Current multifocal intraocular lenses (IOLs) use diffractive or refractive optics to allocate the incoming light to two or three focal points or to create an elongated focus offering a greater number of patients spectacle independence than with monofocal IOLs. As a downside, patients with multifocal IOLs may suffer from unwanted visual symptoms, such as glare, halo, or decreased contrast sensitivity.1 Optical simulations have shown that angular zone designs offer better multifocal performance compared to radial zone designs.2 Among the bifocal IOLs, the Lentis MF IOL models (Oculentis GmbH, Berlin, Germany) use segmented refractive rotationally asymmetrical optics. Clinical studies demonstrate good functional performance with lower unwanted visual symptoms compared to diffractive multifocal optics.3,4 Depending on the patient's preferences, different amounts of near addition are available. The Lentis MF30 and MF15 IOL models provide +3.00 and +1.50 diopters (D) of additional power, respectively.
In the laboratory, several metrics are used to define an IOL's optical performance: the modulation transfer function (MTF) describes the ability of an IOL to project light from an object onto the retina for different spatial frequencies, whereas straylight quantifies light scattering from an IOL and is used to measure a patient's glare symptoms.5
IOL dysfunctions, such as calcification, can affect the optical quality to varying extents. IOL calcification is a rare late postoperative complication, yet the topic is presented frequently in recent literature.6–13 Although the exact pathomechanism of IOL calcification still needs to be eluded, certain ocular procedures are considered to facilitate this pathology, known as secondary IOL calcification.6–8,10,14
IOL calcification might also occur after uneventful cataract surgery, without additional external factors, which is then termed primary calcification.9,11–13 Causes for primary IOL calcification lie within the manufacturing or packaging process of the lens. It is limited to a certain IOL brand or model.15 Some Oculentis brands of monofocal IOLs are known to be affected by primary IOL calcification.9,11
Calcification in bifocal lenses has so far not been described. The purpose of this study was to describe cases of primary IOL calcification in segmented refractive bifocal IOLs and its impact on the optical quality.
Patients and Methods
Table 1 summarizes the patients' histories, including concomitant diseases and visual acuity. The mean patient age at the time of IOL implantation was 67.4 years (range: 47 to 78 years). Of the nine patients, five were female. Average time from implantation to explantation was 5.3 years (range: 2.8 to 7.8 years).
Eight laboratory cases and one clinical case were studied. IOL explantation was performed between February 2017 and August 2018. After explantation, the specimens were sent to our laboratory for analysis. As the standard protocol of our laboratory requires, the German Federal Institute for Drugs and Medical Devices was notified about each case. Donating surgeons provided clinical data on the cases: patients' symptoms prior to explantation, secondary surgical procedures, comorbidities, and best preoperative and postoperative visual acuity. All studied lenses were segmented refractive bifocal IOLs with an additional power of +3.00 D (8 cases) or +1.50 D (1 case) and a mean basic power of 20.70 ± 2.30 D. Lenses comprised three IOL models from the same company (Oculentis GmbH): LS-313 MF30 (5 cases), LS-312 MF30 (3 cases), and LS-313 MF15 (1 case). All lenses had the same segmented refractive optical design: an aspheric zone for the distant focus with an embedded sector-shaped segment for the near focus. The lenses are made from a hydrophilic acrylic copolymer core (25% water content) with a hydrophobic surface coating. The LS-312 model has a one-piece S-shaped haptic design with a 6-mm optical zone and 12-mm overall diameter. The LS-313 model has a one-piece plate haptic design with a 6-mm optical zone and 11-mm overall diameter.
We included one case (IOL 9) with in vivo measurements: a Lentis LS-313 MF30 IOL was implanted in each eye of a man in December 2011. In March 2019, the patient presented for a routine clinical visit. He did not complain of reduced visual quality and he had not undergone any ophthalmic surgical procedure since IOL implantation. On examination, we found opacification of the MF30 IOL in the right eye only, whereas the lens in the left eye remained clear (Figure A, available in the online version of this article).
Slit-lamp photographs of one calcified and one clear segmented refractive bifocal intraocular lens (IOL) inside of one patient's eyes. In both images, the segment mark of the Lentis LS-313 MF30 IOLs (Oculentis GmbH, Berlin, Germany) in the middle peripheral part of the IOL optic can be clearly seen. (A) The MF30 IOL shows fine granular opacification within the whole optic of the right eye. (B) No opacification is visible in the MF30 IOL of the fellow left eye.
