Effect of capsular tension ring implantation on capsular stability after phacoemulsication in patients with weak zonules:a randomized controlled trail.

Background: Patients who had previously undergone pars plana vitrectomy (PPV) or who had severe myopia may have weaker zonules, for which a capsular tension ring (CTR) implantation is still controversial. This study is to test the effect of CTR implantation on capsular stability after phacoemulsication in those patients. Methods: A total of 42 patients who underwent phacoemulsication and received an intraocular lens (IOL) were randomized to undergo CTR implantation or not. The primary outcomes were uncorrected distant visual acuity (UDVA), best corrected distant visual acuity (BCDVA), refractive prediction error, the area of anterior capsulorhexis, and IOL inclination angle. Follow-up visits were conducted postoperatively at 1 day, 1 week, 1 month and 3 months. Outcomes were compared between all CTR and control patients, as well as between subgroups who had previously undergone PPV or who had severe myopia. Results: Surgery signicantly improved UDVA and BCDVA to similar extents in CTR and control patients, and refraction prediction error was similar between the two groups at all follow-up times. At 3 months after surgery, the area of anterior capsulorhexis was signicantly larger in CTR patients than in controls (p = 0.0199). These differences were also signicant between the subgroups of patients with strong myopia. Vertical IOL inclination was less within CTR groups at 3 months after surgery, especially in patients with severe myopia(p=0.0286). At 1 week postoperatively, the proportion of individuals whose posterior lens capsule that had completely adhered to the posterior IOL surface was signicantly higher among CTR patients (p = 0.023). No serious surgical complications were observed.


Background
Zonular bers connect the ciliary body to the equator of the lens and maintain the position of the lens as well as adjust its curvature. Zonules are considered weak if zonular bers are looser than normal, making them more susceptible to damage or rupture, or if they have already been ruptured. Zonular weakness makes the lens unstable, which can complicate intraocular procedures such as cataract surgery and increase risk of intraocular lens (IOL) dislocation [1].
Therefore, these patients are at increased risk of loosened capsular bag, unstable anterior chamber, and lens dislocation during cataract surgery. The chance of capsular shrinkage is also higher after surgery [6,17,18]. Capsular shrinkage increases tension on zonular bers, further lengthening and weakening them [1,4,6].
Patients with severe zonular ber rupture typically undergo extracapsular cataract extraction, intracapsular cataract extraction, or pars plana lensectomy, and the IOL can be implanted in the anterior chamber or sulcus posterior chamber, or it can be sutured to the iris or sclera. However, these surgical procedures are more di cult and time-consuming, and carry high risk of post-operative complications [19][20][21].
For zonular ber relaxation or mild rupture, there is no effective treatment. The most promising approach is the use of a capsular tension ring (CTR) together with small-incision phacoemulsi cation and in-thebag posterior chamber IOL implantation. The CTR maintains the shape of the capsular bag, balances the tension in zonular bers, and decreases the risk of capsular shrinkage and IOL decentration or dislocation [22][23][24][25][26][27][28][29]. While a CTR has been used for focal zonular rupture or diffuse zonulopathy either to stretch out a capsular bag or to facilitate scleral suture xation [7,[22][23][24][25][26][27][28][29][30][31][32][33][34], other studies suggested that whether the capsular bag and IOL can remain stable after CTR implantation during cataract surgery in patients with strong myopia are controversial [7,22,34]. In addition to these uncertainties, the effects of CTR on cataract surgery in patients with an abnormal zonule after PPV are unclear. Therefore, the current study analyzed the effects of CTR on capsular bag changes and complications after cataract surgery, in patients with weak zonules, speci cally with subgroup analyses focused on patients who underwent PPV or who had strong myopia.

Patient enrollment
Consecutive cataract patients referred to the Department of Ophthalmology at West China Hospital of Sichuan University between December 2017 and December 2018 were eligible for enrollment if (1) phacoemulsi cation was proposed as a treatment; (2) patients had an axial length > 28 mm, or more than 3 months had passed since PPV; (3) zonules were considered weak when the average zonular length > 0.7 mm [35,36], as measured by ultrasound biomicroscopy; and (4) patients were eligible for phacoemulsi cation alone or with CTR implants. Exclusion criteria included: (1) zonular issues caused by pseudoexfoliation syndrome, uveitis, retinitis pigmentosa, trauma, other intraocular surgeries than PPV, or connective tissue disorders; (2) zonular rupture >90°; and (3) unsuitability for CTR implants. Only data on the rst operated eye were included in this study, regardless of whether patients underwent operations in both eyes. Patients were randomly assigned to phacoemulsi cation alone or with CTR implants based on permuted-block randomization by an optometrist who was not involved in patient selection or surgery. A computer program for randomization that provided random permuted blocks was used by the optometrist. Using a two-sided α = 0.05, β = 0.2, d( expected difference) =0.17, s( standard deviation) =0.2, we calculated a minimum sample of 21 patients per group. Assuming an expected dropout rate of 10%, 23 patients in each group were needed.
All Patients were provided thorough information about the surgery and possible complications, and they were not blinded to treatments. Written informed consent was obtained from all patients for their anonymized clinical data to be analyzed and published for research purposes. This study was approved by the Ethics Committee of the West China Hospital of Sichuan University, Chengdu, China, and registered in the Chinese Clinical Trial Registry (ChiCTR-INR-17011217).

