|Year : 2018 | Volume
| Issue : 4 | Page : 376-382
Visual and refractive outcomes and tomographic changes after femtosecond laser-assisted intrastromal corneal ring segment implantation in patients with keratoconus
Seyed Javad Hashemian1, Nooshin Farshchian1, Alireza Foroutam-Jazi1, Mohammad Ebrahim Jafari2, Mahsa Sadat Hashemian3, Seyed Mahyar Hashemian4
1 Eye Research Center, Rassoul Akram Hospital, Iran University of Medical Sciences, Tehran, Iran
2 Iranian Eye Clinic, Tehran, Iran
3 School of Pharmacy, International Campus, Tehran University of Medical Sciences, Tehran, Iran
4 Shahid Beheshti University of Medical Sciences, Tehran, Iran
|Date of Submission||28-Feb-2017|
|Date of Acceptance||02-Dec-2017|
|Date of Web Publication||24-Oct-2018|
Seyed Javad Hashemian
Eye Research Center, Rassoul Akram Hospital, Iran University of Medical Sciences, No. 86, 10th Boostan St., Pasdaran Ave., Tehran 16667
Source of Support: None, Conflict of Interest: None
Purpose: To evaluate the visual, refractive, and tomography changes after femtosecond laser-assisted intrastromal corneal ring segment (ICRS; Intacs® SK) implantation in patients with keratoconus.
Methods: In this prospective interventional case series, Intacs SK ICRSs were inserted using a femtosecond laser into eyes with stage I–IV keratoconus. Visual, refractive, and corneal tomography changes, along with surgical complications, were analyzed 1 week, 2 months, and 6 months postoperatively.
Results: The study evaluated 71 eyes of 52 patients (mean age: 27.5 years). Six months postoperatively, the spherical equivalent, mean sphere, and mean cylinder were decreased by 2.07, 1.47, and 1.13 diopters (D), respectively. The mean preoperative uncorrected distance visual acuity (UDVA) increased from 0.87 ± 0.26 to 0.46 ± 0.19 LogMAR and the mean preoperative corrected distance visual acuity (CDVA) increased from 0.55 ± 0.21 to 0.28 ± 0.17 LogMAR (P < 0.001). Flat and steep keratometry decreased by a mean corneal power in the 3-mm zone, and mean anterior elevation decreased by 0.91 D, 2.52 D, and 1.03 microns (P < 0.001), respectively. Among all eyes, 93.0% gained one or more lines of CDVA. Mean internal anterior chamber depth decreased from 3.25 ± 0.33 to 3.14 ± 0.45 mm (P = 0.001), and mean irregularity in the 3-mm zone decreased from 5.63 ± 1.71 to 5.24 ± 1.82 (P = 0.006). However, mean posterior elevation and irregularity in the 5-mm zone did not change significantly.
Conclusion: Implantation of one or two Intacs SK segments is safe and effective to treat keratoconus, leading to significant improvement in UDVA, CDVA, and refractive error.
Keywords: Icrs; Intacs-SK; Intrastromal Corneal Ring Segment; Keratoconus
|How to cite this article:|
Hashemian SJ, Farshchian N, Foroutam-Jazi A, Jafari ME, Hashemian MS, Hashemian SM. Visual and refractive outcomes and tomographic changes after femtosecond laser-assisted intrastromal corneal ring segment implantation in patients with keratoconus. J Ophthalmic Vis Res 2018;13:376-82
|How to cite this URL:|
Hashemian SJ, Farshchian N, Foroutam-Jazi A, Jafari ME, Hashemian MS, Hashemian SM. Visual and refractive outcomes and tomographic changes after femtosecond laser-assisted intrastromal corneal ring segment implantation in patients with keratoconus. J Ophthalmic Vis Res [serial online] 2018 [cited 2019 Mar 24];13:376-82. Available from: http://www.jovr.org/text.asp?2018/13/4/376/243885
| Introduction|| |
Keratoconus is a progressive bilateral, though asymmetric, corneal disease which is characterized by corneal thining and bulging., The diseasse leads to reduced visual acuity due to myopia, irregular astigmatism, and corneal scar., Treatment of the early stage of keratoconus includes glasses and contact lenses. However, with keratoconus progression, spectacles or contact lenses can no longer improve visual acuity, and other treatment modalities are needed,, namely intrastromal corneal ring segments (ICRSs) and corneal transplantation (lamellar or penetrating). However, keratoplasty is irreversible and may be associated with several complications, including graft rejection, endothelial cell loss, and suture-related problems. Thus, it is advisable to seek other options to avoid or delay the need for keratoplasty. The Intacs® SK ICRS (Addition Technology Inc., Sunnyvale, USA) was introduced in 2000 and subsequently became the mainstay of refractive management in keratoconus-affected patients who are contact lens-intolerant and have no central cornea scars.,,,,,,,,,
Sansanayudh et al evaluated the outcomes of Intacs SK ICRS implantation in 10 eyes with advanced keratoconus and found a significant improvement in visual outcomes and aberrometric conditions after 6 months. However, no significant improvement in refractive parameters was observed. Furthermore, several studies have evaluated Intacs SK implantation to treat moderate to severe keratoconus.,
To our knowledge, no previous studies have evaluated femtosecond laser-assisted Intacs SK implantation with regard to its safety, efficacy, stability, refractive and visual outcomes, or topographic changes in all Amsler–Krumeich grades of keratoconus. The present study aimed to do so.