This research adhered to the tenets of the Declaration of Helsinki. Uncorrected distance visual acuity (UDVA), uncorrected near visual acuity (UNVA), and straylight measurement were acquired in the right eye.16 To obtain the straylight value, three consecutive measurements were averaged. Because the patient did not complain about his visual function, we refrained from IOL removal.
All eight explanted lenses were examined using an Olympus BX50 light microscope (Olympus Optical Co. Ltd, Tokyo, Japan) and photographed with an Olympus C-7070 camera (Olympus Optical Co. Ltd). To confirm IOL calcification, we performed Alizarin Red and von Kossa staining and scanning electron microscope imaging as described previously.6,10,14
Optical Quality Assessment
Optical assessment was performed in five explanted, uncut IOLs prior to material assessment. Results were compared with those of a clear MF30 control lens. Through-focus MTF curves and United States Air Force (USAF) target images were obtained using the laboratory's Optispheric IOL Pro 2 (Trioptics GmbH, Wedel, Germany). Measurements were performed in compliance with the International Organization for Standardization ISO 11979 using a monochromatic light source (546 nm), a 3-mm aperture, and an aberration-free model cornea.
Light scattering from each IOL was quantified using a C-Quant straylight meter (Oculus Optikgeräte GmbH, Wetzlar, Germany) adapted for in vitro stray-light measurements of IOLs as described previously.5 Straylight measured in vitro directly corresponds to the straylight experienced by the patient. The straylight meter provides straylight values as the logarithm of the straylight parameter, log(s). However, for the statistical analysis, measured values were converted from logarithmic to linear scale and expressed as the straylight parameter. Straylight of the studied IOLs was graphically compared with that of a 67-year-old patient (9.6 deg2/sr) and a cataractous lens (33.1 deg2/sr).16–18 Also, we tested whether the increase of the straylight parameter in the opacified IOLs was significant compared to an aged crystalline lens. The natural lens' straylight level was calculated using the patient's age as a parameter in the formula derived from the normal population data.16,17 A paired t test was performed with a P value of .05 using Matlab software (Statistics and Machine Learning Toolbox; MathWorks, Natick, MA).
Only one patient underwent an ophthalmic procedure after IOL implantation, which was a Nd:YAG capsulotomy 2.7 years after IOL implantation. Prior to IOL exchange, patients had varying symptoms, such as foggy vision or glare (Table 1).
Severity of opacification differed from case to case (Figure 1). Examination of IOLs 3, 4, 7, and 8 revealed a nearly uniform distribution of deposits throughout the IOL optic and haptics; however, in IOL 4, the density of granules was lower. One of the lenses (case 6) had confined areas of severe opacification in addition to uniformly distributed granular deposits.
Gross examination of all opacified lenses as received. Light microscopy images show a similar pattern of primary calcification of the whole lens affecting the optics and haptics. In intraocular lens 6 there are additional zones of severe opacification.
Material analysis confirmed granular deposits of a calcium phosphate distributed in a uniform pattern underneath the whole surface of the lens including the haptics (Figure 2). Scanning electron microscope imaging confirmed numerous fine crystalline deposits within the material of the lens and transmission electron microscopy revealed the ultrastructure of a single crystal. Electron diffraction pattern analysis confirmed that the deposits were composed of hydroxyapatite.
Material analysis. (A) Alizarin Red staining in 1.25× original magnification for the detection of superficial calcium deposits was negative. (B) Von Kossa staining in 40× original magnification of the intraocular lens' (IOL) cross-section was positive and revealed a fine band of granular deposits within the IOL material in a uniformly distributed pattern underneath the whole IOL surface (anterior and posterior), including the haptics and edges. (C) Scanning electron microscopy image confirmed numerous fine crystalline deposits within the material of the lens. (D) Transmission electron microscopy image showing the ultrastructure of a single crystal.
Optical Quality Assessment
The average MTF (at 50 lp/mm) value of the control and calcified IOLs was 0.36 and 0.34 ± 0.03 at far, and 0.30 and 0.29 ± 0.01 at near, respectively. In all cases, the MTF value was higher at far focus compared to near focus for a 3-mm aperture. Through-focus MTF curves of all lenses with a 3-mm aperture are shown in Figure 3A. All but one lens (case 6) showed two distinct foci for far and near focus.
Optical quality assessment. Measurements contain 5 uncut opacified and 1 clear control segmented bifocal intraocular lens (IOL) with a 3-mm aperture. (A) Through-focus modulation transfer function (MTF) for 50 lp/mm. (B) United States Air Force target images at far (upper row) and near (lower row) focus. D = diopters
USAF target images at far and near focus acquired through all uncut opacified IOLs and the control IOL are shown in Figure 3B. Whereas, for example, in IOL 4, the image quality seems to be reasonable for far and near focus, the USAF target image seen through IOL 6 is blurred for both focal points.
