The ocular surface provides the main focusing power for the eye, but its optical quality relies primarily on the integrity of the tear film, which forms the first and most powerful refracting surface of the eye.1 When the tear film disrupts locally, a phenomenon known as tear film breakup (TBU), non-uniformities in tear film thickness are created,2 resulting in an irregular optical surface and characteristic increases in higher-order aberrations (HOA), with an accompanying reduction in image quality.3–9 Tear instability can also precipitate significant reductions in visual acuity and contrast sensitivity.4,10–14 The optical disturbances associated with TBU are thought to generate the visual disturbances common among dry eye patients, contact lens wearers, and postrefractive surgery patients.14–18 Recently, visual disturbance has been added to the definition of dry eye19 in recognition of the optical effect of tear instability and its impact on vision and quality of life among dry eye patients.20–22
The increase in HOA associated with TBU is typically quantified by a Zernike polynomial fit up to the 6th or 10th order.6,8,9 However, there is evidence that increased HOAs characterized by these Zernike polynomials are not the only optical changes caused by TBU.4 One measure of the magnitude of those aberrations not included in a Zernike description is the root mean square (RMS) fit error between wavefront slope measurements and fitted Zernike polynomials.4,23 These additional aberrations, called very high-order aberrations (VHOA), represent optical disturbances on a spatial scale measurable by current Shack-Hartmann (SH) technology but finer than 6th to 10th order Zernike polynomials.4,24 In addition, TBU causes optical disturbances that are too fine to be resolved by a clinical SH aberrometer.24 These very fine scale “micro-aberrations” scatter light,25 thereby blurring the spot images formed by individual lenslets in an SH wavefront sensor.24 For the same reason, scattered light causes the double-pass point spread function (PSF) for the whole eye to contain a disproportionate amount of light outside of the central core.26 Thus, light scatter associated with microaberrations further reduces retinal image quality24 and potentially hampers vision during late stages of TBU.
To evaluate these numerous effects of TBU that exist over multiple spatial scales, optical changes were measured over relatively long periods of blink suppression to reveal the full range of optical disturbances associated with TBU. The resulting analysis allowed a determination of the spatial correlation between optical disturbances and areas of TBU. Although the temporal evolution of aggregate changes in optical aberrations with tear film instability has been studied previously,4,8,27 this study emphasizes the spatial correlation between individual areas of TBU and the resulting local changes in aberrations over multiple spatial scales.
The SH wavefront aberrometer measures wavefront aberrations at a multitude of locations in the eye’s pupil simultaneously.28 This is achieved by using an array of small lenslets to focus a corresponding array of images from reflected light produced by a quasi-point source on the fundus. A schematic representation of this array of spot images is shown in Fig. 1. Images captured experimentally are the raw data from which optical disturbances produced by TBU were quantified. Conventional analysis of the SH data image measures spot displacement from the optical axis of the corresponding lenslet to calculate mean wavefront slope over the face of each lenslet. Slope measurements may be converted to wavefront phase error (WFE) in two ways. Modal reconstruction uses the method of least squares to fit slope data with a weighted sum of the spatial derivatives of Zernike polynomials. In theory, a modal reconstruction may include as many polynomial modes as there are spots, which is equal to the number of lenslets covering the eye’s pupil. However, clinical aberrometers typically use only a subset of modes from the first order to the sixth (or at most 10th) order when quantifying ocular aberrations. Orders one and two are called lower-order aberrations (LOA) and orders three to six (or 3 to 10) are called HOAs. A wavefront error map made from LOA plus HOA is a smooth surface that may fail to include the highly irregular localized defects characteristic of TBU.29 To capture these missing features, a second wavefront analysis method was used, known as zonal reconstruction, that integrates individual slope measurements to calculate the map of WFE.30 Zonal reconstruction avoids smoothing, and, therefore, it captures local aberrations on a spatial scale finer than modal fitting methods. However, a disadvantage of zonal reconstruction is that the wavefront map is defined only at the sample points corresponding to the lenslet centers. Interpolating these sample points onto a finer grid covering the face of individual lenslets requires additional assumptions for the zonal method, whereas evaluating the Zernike polynomials on a finer grid provides interpolation of the modal wavefront without further assumptions.