| Methods|| |
This prospective, interventional, case series evaluated 101 eyes of 74 kertoconus patients (47 men, 27 women) diagnosed on the basis of Orbscan™ IIz indexes (Bausch and Lomb, NY). All patients had non-progressive disease—that is, the topography and refraction data were stable—and all were aged between 19 and 47 years (mean ± standard deviation [SD]: 27.9 ± 6.9 years). They had been referred to Rassoul Akram Hospital and Iranian Eye Clinic in Tehran. Because of incomplete follow-up of 22 patients, the final data of 71 eyes of 52 patients were analyzed. The tenets of the Declaration of Helsinki were followed, and Iran University Health Network Research Ethics Board approved the study. Intacs SK implantation was performed using a femtosecond laser (FEMTEC; Perfect Vision 20/10, Heidelberg, Germany). All eyes had a corneal thickness of more than 450 μm at the incision site, and all were subjected to preoperative evaluation, including systemic and ophthalmological history, uncorrected (UDVA) and corrected (CDVA) distance visual acuity measurement, subjective refraction, slit-lamp examination, applanation tonometry, indirect ophthalmoscopy, and corneal topography by OrbscanIIZ™ (Bausch and Lomb, NY). Postoperative visits were scheduled after 1 week, 2 months, and 6 months; they included UDVA and CDVA measurement, slit-lamp examination, applanation tonometry, corneal topography, and subjective refraction.
Inclusion criteria were as follows: keratoconus of stage I–IV according to Amsler–Krumeich classification, mean keratometry reading (K) of less than 60 D, mesopic pupil of less than 6.5 mm in diameter, and contact lens intolerance.
Exclusion criteria were as follows: severe dry eye, corneal scar, severe allergic conjunctivitis, a history of intraocular surgery, glaucoma, cataract, a history of herpes simplex keratitis, pregnancy, breast-feeding, and use of certain medications, such as Accutane (Isotretinoin, Accutane™ Roche®, Canada).
Recently, a new Intacs design (Intacs SK; Addition Technology Inc., Sunnyvale, USA) has been introduced. It has an inner diameter of 6.0 mm and an oval cross section, whereas the standard Intacs has a 6.8-mm inner diameter and a hexagonal cross section.,
Due to its smaller diameter, the Intacs-SK is more effective in advanced keratoconus cases and in early cases with low corneal thickness. It is now available in thicknesses of 0.21, 0.25, 0.30, 0.35, 0.40, and 0.45 mm.
Implantation was performed on the basis of cone location, mean refractive sphere, astigmatism, and keratometric data. In eyes with central cones, symmetric segments were implanted, while in those with eccentric cones, single segments were implanted.
The thickness of the ring was selected on the basis of either corneal thickness at the incision site or spherical equivalent (SE) in patients with a central cone. In patients with an eccentric cone, it was selected based on astigmatic power.
We followed the company nomogram and used symmetric pair rings in cases of central conus, asymmetric pairs in cases of keratoconus with myopic spherical refraction and asymmetric conus, and single segments in cases of eccentric conus with astigmatism.
