizes corresponded with 399 and 451 lux adaptation on average. No statistically significant difference was found between the straylight under the two illuminances with average R2 = 0.85, p < 0.05. Although pupil size is influenced by more factors, such as field size and the number of eyes adapted, we derived from the results that under low levels of illumination, pupil size varies more with age. Furthermore, the average pupil diameter showed very little change from low to intermediate illumination conditions. We also did not find a dependency between pupil size and straylight values using two light conditions. The data showed that the standard deviation of straylight difference between right and left eyes increased with age, albeit slightly. However, the average value of these differences and the standard deviations were small under either illuminance level. Collectively, we concluded that the illuminance of the examination room during straylight assessment does not affect the outcome in normal eyes. Under both mesopic and scotopic conditions, the luminance of the test field is so much higher than that of the room, that it determines the pupil size. Regardless of the lighting level, straylight measured in a laboratory, is valid for photopic pupils at an adaptation level corresponding with a room illuminance of about 400 lux. In Chapter 3, we tested the usability of the ocular VSR derived from wavefront aberrations, computed in the frequency domain using the modulation transfer function (VSMTF), for quantifying the severity of age-related cataract in terms of visual acuity. Accordingly, we set out the following objectives: (1) we studied the correlation between the VSMTF and visual acuity in cataract eyes with uncorrected vision and compared the result with that of normal eyes; (2) We furthered with estimating the correlation between VSMTF and visual acuity in cataract eyes after correcting their lower-order aberrations. In this exploratory observational study, we included 18 healthy eyes of 9 subjects and 15 eyes of 15 patients with nuclear, cortical, or posterior subcapsular cataract. Mean age in the healthy group was 36.5 ± 12.6 years (ranging from 25 to 56) and 68.9 ± 9.1 years (ranging from 54 to 82) in the cataract group. We calculated the VSMTF based on lower-order aberrations (defocus Z_2^0, astigmatism Z_2^(-2) and Z_2^2) and several higher-order aberrations (coma Z_3^(-1) and Z_3^1, trefoil Z_3^(-3) and Z_3^3, primary spherical Z_4^0, secondary astigmatism Z_4^(-2) and Z_4^2, and quadrafoil Z_4^(-4) and Z_4^4). The aberrometer used in this study analyzes the total WFAs up to the tenth order. The image plane metric VSMTF is a mathematical function which takes normalized Zernike expansion coefficients as input and delivers a single value between zero and one as output. The VSMTF was computed using a purpose-written Matlab codes (written by Prof. Dr. Larry Thibos from Indiana University). This metric is derived from the wavefront maps as described by Zernike spectra. All the Zernike coefficients were rescaled for a 3-mm pupil. The average Zernike coefficient of each mode was calculated and compared with that of the non-cataract group. The visual acuity test was performed in all subjects using the standard ETDRS chart. The results showed that in these two groups, visual acuity decreased linearly as a function of ocular VSMTF. The slope of the regression line was −0.50 in the healthy group and −0.36 in the cataract group, but the difference in regression between the two groups was not significant. The correlation between ocular logVSR and logMAR was significant in both groups (r = −0.90 in the healthy group and r = −0.81 in the cataract group; P < 0.05 in both groups). The relation we found corresponds with that reported by the original authors. In this chapter, we confirmed that the VSMTF metric has a strong correlation with visual acuity in uncorrected non-cataract eyes. A high correlation between the two measures in uncorrected cataract eyes was also found. The high correlation suggests that this metric may act as a surrogate for testing visual acuity in eyes with normal-functioning retina and cerebrum, regardless of their cataract status. Also the results of the cataract group after correction corresponded with the earlier data. The conclusion was that the VSMTF is a suitable metric for predicting visual acuity in both healthy and cataract eyes. As mentioned earlier, visual acuity is an important criterion in the cataract surgical decision-making process. However, various studies have shown that in a significant number of cataract cases, visual acuity is not an adequate measure to judge visual performance. Subsequent studies have supported this notion. Moreover, there have been reports of no change or even an increase in straylight after cataract surgery when the decision was made solely based on visual acuity. The reason for this is that visual acuity only evaluates the impact of narrow-angle light spreading due to refractive errors, and therefore can only measure a limited part of a patient’s vision. It was noted that additional visual tests were needed that could mirror loss of visual function but at the same time should be unrelated to visual acuity. The compensation-comparison method to quantify straylight has been acknowledged as a standard technique to evaluate the validity of disability glare tests. A literature review established a norm curve for pseudophakic eyes. In addition, a reference curve was constructed that allows estimation of the expected amount of straylight after cataract surgery by calculating straylight improvement as a function