Spatial scales of optical aberrations resolvable by the aberrometer are tightly linked to the lenslet size used in an SH aberrometer (Fig. 1). Lenslets are used to sample the pupil over tightly packed discrete areas with center-to-center spacing equal to lenslet diameter. Mean wavefront slopes measured over this sampling array are fitted with a finite series of Zernike functions by least squares fitting method. Consequently, the maximum number of Zernike functions (or “modes”) is limited by the number of samples, which in turn is limited by lenslet size (Fig. 1). For example, when the lenslet diameter is 0.4 mm, around 178 sample points are available for a circular pupil of radius 3 mm. For this configuration, modes beyond the 18th order (2nd through 18th orders will contain 187 modes) cannot be included in the reconstruction. Even fewer modes are captured in practice because the quality of the least squares fit improves for an over-determined system where the number of data points is larger than the number of modes.31 Therefore, the higher-order modes reported by clinical aberrometers typically include fewer modes than are theoretically possible.
In this report, the term “very high order aberrations (VHOA)” has been used to represent Zernike orders extending from the highest HOA fit to the data to an upper limit set by lenslet diameter.24 RMS fitting error4,23 is a scalar measure of the combined magnitude of all VHOA over the entire pupil. Since zonal reconstructions include HOA and VHOA, but modal reconstructions include only HOA, the algebraic difference between these two wavefront error maps represents VHOA. As depicted in Fig. 1, the term “macro-aberrations” has been used to designate the complete range of resolvable modes from LOA to VHOA. Beyond the resolution limit set by lenslet diameter lies the domain of “micro” aberrations that produce significant variation of wavefront phase over the face of individual lenslets without changing mean slope. These microaberrations are typically present within areas of TBU, and they cause spot enlargement (rather than spot displacement) because they scatter light.24,25 One of the primary goals of this current study was to determine the extent to which TBU generates optical disturbances in the two finer scales of aberrations not included in conventional modal analysis of HOA, namely the macro-VHOA and microaberrations.
The study design followed the tenets of the Declaration of Helsinki and was approved by the Institutional Review Board at Indiana University. Informed consent was obtained from all subjects. Measurements were obtained from five normal subjects (three females and two males) between the ages of 24 to 45 years. Individual subjects are identified in this report using the subject number given in Table 1. None of the subjects had been diagnosed with dry eye or any other ocular condition, none reported anything other than very infrequent dry eye symptoms, and all had a TBU time of >10 s and a Schirmer tear test of >5 mm in 5 min.
Apparatus and Experimental Design
Two methods were used in this study to monitor TBU, the traditional sodium fluorescein method (FL)32 and a non-invasive technique involving retroillumination (RI) of the tear film.29 Optical aberrations of the whole eye were measured using an SH aberrometer. These three methods were used to sequentially measure TBU and monochromatic aberrations during periods of extended blink suppression. The traditional FL method for observing TBU was performed with wide beam (30°) illumination of the eye with a cobalt-blue light source. The tear film was viewed and recorded with a Zeiss biomicroscope system (8× magnification) fitted with a Wratten 8 filter. FL was instilled using an FL sodium ophthalmic strip (Akorn, Buffalo Grove, IL) moistened with non-preserved saline. To obtain the RI image of the full pupil, the light source on the Zeiss biomicroscope was positioned immediately adjacent to the aperture of the channel containing a video camera, as described previously.4,10,29
An SH aberrometer, described elsewhere in detail,1,33,34 was used to measure optical aberrations of the whole eye before and after TBU. The light source was 633 nm and contained a microlenslet array (0.4 mm center-to-center spacing, 24 mm focal length), positioned conjugate to the plane of the eye’s entrance pupil by a unit magnification relay telescope. This configuration provided approximately 180 measurements of wavefront slope over a 6 mm pupil.
The right eye of each subject was dilated with 0.5% tropicamide to maximize the area of the cornea and overlying tear film that could be visualized and studied by the RI and SH methods. Both eyes were anesthetized with 0.5% proparacaine to minimize discomfort during blink suppression and to prevent reflexive tearing and blinking. Because the purpose of this study was to extend TBU to obtain a full range of optical aberrations, the tear film was monitored well beyond the first break.