Preoperative eye examination
Uncorrected distant visual acuity (UDVA) and best corrected distant visual acuity (BCDVA) of all patients were recorded using a Snellen chart. Visual acuity values were converted to logarithms of the minimum angle of resolution (logMAR). Refractive prediction error was determined by measuring the difference between the preoperative refractive target and actual refraction (D, diopters) after surgery. Eye pressure was determined by non-contact tonometry before pupillary dilation. Axial length of the eye was measured by optical biometry (IOL Master 500, Zeiss, Oberkochen, Germany). Zonular weakness was considered if there was an abnormal zonular length which was measured using an ultrasound biomicroscope. Zonular length was reported as an average of 4 measurements at 3, 6, 9, 12 o'clock. Measurements were made between the mid-point of the ciliary process and the end of zonular bers at the lens equator ( Figure 1). Preoperative eye examinations for all patients were conducted by the same investigator.

Surgical procedures and IOL implantation
All enrolled patients received phacoemulsi cation and IOL implantation (Akreos MI60, Bausch & Lomb, Rochester, NY, USA). A 2.0-mm corneal incision was made, a 5.0-5.5mm CCC was performed and the IOL was implanted using a Stellaris System (Bausch & Lomb, Rochester, NY, USA). Patients in the intervention group underwent CTR implantation (ACPi-11, Bausch & Lomb, Rochester, NY, USA) before IOL implantation. All surgical procedures were performed by an experienced surgeon (Wei Fan).
The Akreos MI60 IOL is made up of hydrophilic acrylic with 26% water content (total length 10.5-11 mm; optic diameter 5.6-6.2 mm, depending on the dioptric power). According to the manufacturer, this IOL has a neutral aspheric optic designed to aid image transmission, even during decentration or tilting. Additionally, this IOL has four haptics designed to resist vitreous pressure and provide anteroposterior stability, thus preventing pseudoaccommodation. The thin haptics provide four zones for capsule sealing around the optic, promoting early and stable centration. The progressive resistance of the haptics is designed to prevent capsular bag contraction and optic displacement. The 10° haptic angle pushes the IOL optics backward. This angle and the 360° square-edged design help prevent PCO [35].

Postoperative eye examination
Postoperative eye examination was performed by the same ophthalmologist and optometrist in each patient at 1 day, 1 week, 1 month and 3 months after the surgery. Examination parameters were the same as in the preoperative eye examination. Postoperative complications, if any, were also recorded. Micrographs of anterior continuous curvilinear capsulorhexis and IOL optics were taken using a slit-lamp camera, and areas of anterior capsulorhexis were analyzed by Image J (National Institutes of Health, Bethesda, MD, USA). The position of the IOL and the attachment ratio between the posterior lens capsule and posterior surface of the IOL were evaluated using anterior segment optical coherence tomography (Carl Zeiss Meditec, Jena, Germany). IOL inclination angle, de ned as the angle between the posterior surface of the iris and the anterior surface of the IOL, was measured both vertically and horizontally [35].
The angle was measured from micrographs using Adobe PDF Editor (San Jose, CA, USA).

Statistical analysis
Data were analyzed using SAS 9.4 (IBM, Armonk, NY, USA). Continuous data were presented as mean ± standard deviation, and categorical data as number (percentage). For continuous data involving repeated measurements, inter-group and intragroup differences were assessed for signi cance using repeated measurement variance analysis. For categorical data, inter-group differences were assessed using the chi-squared test. All statistical tests were two-sided. Differences were considered signi cant when p<0.05.

Patient characteristics
A total of 42 patients (21 men) were enrolled in the study and randomized into a CTR group [T(total)-CTR, n = 22, 12 men] and control group (T-CON, n = 20, 9 men. Subgroup analyses within these two groups were performed based on whether patients suffered from zonular problems because of PPV (P-CTR vs. P-CON) or myopia (M-CTR vs. M-CON).
Patients showed the following primary vitreo-retinal diseases: retinal detachment, vitreous hemorrhage, macular pucker, and macular hole. Average length of zonules was (1.08±0.28) mm in the T-CTR group and (1.03±0. 19) mm in the T-CON group, and the two values were not statistically different (Table 1).