In contrast to the image quality metrics, straylight values significantly increased (P = .01) in all of the opacified lenses, with a mean value of 170.1 ± 71.5 deg2/sr compared to the age-matched straylight level of the crystalline lens, which was 9.6 ± 3.2 deg2/sr. Figure 4 shows that the light scattering elevation in the calcified IOLs is 120-fold and 5-fold higher than that of the control eye and the average cataractous lens, respectively.
Straylight levels. Straylight parameters (deg2/sr) at a 7° angle presented on the y-axis in logarithmic scale. Blue and red lines indicate straylight levels of a 67-year-old crystalline lens (9.6 deg2/sr), which was calculated based on the average age of the cases and a crystalline lens with cataract (33.1 deg2/sr), respectively.16 *In vivo measurements. IOL = intraocular lens
In vivo optical performance of an eye with an opacified MF30 IOL was as follows: UDVA and UNVA of 20/20 and 20/25 Snellen visual acuity, respectively, and an elevated straylight value of 199.5 deg2/sr (2.3 log(s)).
We describe cases of IOL opacification in segmented refractive bifocal IOLs, including patient history and material and optical quality analysis. In eight of the nine cases, patients suffered from different symptoms of deteriorated visual quality, ultimately necessitating IOL exchange. The calcium phosphate deposits that caused the opacification had a severe impact on the straylight levels in all analyzed lenses. On the other hand, the effect on MTF was small and in most of the cases bifocal properties could still be clearly seen in the through-focus MTF curves of four of the five lenses (Figure 3A). The opacification pattern seen in these IOLs fits the definition of primary calcification.15 Morphologically, this type of calcification is characterized by a regular band of fine granular deposits distributed underneath the anterior and posterior surfaces of the whole lens, including the haptics (Figure 3). Furthermore, no secondary surgical procedures that are considered to facilitate IOL calcification (eg, pars plana vitrectomy or posterior lamellar keratoplasty) were found in the patients' histories.6,10 Primary IOL calcification has been previously described in IOLs from Oculentis, including the L-312, LS-312, L-313, LS-313, L-402, LS-402, and LS-502 models.9,11,13 After cases of postoperative opacification, the manufacturer issued voluntary recalls and published field safety notifications in 2012, 2014, and 2017.19–21 The company tried to identify causes for the calcification in their lenses and concluded that its origin is most likely multifactorial. For some cases, they suggested that the cause was an interaction between phosphate crystals (originating from the hydration process of the IOL material), and the fluctuating, batch-related presence of silicone residues on some IOLs can facilitate IOL calcification under certain conditions.20 In our study, four cases (IOLs 5, 6, 7, and 9) were from the company's notification from 2012 and one case (IOL 1) was from the 2017 notification. For the remaining cases, serial numbers and expiration dates were not documented in the explant donations and these four lenses were not linked to a safety notification.
The mean time from IOL implantation to explantation in this study was 5.3 years. This accords with the results of Gurabardhi et al.,9 who presented a series of 71 explanted Oculentis IOLs that were exchanged on average 4 years after implantation.
Simulations have shown that bifocal angular zone optic designs produce higher optical quality and through-focus performance than designs based on spherical aberration.22 Interestingly, due to differences in individual aberration profiles, the orientation of angular zone optics results in different optical performance. In a simulation based on a population of 1,564 healthy eyes, de Gracia and Hartung23 showed that left-right orientation resulted in the best optical performance in the group of two-zone bifocal optics. In a study by Gatinel and Houbrechts,24 through-focus MTF curves of nine different bifocal and trifocal IOLs were compared. The lenses were evaluated with different aperture sizes (3, 3.75, and 4.5 mm). For all apertures, the MF30 showed two distinct foci at far and near distance. The through-focus MTF curves of the calcified IOLs from this study showed similar courses (Figure 3A). In all but one IOL, two distinct foci could still be seen despite the opacification.
The visual acuity after IOL exchange did not improve in all cases. This supports the contention that visual acuity is not a sufficient parameter to quantify the effect of IOL calcification. Subjective halo and glare simulators or tests that aim to quantify light scattering, such as a straylight meter measurement, might be more suitable to clinically assess this pathology.