Corneal thickness at the incision site was measured using Orbscan pachymetry with Intracalc software. All surgical procedures were performed by the same surgeon (SJH) under topical anesthesia by 0.5% tetracaine eye drop (Anestocaine; Sina Darou, Tehran, Iran). “Prep and drape” were performed using povidone-iodine (BacterBye 10% povidone iodine; Kishmedipharm, Kish, Iran), blepharostat placement, and conjuctival sac irrigation with normal saline.
Patients were placed under the laser system, and the femtosecond suction ring was centered at the pupil center. Suction was applied and the femtosecond laser was used to create a 360-degree channel at the selected corneal depth (75% of the corneal thickness at the incision site), with an inner diameter of 6.0 mm and an outer diameter of 7.2 mm. The femtosecond laser was also used to create an incision to insert the Intacs SK segment, preferably on the steepest axis. If the patient's BCVA was better than 0.5 logarithm of the minimum angle resolution (LogMAR), the axis of manifest refraction was used for this purpose.
Under microscopic guidance, the Intacs SK segments were implanted inside the channels using forceps and Sinskey hooks placed through dialing holes at the ends of every segment. Each part was centered in the middle of its tunnel, equidistant from the incision. If a single segment was used, it was implanted inferiorly; if two were used, the largest was implanted inferiorly. The incision site was not sutured.
Postoperatively, a bandage contact lens (AIR optix AQUA; Base Curve: 8.6, Diameter: 14.2; CIBA VISION) was fitted for 24 hours. Ciprofloxacin eye drops (Ciplex; Sina Darou, Tehran, Iran) were administered four times a day for one week. Betamethasone eye drops (Betasonate, 0.1% betamethasone disodium phosphate; Sina Darou, Tehran, Iran) were given every 12 hours for 3 weeks, and artificial tears (Artelac™, Hypromellose; Bausch and Lomb, Montpellier, France) were given every 4 hours for 4 weeks.
Data were analyzed using SPSS software (version 20, IBM SPSS statistics, SPSS Inc., USA). After 6 months, preoperative and postoperative parameters were compared using the paired t-test, P values less than 0.05 were considered statistically significant.
| Results|| |
The mean age of the patients was 27.5 years (SD: 7.1 years, range: 19–47). According to the Amsler–Krumeich classification, 25 eyes (35.2%) were grade 1, 28 (39.4%) were grade 2, six (8.5%) were grade 3, and 12 (16.9%) were grade 4.
The mean thinnest pachymetry in the 6-mm zone was 528.2 μm (SD: 40.5 μm, range: 450–615 μm). Thirty-five of the eyes received two ring segments (49.3%), while the remaining 36 eyes (50.7%) received one ring segment. All patients completed the 6-month follow up.
The preoperative UDVA ranged from 0.3 to 1.00 LogMAR, (20/40 to counting fingers). The mean UDVA was significantly better 6 months postoperatively (0.46 ± 0.19) than before surgery (0.87 ± 0.26; P < 0.001).
Six months after surgery, 68 eyes (95.8%) gained one or more lines of UDVA, and none lost any lines, although three eyes (4.2%) showed no change in the Snellen test.
The preoperative CDVA ranged from 0.1 to 1.00 LogMAR (20/25 to 20/200) and the mean postoperative CDVA (0.28 ± 0.17) was significantly better than the preoperative value [0.55 ± 0.21; P < 0.001; [Table 1].
|Table 1: Mean visual and refractive values before, and 6 months after the surgery |
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By 6 months, 66 eyes (93.0%) gained ≥1 line of CDVA, while five (7.0%) showed no change.
The mean subjective refractive astigmatism after 6 months of follow-up changed from a preoperative mean of-3.72 ± 1.51 D to a postoperative mean of -2.59 ± 1.16 D. Moreover, the mean subjective sphere changed from a preoperative mean of-2.11 ± 2.85 to a postoperative mean of -0.60 ± 2.15 D 6 months after surgery.
The mean subjective defocus improved from a preoperative mean of -5.83 ± 3.30D to a postoperative mean of -3.19 ± 2.36D.
The mean subjective SE changed from-3.97 ± 2.99 D before surgery to -1.90 ± 2.18 D after surgery [Table 1].
