Purpose
Corneal allogeneic intrastromal ring segments (CAIRS) are a novel therapeutic approach to treat ectatic diseases such as keratoconus and improve visual acuity as well as corneal topography. This analysis aimed to evaluate the visual outcomes and corneal topography changes after CAIRS implantation for keratoconus.
Design
Systematic Review and Meta-Analysis.
Methods
In this systematic literature review and meta-analysis (ID: CRD42024612508) original peer-reviewed clinical studies on the effect of CAIRS in eyes with keratoconus were included. Exclusion criteria were preimplanted ring segments, ectatic diseases other than keratoconus, as well as no reported pre- or postoperative outcome parameters. Cochrane, Embase, PubMed and Web of Science libraries were screened in November 2024 by 2 researchers independently. The risk of bias was assessed using the Evidence Project risk of bias tool. The primary effect measure was the difference in corrected distance visual acuity (CDVA) before and after CAIRS. Additionally, changes in uncorrected distance visual acuity (UDVA), spherical equivalent (SE), cylinder, flat keratometry, steep keratometry, maximum keratometry (Kmax), mean keratometry, thinnest corneal thickness, and higher order aberrations (HOAs) after CAIRS were analyzed and compared using a random effects model. In addition, postoperative complications were documented.
Results
Fourteen clinical studies with a total of 442 eyes were included in the meta-analysis. The mean improvement in CDVA was 0.37 logMAR (95% CI: 0.28, 0.46; 14 studies; n = 442 eyes). UDVA improved by 0.43 logMAR (95% CI: 0.34, 0.55; 11 studies; n = 427 eyes). SE improved by 4.59 D (95% CI: 3.35, 5.84; 12 studies; n = 430 eyes). Kmax was reduced by -4.49 D (95% CI: -6.05, -2.92; 13 studies; n = 439 eyes) and total HOAs decreased by -0.33 µm (95% CI: -0.62, -0.03; 6 studies; n = 171 eyes). One severe adverse event (0.2%) reported was an acute rejection, which necessitated explantation.
Conclusions
This meta-analysis demonstrates that CAIRS transplantation is an effective procedure that can significantly improve UDVA, CDVA, and topographic outcomes in keratoconus eyes with low complication rates.
E ctatic corneal disorders such as keratoconus may cause considerable visual impairment. While spectacles and contact lenses may provide functional vision in mild to moderate cases, more advanced cases with significant scarring often require surgical treatment such as keratoplasty. However, both penetrating keratoplasty (PKP) or deep anterior lamellar keratoplasty (DALK) are invasive, technically challenging, and associated with risks of complications such as graft rejection, central corneal edema or scarring, perforations, suture-related complications (e.g. irregular astigmatism), Urrets Zavalia syndrome, and secondary glaucoma. ,
Implantation of corneal allogeneic intrastromal ring segments (CAIRS) has recently emerged as a novel, effective, and safe procedure for keratoconus. In contrast to keratoplasty, CAIRS is minimally invasive, easier to learn, and can provide rapid improvement in visual outcomes. The insertion of the ring segments into the steep meridian causes flattening of the corneal curvature central to the segments, which flattens and centralizes the cone, reduces irregular astigmatism, and induces hyperopic shift, thereby improving both visual and refractive outcomes. Thanks to its allogeneic nature, it is hypothesized to be associated with a lower risk of anterior or posterior stromal necrosis, , migration, extrusion or intrusion into the anterior chamber, , and corneal melt or neovascularization , which were associated with previous intrastromal ring segments (ICRS) composed of synthetic (e.g., polymethyl methacrylate (PMMA)) materials.
However, the effect of CAIRS on the visual acuity as well as the corneal topography in eyes with keratoconus has only been studied in relatively small case series producing highly varying results. Thus, the aim of this meta-analysis was to determine the effect of CAIRS on visual and topographic parameters in keratoconus eyes.
METHODS
Search Strategy
This meta-analysis and systematic literature review adhered to the guidelines stated by PRISMA (Supplementary Figure 1) and was registered in PROSPERO (ID: CRD42024612508). Inclusion criteria were RCTs, non-randomized controlled clinical trials, cohort studies, case series, or case reports, which analyze the effect of CAIRS in patients with keratoconus on visual acuity and corneal topography. Exclusion criteria were other intrastromal tissue transplantations (e.g. myopic cornea lenticule transplantation), CAIRS performed as a secondary procedure, i.e. after removal of synthetic ICRS, as well as a focus on other ectatic diseases or the presence of ocular comorbidities. Additionally, narrative reviews, ex-vivo experiments, animal experiments, and technique reports without reported or measured clinical outcomes were excluded.