The aberrometer was immediately adjacent to the biomicroscope (used to monitor both RI and FL images), and subjects altered head position from one instrument to the next. For FL and RI measurements, the subject’s head was positioned and stabilized using a standard biomicroscope headrest. Baseline SH measurements were obtained just after a blink. For each subject, the experiment began by monitoring TBU with the RI technique. When intensity fluctuations in the RI image were clearly evident, the light source on the biomicroscope was switched to cobalt blue to record tear film fluorescence. The subject then rotated his or her head, without blinking to view through the adjacent SH aberrometer for a single measurement. A short training session was sufficient to master this protocol.
The spot displacements in the SH aberrometer were converted into WFE maps using custom-designed MATLAB (The MATHWORKS, Natick, MA) programs,1,28 which use the raw wavefront slopes measured by the aberrometer to develop both modal and zonal wavefronts. A pupil size of 6 mm was used for WFE analysis. Modal maps were interpolated with Zernike polynomials to produce (101 × 101) arrays of phase values over each 6 mm diameter pupil for computing the corresponding PSF by conventional Fourier optics techniques.
Individual SH spot images were analyzed to determine their size and regional variation over the pupil. Because microaberrations and light scatter encountered on the first pass of the SH system will uniformly blur all SH spot images,24 regional increases in the double-pass size of SH spots are a measure of microaberrations and scatter encountered on the second pass. Spot size was quantified by the equivalent width (EW), defined as the diameter of the circular base of a cylinder with the same height and volume as the distribution of light intensity within the spot.35 The EW quantifies microaberrations that modulate wavefront slope across each lenslet,24 but it does not fully capture wide-angle optical scatter, such as that associated with cataracts.36,37 All aberration and scatter analysis was performed using custom MATLAB programs.
Spatial Correlation Analysis between TBU and Optical Aberrations
Digital FL and RI images were obtained from video-capture of slit lamp images. Regions of TBU were identified in the FL images by thresholding based on pixel luminance, using custom MATLAB programs.38 TBU areas in the RI images were identified as regions containing the characteristic intensity fluctuations associated with TBU using Image J (available at: http://rsbweb.nih.gov).29 TBU regions were identified in the raw SH images as those areas with missing, blurred, and/or highly displaced spots. Mapping of TBU regions from raw SH images was performed by observers unaware of subject identification or the appearance of FL or RI images. FL images were masked to the pupil for comparison with SH and RI images. Registration of TBU maps was complicated by small eye movements and pupil size fluctuations that occurred during the short intervals between these sequential measurements. Therefore, images were adjusted to find the position that achieved maximum TBU map overlap. Overlap of the TBU regions was calculated for pairs of SH and FL TBU maps and SH and RI TBU maps obtained at similar times within individual periods of blink suppression.
One of the primary goals of this study was to determine the extent to which TBU is manifest in the two finer scales of aberrations (macro-VHOA and microaberrations) not included in conventional modal analysis of HOA. To link regional optical changes to disruption of the tear film, a preliminary investigation was performed of the spatial correlation between TBU as manifest in three clinical imaging modalities: fluorescein (FL), RI, and SH wavefront aberrometry.
Spatial Correlation of TBU with SH Data Images
TBU developed at the end of blink suppression trials in all eyes. Fig. 2 shows an example from subject 1 of FL, RI, and SH images obtained at the beginning and end of a single trial. The FL image shows no TBU in the beginning and extensive TBU after refraining from blinking (Fig. 2A, B). Dark areas in the FL image are traditionally interpreted as areas of TBU.32 Intensity fluctuations in the RI image (Fig. 2C, D) appear in the same general locations as TBU in the FL image (compare Fig. 2B, D), which our group has previously shown to be spatially correlated.29 Anomalies in the SH image after TBU (Fig. 2F) also appear most obvious in the same general regions as TBU in the FL and RI images. Similar results after TBU for the other four subjects are shown in Fig. 3. These images reveal the idiosyncratic nature of the FL patterns because of TBU in different eyes (Fig. 3A to D).2,38 However, despite the varied location of TBU and the fact that post-TBU measurements were recorded at different times after blinking, the general pattern and location of tear disruption in the FL images appear similar to RI (Fig. 3E to H) and SH images (Fig. 3I to L) for each subject.