Changes in Keratometric and Elevation Parameters
Themean preoperative steep K (52.39 ± 4.48 D) changed to 49.53 ± 4.49 D (P<0.001) after 1 week, 49.68 ± 4.19 D (P = <0.001) after 2 months, and 49.40 ± 4.02 D (P < 0.001) after 6 months [Table 2].
|Table 2: Mean topographic values before, and 6 months after the surgery |
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The mean preoperative flat K (46.95 ± 3.74 D) had changed to 46.30 ± 13.01 D (P = 0.67) after 1 week, 45.05 ± 3.45 D (P < 0.001) after 2 months, and 44.91 ± 3.33 D (P < 0.001) after 6 months.
Simulated keratometric astigmatism
The mean preoperative simulated K astigmatism (5.41 ± 2.14 D) had changed to 4.02 ± 7.01 D (P = 0.11) after 1 week, 4.63 ± 2.09 D (P < 0.001) after 2 months, and 4.49 ± 1.82 D (P < 0.001) after 6 months.
The mean preoperative mean K (49.67 ± 3.98 D) had changed to 47.22 ± 3.91 D (P < 0.001) after 1 week, 47.37 ± 3.69 D (P < 0.001) after 2 months, and 47.16 ± 3.58 D (P < 0.001) after 6 months.
Irregularity in the 3-mm zone
The mean preoperative irregularity in the 3-mm zone (5.63 ± 1.71) changed to postoperative values of 6.03 ± 1.82 (P = 0.02), 5.57 ± 1.80 (P = 0.67), and 5.24 ± 1.82 (P = 0.006), respectively, after 1 week, 2 months, and 6 months.
Irregularity in the 5-mm zone
The mean preoperative irregularity of 5.89 ± 1.57D changed to 7.24 ± 2.44D (P < 0.001), 6.71 ± 2.30 (P < 0.001), and 6.06 ± 1.88 (P = 0.27), respectively, after 1 week, 2 months, and 6 months.
Anterior chamber depth
The mean preoperative ACD of 3.25 ± 0.33 mm changed to 3.16 ± 0.34 mm (P = 0.40), 3.17 ± 0.34 mm (P < 0.001), and 3.11 ± 0.45 mm (P = 0.001), respectively, at the 1-week, 2-month, and 6-month follow-up visits.
The changes in anterior elevation (anterior best fit sphere [BFS]) and posterior elevation (posterior BFS) at the 6-month follow-up are shown in [Table 1]. In terms of stability, during 6 months of follow-up, there were no statistically significant changes in any parameters (P = 0.006) except for irregularities (P < 0.05; [Table 2]).
Safety and Efficacy Indexes
The mean safety index, (the mean postoperative CDVA divided by the mean preoperative CDVA) was 2.04 ± 0.93, while the efficacy index (the mean postoperative UCVA/the mean preoperative CDVA) was 1.38 ± 0.69 after 6 months of follow-up.
No intraoperative complications occurred, such as corneal perforation or incomplete tunnel creation, and there were no postoperative complications, such as segment migration, in the present study.
| Discussion|| |
It has been demonstrated that Intacs SK implantation is safe and effective in the treatment of advanced keratoconus. We found that the mean postoperative UDVA and CDVA were significantly improved over the preoperative values. At the 6-month postoperative visit, the mean defocus had decreased by about 2.50 D compared to the preoperative value. The mean subjective refractive astigmatism (cylinder) had decreased by 1.134 D, corroborating the results of a study by Sansanayudh et al who reported a decrease of 1.1 D.
The mean subjective SE had decreased by 2.07 D, while Sansanayudh et al reported a greater reduction (3.02 D). The mean subjective sphere in the present study had decreased by about 1.50 D.
Our study assessed the earliest effect of ring segment implantation and evaluated the topographic and refractive outcome changes during 6 months of follow-up. In most patients, the outcomes were stable after 1 week. Similarly, Kotb and Hantera reported that the implantation of Intacs SK insertion in grade II or III keratoconus was safe and effective. The mean UDVA, spherical equivalent (SE), and average K showed significant improvement after 6 months, but there were no significant improvements in mean CDVA and manifest cylinder.
