keratoconus is a progressive noninflammatory thinning disorder of the cornea leading to a decrease in visual acuity as a result of myopia and irregular astigmatism [ 1 , 2 ] . corneal collagen cross - linking ( cxl ) can effectively halt the progression of the disease , but visual acuity following cxl remains poor . in patients intolerant to rigid gas permeable contact lenses after corneal cxl , additional interventions are often necessary to improve their vision [ 1 , 2 ] . many visual rehabilitation options are available to manage keratoconus including intracorneal ring segment implantation ( icrs ) , phakic intraocular lenses ( piol ) , and photorefractive keratectomy ( prk ) and all can be combined with cxl [ 36 ] . in patients with poor best - corrected visual acuity icrs implantation the prk is used to correct mild refraction error [ 3 , 4 ] , while the piol 's are used to correct moderate to severe ametropia in patient with good best - corrected visual acuity [ 5 , 6 ] . our study group recently published the 6-month data on the safety and efficacy of cxl followed by insertion of a phakic toric implantable collamer lens ( icl ) ( visian toric v4 icl ; staar surgical , monrovia , ca ) in the posterior chamber for correction of myopia and astigmatism in patients with keratoconus . in this paper , we report the long - term safety and efficacy of sequential cxl , then icl implantation , separated by 6 months , in a larger cohort of patients with moderate to severe keratoconus with moderate to severe myopia and astigmatism , and good best - corrected visual acuity . this was a retrospective study of patients with keratoconus who underwent sequential cxl - icl procedure between december 2010 and march 2012 at the beirut eye specialist hospital ( besh ) , beirut , lebanon . this study was approved by the institutional review board at besh and complied with the declaration of helsinki . all patients signed an informed consent prior to treatment and all surgical procedures were performed by one surgeon ( e.j ) . jarade 's protocol   were included if they had a preoperative best - correct visual acuity better than 20/40 , were hard contact lens intolerant ( defined as a comfortable wearing time of less than 8 hours per day ) , had an endothelial count > 2,200  cells / mm ( noncon robo , konan medical ) , had history of progressive keratoconus in one or both eyes ( defined as an increase in maximum keratometry of 1.00 diopter ( d ) or more in 1 year and/or the need for new contact lens fitting more than once in the previous 2 years ) , and did not have any corneal surgery ( including prk and icrs ) before or after the cxl and icl implantation . patients were considered eligible for icl implantation after cxl only if the keratoconus was considered stable ( defined as subjective refractions [ 5 , 9 , 10 ] within 0.50  d of spherical equivalent at 4 and 6 months postoperatively and was most of the time equivalent to the refraction prior to cxl ) . the exclusion criteria for enrollment in this study ( those who could not undergo the cxl and phakic iol procedures consecutively ) were central corneal thickness of less than 450  m ( measured by optical pachymetry ( pentacam ; oculus optikgerate gmbh , wetzlar , germany ) ) , mean k reading > 56.00 , endothelial cell count of less than 2,000  cells / mm measured on the central part of the cornea by specular microscopy , anterior chamber depth of < 2.8  mm from endothelium to anterior capsule measured by pentacam ( oculus optikgerate gmbh , wetzlar , germany ) , corneal opacification or scars , history of keratitis ( any form ) , peripheral marginal degeneration , previous corneal and/or intraocular surgeries , and autoimmune and/or connective tissue disease . the central corneal thickness limit of 450  m would account for around 400  m of remaining stromal thickness after removal of the epithelium , which is considered as the safety thickness for the residual stroma to avoid endothelial cell damage during the cxl procedure . the criteria for diagnosing keratoconus were based on a combination of computed slit - scanning videokeratography of the anterior and posterior corneal surfaces , keratometric readings , and corneal pachymetry [ 1316 ] . keratoconus was classified , according to the amsler - krumeich criteria , into four stages based on corneal power , thickness , transparency , and astigmatism . contact lens use was discontinued for at least 3 weeks for rigid lenses and 1 week for soft lenses prior to any ophthalmic examination , investigation , and treatment . it included uncorrected distance visual acuity ( udva ) , corrected distance visual acuity ( cdva ) , manifest and cycloplegic refractions , anterior and posterior segments evaluation with dilated fundus examination , and keratometric