To quantify the similarity of spatial location of TBU identified by FL and SH images, the percentage of overlap of TBU areas was calculated using the method demonstrated in Fig. 4. Each image in Fig. 4 was constructed by overlapping the thresholded FL image (areas of TBU indicated by stripes) with the SH image (areas indicated by dots) with any areas of overlap showing a combination of stripes and dots. The percent overlap (values in lower right corner of each image) was calculated by dividing the number overlap pixels by the number of pixels within the FL defined TBU regions. The area of FL TBU was used in the denominator because it is considered defined TBU in the traditional clinical sense.32 For our study population of 5 subjects, the overlap ranged from 70 to 95%, with an average of 77% (SD = 13%). Similar analysis was performed for the overlap TBU defined by intensity modulations in the RI images and disruptions in the SH images. The range of overlap was 57 to 99%, with a mean of 74% (SD = 17%). These results reveal that missing, displaced, and/or blurred spots in raw SH images occur predominantly within areas of TBU defined by reduced fluorescence. Since the FL, RI, and SH images were not recorded at exactly the same time, the high spatial correlation indicates that regions of TBU remain stable over time if there are no blinks.
An example of the spatial overlap of TBU in FL images with the wavefront aberration map derived from the displacement of SH spots using the zonal reconstruction method is shown in Fig. 5 for subject 1. The wavefront map has been aligned to the pupil in the FL image. Theory predicts that the exiting wavefront will appear phase advanced due to a decrease in optical path length in regions of tear thinning or TBU. Conversely, phase retardation should occur in areas of relatively thick tears (or possibly an increase in refractive index) where the optical path length is relatively long. As predicted, phase advancement (positive wavefront error) occurred in areas of TBU relative to areas where tears are still intact (negative wavefront error).
Effect of TBU on Macroaberrations
The effect of TBU on macroaberrations of all three scales: LOA, HOA, and VHOA, is illustrated in Fig. 6 for subject 1. The first two rows show the wavefront error maps reconstructed by the modal and zonal methods. Both reconstruction methods revealed new features in the WFE maps after TBU that indicate increased aberrations associated with TBU. As expected, the zonal map reveals a similar overall but somewhat more irregular pattern than the smoothed modal map. The magnitude of increased wavefront aberration associated with TBU, as quantified by the RMS of the modal wavefront, is consistent with the literature.1,4,6–9,39 The modal WFE map is the sum of two other maps (LOA, HOA) displayed in the third and fourth rows. The VHOA map displayed in the fifth row is the difference between the zonal and modal maps. In this eye, RMS after TBU increased by a factor of 3.5 (HOA) and 2.9 (VHOA) compared with modest increase in LOA (ratio of 1.4). Similarly, the absolute changes in RMS for HOA (0.47 microns) and for VHOA (0.37 microns) for this subject were both greater than the change in LOA (0.26 microns). This LOA ratio may in fact be an overestimate of the TBU effect because the spherical defocus change observed in the LOA might be due in part to accommodation rather than TBU. Table 1 summarizes the changes in macroaberrations for all subjects before and after TBU. All five subjects showed an increase in optical aberrations at all spatial scales following TBU. The average relative increase in RMS after TBU for the five subjects in this study was larger for HOA (1.90, SD = 0.87) and VHOA (2.94, SD = 1.07) than for LOA (1.48). With the exception of subject 3, the absolute change in HOA and VHOA was also greater than for LOA. Taken together, these results indicate that the optical effect of sustained blink suppression on macroaberrations is larger at the finer spatial scales.