Light scattering can be caused by particles within the IOL material. Small liquid-filled vacuoles (ie, glistenings) are known to cause light scattering in hydrophobic lenses. In a study from 2017, glistenings were induced in seven Acrysof IOLs (Alcon Laboratories, Inc., Fort Worth, TX) and their effect on straylight levels was found to be proportional to their total number and surface portion.25 We recently assessed MTF and straylight levels in hydrophilic acrylic monofocal IOLs with centrally localized calcification, showing that the reduction in the IOLs' optical quality strongly depends on the density and size of the calcium deposits.14 In the current study, we also observed that the density of calcium phosphate granules affects straylight, because the highest values were found in the most severe cases (IOL 3, 7, and 8). Although IOL 6 demonstrated a more confined type of opacification (Figure 2), the patches of densely distributed deposits of calcium phosphate resulted in a marked straylight increase and, as opposed to the other cases, the degradation of the MTF. The image quality at near was most affected, given a more central location of the patches in the near segment of the IOL.
The reason for the lack of a strong correlation between light scattering and the MTF or visual acuity can be explained. The light entering the eye or an optical bench system is divided into two parts. One part consists of unscattered light that forms the image, which is under a strong influence of aberrations.26 The other part is the scattered light, which in a healthy eye is approximately 5%.17 Given that both parts are simultaneously projected on the retina or a camera sensor, the scattered light adds a more or less homogeneous veil over the image and reduces its contrast. Typically, the contrast reduction is minimal and has no effect. However, the veil depends on the geometry and homogeneity of a target because, if the object is small and homogeneous (eg, visual acuity chart or a slit for MTF measurements), the veil is weak.27,28 For larger targets, the contrast reduction equals the ratio between scattered and unscattered portions, but it may deteriorate even further in inhomogeneous situations (a typical glare situation).27,28 A study by van den Berg26 confirmed that straylight and visual acuity remain fairly independent. In that study, the author used a set of filters to increase straylight in healthy individuals to approximately 158 deg2/sr, which is close to the average level found in the current study. Despite this extreme straylight elevation, only a small decrease in the individuals' acuity was noted.26 The impact of light scattering on optical metrics, such as the point spread function (from which the MTF is derived), was also small.26 On the other hand, the literature shows studies that report a serious MTF loss in calcified IOLs. However, this is more likely to be related to changes of the optical surface, such as in case 6, inducing microaberrations, which have the potential to affect the point spread function and thus the MTF. Werner et al.29 found elevated straylight of 61.7 deg2/sr (at 10°) in 13 calcified monofocal hydrophilic acrylic IOL with a manifest deterioration of the MTF. In the presented series of calcified bifocal hydrophilic acrylic IOLs, stray-light values were much higher (195.6 deg2/sr), but the MTF was hardly affected.
Several clinical studies also show a weak correlation between straylight and visual acuity, because patients with high straylight and 20/20 visual acuity have been reported.30 Accordingly, in our clinical case, patient's UDVA and UNVA were also good despite IOL calcification. The same IOL model from two different production batches was implanted in both eyes by the same experienced surgeon, using the same surgical technique, instruments, and intraoperative medication in operations 2 weeks apart. Postoperative patient history was uneventful. One can only speculate why one of the IOLs calcified but the other one remained clear. Because primary calcification is regarded as a problem of IOL manufacturing, the authors postulate that there may have been differences in the manufacturing of the two batches that caused calcification in the right eye's IOL, whereas the lens in the left eye remained clear.
Because multifocal IOLs are known to be more likely to induce photic phenomena than monofocal lenses, several studies aim to quantify and compare photic phenomena in multifocal IOLs. Buckhurst et al.3 compared dysphotopsia in 45 patients implanted with two different bifocal IOLs (Lentis MF30; Oculentis, Berlin, Germany, and Tecnis ZM900; J&J Vision, Jacksonville, FL) and one monofocal lens (Softec-1; Lenstec Inc., St. Petersburg, FL). The authors used halometry and the C-Quant straylight meter to find differences between the lenses. They found that all bifocal IOL models induced symptoms of dysphotopsia in different amounts, but the straylight level was not elevated. Contrarily, the calcified MF30 IOLs from our study showed severely increased straylight levels. Because patients with multifocal IOLs are more likely to experience symptoms such as halo and glare, calcification in multifocal lenses might lead to more severe symptoms than in monofocal lenses.1
The only treatment option for IOL calcification is a surgical lens exchange, which is associated with an increased risk for complications such as posterior capsular rupture.31 Posterior capsular defects might require a different method of IOL fixation. Currently, there are only limited possibilities to use multifocal IOLs in aphakic eyes that do not offer capsular bag support. Thus, in cases of multifocal IOL calcification, lens exchange most likely leads to a loss of the multifocal optic apart from the other drawbacks of an IOL exchange.