Area of continuous curvilinear capsulorhexis (A CCC )
A CCC was significantly larger in total CTR patients than control patients at 3 months after surgery (p = 0.0199), but not at 1 week or 1 month (Table 2). Among CTR patients, A CCC was lower at 3 months than at 1 week but not 1 month after surgery. Among control patients, A CCC was lower at 3 months than at 1 week or 1 month after surgery. These findings suggest earlier stabilization of Accc in the CTR group.  Since we implanted IOLs of two diameters (6.0 and 6.2 mm), the ratio of A CCC to AIOL was also compared between CTR and control groups. When IOL diopter was ≤ +15.0 D, Page 9/19 A CCC was relatively large (5.5-6.0mm). Similar to the trends in A CCC values, the A CCC /A IOL ratio at 3 months after surgery was significantly higher in the CTR group than in the control group (p = 0.0172). This trend was also observed in the myopia subgroup (p = 0.0124; Table 3). Attachment ratio between posterior lens capsule and IOL surface Among patients with history of PPV, the attachment ratio between posterior lens capsule and IOL surface was higher in the P-CTR group than in the P-CON group at 1 week and 1 month after surgery ( Table 4). The ratio was not significantly different between the M-CTR and M-CON groups at 1 week, 1 month or 3 months after surgery.  Figure   4b).

Depth of central anterior chamber
Depth of the central anterior chamber did not differ significantly between CTR and control patients in the total sample or in subgroups of those with PPV history or severe myopia at 1 week, 1 month or 3 months after surgery.

Post-operative complications
All the patients in this study showed well-controlled postoperative inflammation. One