Ibrahim and Elmor reported outcomes in 114 patients, finding that CDVA, UDVA, and mean K were significantly improved after 3 years. Sánchez-Thorin and Navarro reported the results of femtosecond laser-assisted Intacs SK insertion in 18 eyes with a 9-month follow-up. They noted a significant change in manifest cylinder (3.00 ± 2.00 D) and sphere in 14 eyes (78%).
Sansanayudh et al reported that the mean UDVA had significantly improved 6 months after femtosecond laser-assisted ring segment implantation. The mean preoperative UDVA was 1.19 ± 0.57 LogMAR, compared to 0.66 ± 0.21 LogMAR postoperatively (P = 0.004), while the mean preoperative CDVA was 0.51 ± 0.20 LogMAR, compared to 0.25 ± 0.15 LogMAR postoperatively (P = 0.018). The mean spherical equivalent refractive error was -8.08 D preoperatively and-5.03 D after 6 months (P = 0.65). The mean preoperative refractive astigmatism of -5.05 D had reduced to -3.90 D postoperatively (P = 0.22), and the mean sim K value had decreased from 5.794 D to 5.007 D (P = 0.15).
Other researchers have shown that femtosecond laser-assisted implantation of the Intacs SK ring segment is effective and safe in patients with severe keratoconus, while our results showed that the procedure is effective and safe in patients with mild keratoconus, as 74.6% of the eyes in the present study had grade I or II keratoconus. In fact, more than 90% of the eyes that received a single segment implantation in the present study were of grade I or II. After 6 months of follow-up, the mean steep K and mean flat K had significantly decreased. Postoperatively, the mean simulated K astigmatism had decreased (0.9–1.4 D), although this reduction was smaller than that in similar studies. The preoperative mean K had decreased significantly (by 2.5 D) after 1 week, 2 months, and 6 months; this reduction was less than that seen in other studies by Kotb and Hantera and Ibrahim and Elmor, which reported decreases of 4.10 D and 4.00 D, respectively [Table 3]. These differences are probably related to the severity of keratoconus which was less in our patients and resulted in the implantation of one segment instead of two. Our study showed that both one-and two-segment implantation of Intacs SK was effective and significantly reduced the mean K, flat K, and steep K in all grades of keratoconus [Table 4]. Moreover, the postoperative results showed a significant reduction in spherical equivalent error, a decrease in refractive astigmatism, and an improvement in visual acuity in all patients [Table 5].
|Table 3: Visual and refractive outcomes after femtosecond laser assisted implantation of Intacs SK in keratoconic eyes |
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|Table 4: Keratometric changes after intracorneal ring segment implantation (Intacs SK) classified according to the preoperative keratoconus severity |
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|Table 5: Preoperative and 6 months postoperative refractive characteristics by single versus paired segments |
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All patients with grade I keratoconus gained one or more lines of CDVA, and none of the treated eyes lost any lines of CDVA [Table 6].
|Table 6: Percentage of cases that gained or lost lines of corrected distance visual acuity 6 months after Intacs severe keratoconus intracorneal ring segment implantation, classified according to preoperative keratoconus severity |
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We found a significant increase in mean irregularity in the 3-mm zone 1 week postoperatively; this had improved 2 months after the operation. We could not find any justification for increasing irregularity despite the improvement of visual acuity.
The mean postoperative anterior elevation had improved significantly 1 week, 2 months, and 6 months after surgery, while the mean postoperative posterior elevation had improved significantly after 1 week, but not after 2 or 6 months, indicating that the Intacs SK had a greater effect on the anterior surface of the cornea than on the posterior surface.
We found that the internal (endothelial) ACD had decreased significantly at all postoperative visits.
Use of the femtosecond laser leads to a more uniform depth of stromal tunnel and thus to a safer procedure, faster surgery, and a patient-and surgeon-friendly procedure.,,,,
There were no intraoperative or postoperative complications, but peri-segment deposits were seen in two patients. The limitations of our study were its short-term follow-up and our neglect to measure corneal aberrometric changes.