We conducted a systematic literature research in Cochrane, Embase, PubMed and Web of Science databases until 11/11/2024 using the following search terms: (“CAIRS” [All Fields]) OR (“corneal allogenic intrastromal ring segment*” [All Fields]) OR (“allograft corneal ring*” [All Fields]) OR (“corneal allograft ring” [All Fields]). The search was restricted to peer-reviewed articles written in English or German. Two independent reviewers (M.F. and H.-S.S.) screened each record independently and disagreements were resolved by the blinded assessment of a third reviewer (V.A.A.). Data was collected from the included studies by both reviewers independently and compared afterwards to prevent documentation errors.
Risk of bias and Certainty assessment
To assess the risk of bias, both reviewers (M.F. and H.-S.S.) independently applied the Evidence Project risk of bias tool on all included studies. Disagreements were resolved by the assessment of another researcher (V.A.A.) who was also blinded to the previous decisions. The evidence certainty assessment of the primary outcome was performed by both reviewers using the GRADE approach.
Effect measures and Synthesis
The primary effect measure was the mean change of the corrected distance visual acuity (CDVA) after CAIRS. Secondary outcomes were the change in uncorrected distance visual acuity (UDVA), spherical equivalent (SE), refractive cylinder, flat keratometry (K1), steep keratometry (K2), mean keratometry (Kmean), maximum keratometry (Kmax), and thinnest corneal thickness (TCT). Additionally, the changes in higher order aberrations (HOAs), including the root mean square (RMS) of total HOAs, total coma, vertical coma, horizontal coma, spherical aberration, trefoil 3/-3, and trefoil 3/3 were derived. The preoperative values, the last postoperative values, and the mean difference ± SD of all outcome parameters were obtained. If a study did not report a secondary outcome pre- or postoperatively, this study was excluded from the synthesis of the secondary outcome parameter. Reports of follow-up examinations without all included eyes were not considered in this meta-analysis and study-wise excluded. Summary visual acuity measures reported in other units than the logarithm of the minimum angle of resolution (logMAR) were converted to logMAR according to Khoshnood et al. If the difference in outcome parameters and standard error were not reported, these values were calculated out of individual level data. If no individual level data was available, they were estimated from confidence intervals (CIs). If no CIs were available, they were calculated using the pre- and postoperative summary values, reported correlation coefficients and the within-group mean difference formulae described by Borkenstein et al. If no correlation coefficients were available, we assumed a moderate correlation between pre- and postoperative values of r = 0.5 due to the paired structure of the data. If studies only reported their results divided into subgroups (e.g. early-stage and late-stage keratoconus), the means and standard deviations were summarized using the Cochrane formulae. Additionally, study characteristics such as the number of eyes and patients, age, gender distribution, distribution of right/left eyes, follow-up interval, planning and technique for CAIRS, and complications were documented.
Statistical Analysis
As considerable heterogeneity between the studies was expected, the pooled outcome measure was calculated using a random effects model with the inverse variance method, the restricted maximum likelihood variance estimator, and the Hartung-Knapp-Sidik-Jonkman adjustment method, whereas results from a fixed effects model were supplemented as a sensitivity analysis. Heterogeneity was statistically assessed by calculating the I ² statistic. The presence of publication bias was assessed by a funnel plot of the change in CDVA and the Egger’s test for asymmetry. All analyses were performed using R v. 4.2.2 (meta package v. 4.19-1).
RESULTS
Study selection
Literature research yielded a total sum of 362 results across all the aforementioned databases. As shown in the CONSORT flow chart ( Figure 1 ), 48 duplicate records were removed and the abstract of 314 studies were screened. After excluding 279 records for not analyzing CAIRS, 35 reports were retrieved for full-text review. After excluding 21 studies due to fulfillment of the exclusion criteria, 14 studies with a total of 442 eyes from 353 patients were included in the meta-analysis. We included 1 study where the majority of all patients (90.4%) had keratoconus and only 5 eyes (9.6%) had corneal ectasia after laser vision correction. Data was extracted from individual level data in 3 studies, subgroup level data in 2 studies, , and summary level data in 9 studies. , , The mean age of the participants ranged from 29.04 years to 66 years (no data in 4 studies). , , , The median follow-up period was 6 months (minimum: 1 month; maximum: 12 months). Other study characteristics are shown in Table 1 . The techniques used for CAIRS planning and CAIRS implantation are shown in Table 2 . The preoperative and postoperative values of the primary and secondary outcome parameters are displayed in Supplementary Table 1.