Discussion
CTR is widely used in clinical treatment of cataracts complicated with lens dislocation. CTR can effectively balance the tension of zonular bers, uniformly distribute the tension of the capsular bag, maintain the shape of the capsular bag, reduce loss of the vitreous body, and increase attachment between posterior capsule and IOL surface. These effects of CTR increase IOL stability after cataract extraction involving IOL implantation and reduce the occurrence of posterior capsule opaci cation and IOL dislocation [7,[22][23][24][25][26][27][28][29][30][31][32][33][34]. Whether and how CTR implantation can also bene t patients with weakened zonular bers but no lens dislocation is unclear. The present randomized controlled trial suggests that CTR in such patients can reduce the incidence of capsular shrinkage, maintain capsular bag stability, make IOL inclination more manageable and stable, as well as increase the rate of complete attachment between the posterior capsule of the lens and posterior surface of the IOL.
In a previous study, the capsulorhexis demonstrated a steady trend of contraction from 1 week to 3 months after surgery. The capsulorhexis stabilized after 3 months and showed no signi cant differences between 3 and 6 months after surgery [27]. In cataract patients with lens dislocation, CTR implantation during surgery can lead to better capsular shape and IOL positioning, as well as reduce risk of capsular shrinkage, starting at 1 day up to 6 months after surgery [27]. Studies in humans [36,37] and animals [38] showed similar results, even in cases without weak zonules. However, other studies found that CTR implantation did not reduce incidence of IOL dislocation by at 3 months after cataract surgery [29,30].
Our results indicated that CTR implantation can prevent capsular shrinkage starting from 1 week postoperatively in patients with high myopia. This effect was even greater at 3 months after surgery, indicating that CTR is effective in delaying shrinkage and maintaining capsular bag stability in patients with severe myopia in early stage(3 months) after cataract surgery, and this may suggest a possible bene cial effect in the longer term.
In contrast to these results in patients with myopia, our analysis of patients who had undergone PPV showed no clear bene cial effects of CTR, especially on the anterior capsulorhexis shrinkage. This could be due to the adverse effects of silicone oil or gas bubbles injected into the eye after vitrectomy. Among the 22 PPV patients included in our study, 9 had silicon oil tamponades and 13 had gas tamponades after PPV. Vitreous loss or vitreous lling with gas or silicone oil can change the metabolism of the lens and cause cataracts with plaque and opaci cation [39]. Thus, the bene ts of CTR implantation may be masked by the adverse effects of PPV, silicone oil or gas bubbles on capsule, which include reduced capsular elasticity, altered capsule structure, and its response to capsulorhexis [39]. The underlying mechanisms of capsular changes induced by silicone oil or gas remains to be clari ed.
Capsular contraction syndrome is a more serious complication following capsular shrinkage [27,28], and is usually accompanied by posterior capsule opaci cation and even causes IOL dislocation. Timely intervention is necessary in order to prevent further visual impairment. In this study, we found that the incidence of signi cant capsular contraction syndrome was lower in CTR patients (4.55%, 1 case in PPV subgroup, 0 in myopia subgroup) than in control patients (15.00%, 0 in PPV subgroup, 3 cases in myopia subgroup) at 3 months after surgery, which made it mandatory for these patients to have Nd:YAG treatment. This suggests that CTR implantation can reduce, but can't completely eliminate, the incidence of capsular shrinkage and contraction, especially in patients with severe myopia [38].
We also found that the rate of complete attachment between the posterior capsule of the lens and the posterior surface of the IOL was higher in the CTR group than the control group at 1 week and 3 months after surgery. This can occur because the CTR mechanically compresses the capsular bag closer to the IOL surface [26,34,40,41]. This effect of CTR was not obvious in patients with severe myopia, perhaps because of their longer axial dimension and larger capsular bags. We speculate that the CTR used in this study, with a diameter of 11 mm, may not be large enough to completely open the capsular bag in patients with severe myopia.
Previous animal and human studies have demonstrated minor IOL eccentricity and inclination that remained stable within 2 years after CTR implantation during cataract surgery [36,38]. Our study showed that the vertical inclination angle gradually decreased in CTR patients but increased in control patients. In contrast, horizontal IOL inclination angle remained stable within 3 months after surgery in both CTR and control patients. These results support the theory that IOL inclination after CTR implantation is manageable and stable [22,42].
Whether CTR implantation during cataract surgery affects postoperative refractive prediction error is unclear. A retrospective study on CTR implantation in 25 patients with abnormal zonules found that the position of the posterior chamber IOL exceeded the predicted value by +0.5 to +2.0 D [31]. A randomized controlled trial in 52 cataract patients without other complications showed hyperopia drift after CTR implantation [29], leading those authors to recommend reducing preoperative refractive predictions by 0.5 D. Our results, in contrast, argue against adjusting preoperative refractive predictions should not be adjusted for patients undergoing CTR implantation: we did not observe substantial differences in refractive prediction error values between CTR and control patients, consistent with other studies [33,[43][44][45].
CTR implantation increases the di culty and risk of cataract surgery, especially in patients who may have hidden capsular rupture. Implanting a CTR may aggravate the rupture of the capsular bag and cause the lens and CTR to fall off. Therefore, surgeons will have a longer learning curve before they achieve pro ciency in cataract surgery skills. In addition, the limited adaptations for CTR implantation require special attention in order to prevent severe complications, such as lens and CTR dislocation.
Our results must be interpreted with caution in the light of certain limitations. First, CTR with a diameter of 11 mm was used in all patients. However, Individualized optimization of CTR diameter is more desirable, especially for cataract patients with severe myopia. Second, due to limited pupil dilation, the IOL pro le of certain patients was not fully visible during anterior segment optical coherence tomography.
Therefore, only IOL tilt was measured in our study, resulting in inconclusive IOL inclination angle measurements. Third, based on previous studies that have reported the bene cial and adverse effects of CTR implantation, we followed up patients only up to 3 months after surgery. Although we were able to provide some insights into the early bene cial effects of CTR on capsular stability in patients with weak zonules after uneventful cataract surgery, future studies must investigate the long-term stability of the capsule and the effects of CTR on IOL positioning over a long period of time. Further, we could not study the early changes in the anterior continuous curvilinear capsulorhexis (e.g., within 1 week after surgery), since we did not measure Accc value at 1 day after surgery.
Despite these limitations, our study provides evidence showing that the bene ts of CTR implantation can outweigh its disadvantages in cataract patients with slightly abnormal zonules, especially those with severe myopia or those who have undergone PPV.

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CTR is effective in delaying shrinkage and maintaining capsular bag stability in patients with severe myopia, especially in the early stages (3months) after cataract surgery, indicating possible long-term bene cial effects. However, this early effect was not observed in patients who had undergone PPV. CTR implantation can also promote adhesion between the posterior capsule and the posterior surface of IOL in patients with weak zonules, especially those after PPV. In a word, CTR implantation can bene t cataract patients with weak zonules by maintaining the shape of the capsular bag, reducing capsule shrinkage and stabilizing IOL inclination, which may reduce risk of IOL dislocation in the longer term. All authors read and approved the nal manuscript.
Ethics approval and consent to participate These procedures were approved by the Ethics Committee of West China Hospital of Sichuan University. Written informed consent was obtained from all participants before the surgery. This study was registered at the Chinese Clinical Trial Registry (ChiCTR-INR-17011217).

Consent for publication
Was taken in writing from all the patients before surgery. All the patients in the study consented for their individual data to be published.

Competing interests
The authors declare that they have no competing interests.

Funding
This work was supported by the National Natural Science Foundation of China (No. 81670869). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.