of age and preoperative straylight. Although this reference is a good measure for cataract management in an average eye, it may overlook the influence of the type, location and intensity of the cataract on the outcome because the type of cataract was not specified in the norm curve. To establish morphologically categorized references, we need a phakic norm stratified to the type of cataract. Therefore, we investigated straylight in eyes with cataracts of varying morphologies, as a function of age and visual acuity. In Chapter 4, we performed a literature review to identify relevant publications on straylight, age, and visual acuity in three common types of cataract. In addition, we recalculated the significance of the relation between straylight and visual acuity while taking cataract morphology into account. The published studies included in this literature review evidenced individually that such correlation varies from one type of cataract to another. The population sizes and severity of the cataracts were different across these studies. However, we considered the relatively large final number of observations and their diverse degrees of cataract intensity as the strength of this study to improve the generalizability of the results. This chapter includes two parts. The first part encompasses a comprehensive literature review to study the effect of different cataract morphologies, i.e. nuclear cataract, cortical cataract, and posterior-subcapsular cataract (PSC), on straylight and to determine models for straylight values as a function of age for different types of cataract. Second, we calculated the correlations between straylight and visual acuity, the amount of progression of straylight and visual acuity from those of a normal group, and the ratios of straylight to age and visual acuity in each cataract group. A literature examination was carried out including all available studies that reported straylight values, in cataract eyes with specification of its morphology. The language of the articles, and age, gender, and race of the participants had no influence in this process. All papers provided information on intraocular straylight, age and visual acuity of participants with the specification of the type of cataract. All papers had excluded patients with a history of ocular surgery or diseases, such as diabetic retinopathy, glaucoma, and age-related macular degeneration. We considered straylight data with an expected standard deviation of 0.12 log units or less reliable for analysis. Data from five articles were used to develop the log(s)-age normative curves for the three types of cataract. The correlations between the two variables were calculated and compared with each other. We calculated the normally expected mean straylight value for each cataract type, all types of cataract combined and the control group by using a log(s)-age normative equation. The mean straylight value was 1.22 log(s) ± 0.20 (SD) in nuclear (592 eyes), 1.26 log(s) ± 0.23 in cortical (776 eyes), and 1.48 log(s) ± 0.34 in PSC (75 eyes) cataract. The slope of straylight-age relationship was 0.009 (R2 = 0.20) in nuclear, 0.012 (R2 = 0.22) in cortical, and 0.014 (R2 = 0.11) in PSC cataract. The slope of straylight-visual acuity relationship was 0.62 (R2 = 0.25) in nuclear, 0.33 (R2 = 0.13) in cortical, and 1.03 (R2 = 0.34) in PSC cataract. Further findings were the ratios between straylight and age, and between straylight and visual acuity. The median of straylight parameter/age had the lowest value in nuclear cataract group and the highest value in PSC group, albeit with a rather more skewed distribution comparing the two other cataract groups. The median of log(s)/logMAR showed similarly lower values in nuclear and cortical groups in comparison to that of PSC group. In both cases, the median values of both the nuclear and the cortical groups were statistically significantly lower than that of the PSC group. In agreement with the literature, we found that the average age of the population PSC population developing or undergoing surgery for PSC is younger that for other types of cataract. In each cataract group, the difference in the mean straylight values of individual studies and the respective dependency function was significant. This was explained by different levels of cataract severity and significant difference in the number of eyes of the largest study and the rest. Such a difference, however, was not observed between the slopes of each study and the respective dependency functions. Regardless of severity of cataracts, this study supported the notion that the straylight is the highest in PSC. Fluctuations in density and discontinuous refractive index were understood to be responsible for such amplification. Our results also confirmed that in the earlier stages of cataracts, for patients with PSC, visual acuity alone is not an adequate assessment of visual performance and cataract management. The correlation between log(s) and logMAR visual acuity varied from none to a moderate one in individual studies and within cataract types, but it never was strong. Overall, no type of cataract showed strong log(s)-logMAR correlation. In clinical practice, this means straylight cannot be predicted on the basis of visual acuity for any type of cataract. This chapter thus corroborated that straylight in cataract eyes varies rather independently from age and best-corrected visual acuity. The independence of these two aspects was speculated to be caused by different optical processes in the crystalline lens of very different spatial scales. In conclusion, considering the morphology of