The impact of different scales of macroaberrations on retinal image quality can be evaluated by examining the computed PSFs derived from measured wavefronts after select orders of aberrations have been computationally corrected. The wavefront determined by the zonal fitting method was subtracted from the wavefronts generated by a select number of Zernike modes. PSF are then computed using standard Fourier methods from these remaining WFE maps, which include all of the macroaberrations that have not been corrected. Three examples of this approach are shown in Fig. 7. Soon after blinking (“Baseline” data, left hand column), the PSF computed with all LOAs corrected is dominated by the 3-lobed trefoil, and after correcting all modes ≤4th order, a small central core in the PSFs emerges that is similar to the central core observed when all orders up to the 10th are corrected (bottom left panel). In these latter two cases, the impact of the remaining uncorrected HOAs can be seen as PSF intensity beyond this central core. For comparison, a diffraction limited PSF for the 6 mm pupil used in these analyses is shown as an inset in the bottom left panel. These PSF computations show that, in the presence of an intact tear film, macroaberrations lower than fifth order can prevent a high intensity core forming in the PSF. In contrast to these baseline data, the PSFs computed from post-TBU wavefronts (center and right hand column in Fig. 7 show examples from two different eyes) fail to develop a single high intensity core even when macroaberrations up to the 10th order have been corrected (Fig. 7) showing the importance of the VHOA (those beyond 10th order) in degrading retinal image quality after TBU.
Effect of TBU on Microaberrations
Close inspection of the raw SH images in Figs. 2 and 3 shows blurring and enlargement as well as displacement of some SH spot images after TBU. For example, Fig. 8 shows an enlarged portion of the SH spot images from the subject in Fig. 2. Before TBU, spot images are well focused and form a highly regular pattern (Fig. 8A), but after TBU, many spot images are noticeably blurred (Fig. 8D) and peak intensity is greatly reduced. To determine the extent to which this blurring of individual spots can be accounted for by macroaberrations, the expected image was computed as predicted by diffraction effects plus the wavefront errors over the face of the corresponding lenslet.24,39 The modal wavefront map for this purpose was used with Zernike interpolation of wavefront values over the lenslet face. These computed spot images are shown in Fig. 8C and F for the same lenslets responsible for the spot images displayed in Fig. 8B and E. Before TBU, the computed spot image (Fig. 8C) is similar to that expected from double pass through a diffraction limited system with a 1 mm entry beam and a 0.4 mm square lenslet aperture on the second pass.24 The close agreement between the observed and calculated baseline images provides evidence that SH spot quality in an eye with a high-quality tear film is limited primarily by diffraction and macroaberrations. In contrast, many of the spot images after TBU are significantly more blurred (e.g., in Fig. 8 compare E with F) than expected based on the HOAs and diffraction. This result implies that the blur seen in SH spot images after TBU is due primarily to the combined effect of increased VHOA and microaberrations beyond the resolution of the aberrometer (Fig. 1). As blurring of SH spots is due primarily to microaberrations, the levels of microaberrations were quantified using the EW of each spot image.35 If both optical paths in our double pass SH system were diffraction limited, then SH spots that are not located within areas of TBU should have an EW of 9.7 arc minutes in our system (1 mm beam entering eye and a lenslet diameter of 0.4 mm in the exiting beam).24 Experimentally, the EW of the least blurred SH spot images before TBU was found to be approximately 10 to 12 arc minutes, which is close to the diffraction-limited prediction. The average EW increased to 16 arc minutes after TBU, but this average includes regions of TBU and regions with intact tears. The spatial distribution of these EW increases after TBU was examined by mapping the EW magnitudes across the pupil (Fig. 9). Regions where blurring of spots was greatest, matched the TBU regions for these eyes shown in Figs. 2 and 3 and also matched the TBU/SH overlap maps shown in Fig. 4. Frequency histograms of EW values in an SH image were unimodal before TBU, but after TBU, the magnitudes of EW typically formed a bimodal distribution. That is, EWs were either very large within regions of TBU (range approximately 30 to 40 arc minutes) or else much smaller in regions with intact tears before TBU (10 to 20 arc minutes). These results indicate that TBU caused by sustained blink suppression can also increase the eye’s microaberrations that exist on a spatial scale less than the 0.4 mm diameter of the lenslets used in our SH aberrometer.