| Year | Author | Study type | Prospective | N (Eyes) | N (Patients) | Follow-up (Months) | Mean Age | Male (%) | Right eye (%) | Diagnosis |
|---|---|---|---|---|---|---|---|---|---|---|
| 2018 | Jacob et al. | Case series | No | 24 | 22 | 11.58 ± 3.6 | NR | NR | NR | Progressive keratoconus |
| 2023 | Haciagaoglu et al. | Case series | No | 44 | 32 | 6 | 30.32 ± 7.43 | 75 | NR | Keratoconus |
| 2023 | Bteich et al. | Case series | Yes | 4 | 2 | 6 | 66.0 ± 2.0 | NR | 50 | Irregular keratoconus |
| 2023 | Bteich et al. | Case series | No | 52 | 39 | 6.9 ± 5.2 | 31.2 ± 13.6 | 63.3 | NR | Stable keratoconus (47), corneal ectasia after LVC (5) |
| 2023 | Jacob et al. | Case series | Yes | 32 | 29 | 12 | NR | 55.2 | NR | Mostly progressive asymmetric keratoconus |
| 2024 | Nacaroglu et al. | Case series | No | 65 | 49 | 12 | 29.54 ± 7.34 | 77.6 | 52.3 | Stable keratoconus |
| 2024 | Bteich et al. | Case series | No | 20 | 15 | 12 | NR | NR | NR | Stable keratoconus |
| 2024 | Coscarelli et al. | Case series | Yes | 3 | 3 | 6.01 ± 1.02 | 26.00 ± 4.0 | NR | 33.3 | Advanced keratoconus |
| 2024 | Keskin Perk et al. | Case series | Yes | 62 | 49 | 6 | 29.04 ± 8.13 | 67 | NR | Keratoconus |
| 2024 | Kirgiz et al. | Case series | No | 23 | 23 | 6 | 29.3 ± 7.2 | 78.3 | 73.9 | Stable keratoconus |
| 2024 | Mazzotta et al. | Case series | Yes | 2 | 2 | 3 | 48.5 ± 3.54 | 100 | 50 | Keratoconus |
| 2024 | Mechleb et al. | Case series | Yes | 10 | 10 | 1 | NR | NR | NR | Kertoconus (Kmax <75D) |
| 2024 | Yucekul et al. | Case series | No | 67 | 47 | 6 | 29 (CXL) 24 (No CXL) | 72 | NR | Asymmetric non-central keratoconus |
| 2024 | Asfar et al. | Cohort study | No | 34 | 31 | 9.2 | 34.1 ± 15.5 | 72.4 | NR | Stable keratoconus |
| Year | Author | CAIRS Calculation | CAIRS Preparation | CAIRS Hydration | CXL? |
|---|---|---|---|---|---|
| 2018 | Jacob et al. | Uniform size | Trephine | Hydrated | Intraoperatively |
| 2023 | Haciagaoglu et al. | Nomogram (Istanbul) | KeraNatural | NR | No |
| 2023 | Bteich et al. | Individual topographical plan | Femtosecond Laser | Dehydrated | No |
| 2023 | Bteich et al. | Modified Nomogram (Fahd) | Trephine | Dehydrated | No |
| 2023 | Jacob et al. | Individual topographical plan | Trephine + CAIRS Customizer | Hydrated | Intraoperatively (31 out of 32 eyes) |
| 2024 | Nacaroglu et al. | Nomogram (Istanbul) | KeraNatural | NR | Preoperatively (mean 60,9 months prior CAIRS) |
| 2024 | Bteich et al. | Modified Nomogram (Fahd) | Femtosecond Laser (multiple) | Dehydrated | No |
| 2024 | Coscarelli et al. | Uniform size | Trephine | Dehydrated | No |
| 2024 | Keskin Perk et al. | Nomogram (Istanbul) | KeraNatural | NR | No |
| 2024 | Kirgiz et al. | NR | Trephine | Dehydrated | No |
| 2024 | Mazzotta et al. | Modified MS39 integrated nomogram (Alfonso) | Femtosecond Laser + CXL | CXL | Preoperative CXL of CAIRS |
| 2024 | Mechleb et al. | Individual topographical plan & Nomogram (Fahd) | Femtosecond Laser (multiple) | Dehydrated | No |
| 2024 | Yucekul et al. | Nomogram (Istanbul) | KeraNatural | NR | Partly (n = 30 CXL preop, n = 37 no CXL) |
| 2024 | Asfar et al. | Modified Nomogram (Fahd) | Trephine | Dehydrated | No |
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