cataract will provide a better insight in the visual dysfunction of a cataractous eye. In PSC, particularly, notable elevated straylight values do not necessarily coincide with a loss in visual acuity. Cataract is a multifactorial optical defect, affecting the PSF of the eye in different ways. A cataractous lens may have several ultrastructural light scatterers causing various amounts of backward and forward light scattering. However, the central part of the PSF is associated with optical aberrations, and is formed by part of the entering light which is not disturbed by the scatterers in the eye’s media. Merely a few percent of the entering light is affected by the scattering irregularities in the media, and projects a veil of unwanted light over the retinal image. It has been established that straylight intensity decreases greatly with angle (θ), with an approximately quadratic dependence. The straylight parameter defined as θ2 x PSF, changes slightly from 2.5° to 25.4° with a parabolic behavior with a minimum in proximity to 7° in healthy as well as cataract eyes. In one type of congenital cataract, i.e., pulverulent congenital cataract, it has been noted that vision can be strongly disturbed without much acuity loss. We accidentally came across one dramatic case where a high-level professional was threatened to lose his job because of strongly elevated straylight, whereas visual acuity was normal. We decided to study the straylight effects of this condition. The primary interest in Chapter 5, was to study the degree to which straylight is elevated in eyes with pulverulent congenital cataract. The secondary goal was to test whether the angular-dependence of straylight corresponded to what is typical for cataracts as mentioned above. Three cases were included. In 6 eyes of 3 young cases with pulverulent congenital cataract, remarkably elevated straylight was observed, whereas visual acuity was well preserved. One case (Case 1) was studied in more detail, i.e. cataract morphology, multi-angle straylight, visual acuity, and wavefront aberrations (VSMTF). Results were compared with those from previously conducted studies on non-cataract and age-related cataract groups. The angular-dependence of straylight of this case was compared with that of 33 blue-eyed Caucasians with no cataract and 65 patients with cortical, nuclear and posterior subcapsular cataracts from two previous studies. In Case 1, the cataract was a central pulverulent congenital type, bilateral, static, and perfectly symmetrical in both eyes. It can be described best as a granular floriform cataract with 3 petal-shaped lamellar structures inscribed in two concentric circular punctuate opacities in the nucleus. His best corrected visual acuity was −0.24 logMAR (right eye) and −0.30 logMAR (left eye), despite 5x elevated straylight values (right eye: 1.62 log(s), left eye: 1.59 log(s)). Wavefront aberrations were within normal limits. The angular-dependence of straylight was different in this case from that in normal eyes or the usual age-related forms of cataract. This peculiarity has been interpreted as the result of much larger scattering particles (approximately 20−30 μm in diameter) than those in normal and cataract lenses. Namely, for young and aged human eye lenses it has been found that particles with average radius of approximately 0.7 μm dominate straylight. Scattering at large angles (30°−180°) is dominated by particles much smaller than the wavelength of the incident light. In contrast, when the particle size is much larger than the wavelength of the incident light, as it is in Case 1, diffraction causes scattering patterns with a stronger distribution in the forward direction and smaller angles. This explains the difference in angular-dependence as reported in this chapter. We explained the very good visual acuities of the three cases, despite elevated light scattering, by different contributions to the PSF of optical aberrations (assessed by visual acuity) and straylight as well as the different provenances. From an optical standpoint, this lack of relation explains why the process of light scatter (resulting in straylight) has little impact on the central region of the PSF, which is associated with visual acuity, regardless of the level of straylight. As general conclusion of this doctoral thesis, it should be noted that straylight and visual acuity seem to be quite autonomous. However, on average, some correlation exists. The rate of this dependency appeared to be a function of cataract morphology. These findings are in accordance with the literature and ensure that straylight is potentially an important measure for quality of vision and indicator for cataract surgery, along with visual acuity and cataract morphology. Another important finding of this thesis is the competence of VSMTF in predicting visual acuity objectively in cataract eyes. The results show that the combination of mentioned optical-visual functions and lens morphology could be dependable ingredients for an algorithm to predict the optimal timing for performing surgery. Many studies have been conducted on the importance of considering straylight in such equation. This thesis confirms this notion. However, further investigation is needed to validate the liability of the VSMTF to predict the visual acuity in cataract population with taking the lens morphology into account. Moreover, the peculiar angular-dependence of straylight in pulverulent congenital cataract eyes deserves an extensive study in more subjects with more diverse types of optical scattering defects.
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