In conclusion; implantation of one or two Intacs SK segments using a femtosecond laser to create the channels is safe and effective to treat stage I–IV keratoconus, leading to significant improvement in UDVA, CDVA, and refractive error.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Krachmer JH, Feder RS, Belin MW. Keratoconus and related noninflammatory corneal thinning disorders. Surv Ophthalmol
Rabinowitz YS. Keratoconus. Surv Ophthalmol
Jhanji V, Sharma N, Vajpayee RB. Management of keratoconus: Current scenario. Br J Ophthalmol
Colin J, Cochener B, Savary G, Malet F, Holmes-Higgin D. INTACS inserts for treating keratoconus: One-year results. Ophthalmology
Alió JL, Shabayek MH, Belda JI, Correas P, Feijoo ED. Analysis of results related to good and bad outcomes of intacs implantation for keratoconus correction. J Cataract Refract Surg
Colin J, Cochener B, Savary G, Malet F. Correcting keratoconus with intracorneal rings. J Cataract Refract Surg
Levinger S, Pokroy R. Keratoconus managed with intacs: One-year results. Arch Ophthalmol
Colin J. European clinical evaluation: Use of intacs for the treatment of keratoconus. J Cataract Refract Surg
Colin J, Malet FJ. Intacs for the correction of keratoconus: Two-year follow-up. J Cataract Refract Surg
Rabinowitz YS. INTACS for keratoconus. Int Ophthalmol Clin
Ertan A, Kamburoğlu G. Intacs implantation using a femtosecond laser for management of keratoconus: Comparison of 306 cases in different stages. J Cataract Refract Surg
Rodríguez LA, Villegas AE, Porras D, Benavides MA, Molina J. Treatment of six cases of advanced ectasia after LASIK with 6-mm intacs SK. J Refract Surg
Kamburoglu GE, Altuner U. Comparison of response to Intacs SK and Intacs implantation in patients with advanced keratoconus. In: Free Paper Presented at the 12th
ESCRS Winter Refractive Surgery Meeting and Cornea Day. Barcelona; 2008.
Boxer Wachler BS, Christie JP, Chandra NS, Chou B, Korn T, Nepomuceno R, et al.
Intacs for keratoconus. Ophthalmology
Sansanayudh W, Bahar I, Kumar NL, Shehadeh-Mashour R, Ritenour R, Singal N, et al.
Intrastromal corneal ring segment SK implantation for moderate to severe keratoconus. J Cataract Refract Surg
Kymionis GD, Bouzoukis DI, Portaliou DM, Pallikaris IG. New INTACS SK implantation in patients with post-laser in situ
keratomileusis corneal ectasia. Cornea
Ertan A, Colin J. Intracorneal rings for keratoconus and keratectasia. J Cataract Refract Surg
Niknam S, Shamshiri M, Shahrzad SS, Alipour A, Rajabi MB, Rajabi MT, et al.
Treatment of moderate to severe keratoconus with 6-mm intacs SK. Int J Ophthalmol
Kanellopoulos AJ, Pe LH, Perry HD, Donnenfeld ED. Modified intracorneal ring segment implantations (INTACS) for the management of moderate to advanced keratoconus: Efficacy and complications. Cornea
Kotb AM, Hantera M. Efficacy and safety of intacs SK in moderate to severe keratoconus. Middle East Afr J Ophthalmol
A Ibrahim T, Elmor O. Intracorneal rings (INTACS SK) might be beneficial in keratoconus; A prospective nonrandomized study. Med Hypothesis Discov Innov Ophthalmol
Sánchez-Thorin JC, Navarro PI. Single-segment intacs severe keratoconus 80% stromal depth insertion with a femtosecond laser for asymmetric keratoconus: A case series. Asia Pac J Ophthalmol (Phila)
Ertan A, Bahadir M. Intrastromal ring segment insertion using a femtosecond laser to correct pellucid marginal corneal degeneration. J Cataract Refract Surg
Carrasquillo KG, Rand J, Talamo JH. Intacs for keratoconus and post-LASIK ectasia: Mechanical versus femtosecond laser-assisted channel creation. Cornea
Ratkay-Traub I, Ferincz IE, Juhasz T, Kurtz RM, Krueger RR. First clinical results with the femtosecond neodynium-glass laser in refractive surgery. J Refract Surg
Shabayek MH, Alió JL. Intrastromal corneal ring segment implantation by femtosecond laser for keratoconus correction. Ophthalmology
Hill SH, O'Brien B, Panchal L, Swartz T. Technique for intralase femtosecond laser lamellar channel creation and intacs insertion for the treatment of keratoconus and pellucid marginal degeneration. Tech Ophthalmol
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]