DISCUSSION AND CONCLUSIONS
The primary goal of this study was to measure the spatial distribution and scale of optical aberrations produced by thinning and TBU. To do so, periods of blink suppression were purposefully extended to allow the full range of TBU and its optical consequences to be studied. The principal finding is that degradation of the tear film’s optical quality after sustained blink suppression causes wavefront aberrations on all four spatial scales enumerated: LOA, HOA, VHOA, and microaberrations smaller than the 0.4 mm width of the lenslets used in our aberrometer. Although blink suppression was artificially extended in this study, the results suggests that prior clinical studies that reported only LOA and HOA wavefront aberrations of the tear film2,8,9,27,39 could have under-reported the full extent of optical effects of TBU because no other optical aberrations were considered. The missing components of a conventional modal analysis are the very high-order macro-aberrations (VHOA that are measured by wavefront sensors but not included in the Zernike model plus scatter generated by microaberrations.24,26,36,39 Computed retinal PSFs after typical HOAs have been corrected (Fig. 7) emphasize that VHOAs create significant image blur after TBU. Also, this study demonstrated major increases of spot size in the raw SH images in the same tear film locations where FL images are dark (Figs. 2 and 3), showing that scatter-producing microaberrations emerge after the tear film dissipates. These light-scattering aberrations in regions of extensive TBU may be caused by exposure of the microscopically rough epithelial surface or an epithelial surface covered by mucins or other tear remnants (proteins, lipids, etc).40 A similar situation has been observed in the SH spot images of eyes with cataracts, which reveal a spatial map of forward light scatter caused by the cataract.36,39,41 SH spot image blur in these eyes has been attributed to narrow angle scatter caused by microscopic optical disturbances larger than the wavelength of light.39 However, if the optical characteristics of TBU include wide angle scatter (as observed with cataracts36,39), much of the scattered light may not reach the image plane of the SH aberrometer,24 and the resulting spot images will have less light (e.g., examples of missing spots are given in Fig. 3).
Although the extensive TBU observed in our study is unlikely to occur under normal conditions for the healthy eye, there is evidence that the highly unstable and inadequate tear film of dry eye subjects may experience microaberrations.42,43 Several studies have shown that extensive TBU occurs in dry eye and contact lens wearers, especially when engaged in tasks requiring concentration, when blinking can be incomplete or slowed by as much as a factor of 10.44–46 Therefore, the blink suppression paradigm used in this study to demonstrate the full range of optical aberrations may serve as a model for the full scope of optical changes that are possible with tear instability. Moreover, studying the optical consequences of extensive TBU underscored the optical role played by an intact tear film in the normal healthy eye.
Mydriatics and anesthetic were instilled into test eyes to allow extended blink suppression with the pupil large enough to obtain adequate wavefront data. It is possible that these pharmaceutical agents may have affected tear film stability and thus the time course, distribution, and extent of TBU. In addition, subjects moved sequentially through FL, SH, and RI imaging in this study, so eye movements or head position could have had some effect on our data, although it was minimized by training and alignment of images by the center of the pupil. This failure to capture the different images of the tear film simultaneously may have contributed to the less than perfect (<100%) spatial correspondence in the TBU regions identified by each method (Fig. 4).
In summary, optical aberrations at all spatial scales measured by the SH aberrometer developed in the same spatial location as TBU during periods of blink suppression and contributed to reduced optical quality of the eye. Our results suggest that the optical signature of TBU can include a combination of wavefront aberrations on macroscopic and microscopic scales because of nonuniform tear film thinning and exposure of a rough epithelial surface. Thus, these aberrations are likely to be a primary cause of the loss of retinal image quality that has been postulated previously to explain symptoms of visual disturbances reported by dry eye patients.
Nikole L. Himebaugh
Indiana University School of Optometry
800 East Atwater Avenue
Bloomington, IN 47405
We gratefully acknowledge the support of Xin Hong and Kevin Haggerty for computer programming used in data analysis. This work was supported by NEI grant R01-EY05109 (to LNT), 1R01EY021794–01 (to CGB), and Indiana CTSI Career Development Award KL2RR025760–01(to NLH).
Received March 29, 2012; accepted July 13, 2012.
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Keywords:© 2012 American Academy of Optometry
tear film stability; tear film breakup; optical aberrations; Shack-Hartmann aberrometry; scatter