evaluation . since the autorefractometer results of refraction are not always accurate in keratoconus and after both cxl procedures , all refractions were based on refined refraction using trial lenses , and the axis of astigmatism was chosen according to the best visual acuity obtained while rotating the astigmatism trial axis . follow - up examinations were scheduled at baseline and at 1 , 3 , 6 , and 12 months and every 6 months thereafter . the eye to be treated was anesthetized by applying proparacaine hydrochloride 0.5% drops on three occasions at 5-minute intervals . after positioning the patient under the operating microscope , an eyelid speculum was inserted and the central 9  mm corneal epithelium was removed with a blunt spatula . a mixed riboflavin 0.1%20% dextran solution was instilled every 5 minutes until the riboflavin penetrated the cornea ( i.e. , approximately 30 minutes ) . the ultraviolet lamp ( uv - x illumination system , version 1000 ; iroc ag , zurich , switzerland ) was then focused on the apex of the cornea at a distance of 5  cm for a total of 30 minutes , providing a radiant energy of 3.0  0.3  mw / cm . the required irradiance of 3.0  mw / cm was calibrated prior to each treatment using an ultraviolet a meter ( lasermate - q ; laser 2000 , wessling , germany ) . during ultraviolet a administration , the cross - linking procedure adopted in our study is in accordance with the standard dresden  protocol , which has been shown to result in absorption limited to the anterior two - thirds ( 200400  m ) of the stroma as demonstrated by stress - strain measurements , thermomechanical measurements , and swelling studies . thinnest and central corneal thickness were continuously monitored ( sonogage pachymeter ; sonogage , inc . , cleveland , oh ) to ensure that neither of the two parameters dropped below 400  m . after treatment , the eye surface was washed with balanced salt solution and two drops of gatifloxacin 0.3% were instilled , followed by placement of a bandage soft contact lens . postoperatively , patients received acetaminophen 500  mg twice daily for 3 days , one drop of gatifloxacin 0.3% six times daily for 7 days with one drop of tobramycin - dexamethasone 0.1% four times daily for 10 days , and one drop of loteprednol 0.5% five times daily , slowly tapered over 5 weeks . the bandage soft contact lens was removed on postoperative day 4 and the eye examined by slit - lamp microscopy to confirm complete corneal epithelialization . complete assessment was performed 1 and 6 months postoperatively and included udva , cdva , refraction , and anterior / posterior topography . no further progression of keratoconus was noted in any eyes throughout the 6 months of follow - up period . the appropriate icl size was determined based on the horizontal white - to - white distance measured manually with a caliper , and the anterior chamber depth was measured with the pentacam . a minor clinical adjustment of anterior chamber depth was performed by subtracting no more than 0.2  mm whenever corneal anterior bulging was advanced . regarding the inaccuracy of the autorefractometer in predicting the k - reading in many keratoconus cases and to obtain accurate icl choice using the online icl calculator software , adjustment of extreme values of k readings obtained by autorefractometer was performed by attenuating the k - reading values to reflect the magnitude of astigmatism obtained by manifest refraction and the chosen axis of astigmatism was always the axis obtained by manifest refraction . the pupil was dilated with cyclopentolate and phenylephrine drops , instilled 30 minutes prior to surgery , and the horizontal axis was marked by the surgeon with the patient upright to control for cyclotorsion . a 3.2  mm clear corneal tunnel incision was performed in the horizontal temporal meridian ( regardless of the astigmatism axis ) . the icl was inserted in the posterior chamber through the incision using the injector cartridge supplied by the manufacturer . after the icl was gently positioned in the sulcus with the axis properly aligned , the remaining viscoelastic material was completely washed out of the anterior chamber with balanced salt solution and a miotic agent was instilled . tobramycin - dexamethasone 0.1% eye drops were used four times a day for 10 days and then slowly tapered over 3 weeks . descriptive statistics were reported as mean and standard deviation for continuous variables . repeated - measures analysis with the bonferroni test for post hoc analysis and the wilcoxon signed rank test were computed . the study included 30 eyes of 19 patients , among those 13 males and 6 females . mean age was 30.44  8.14 years ( range : 20 to 45 years ) . mean follow - up was 16  5.75 months ; all patients ( 100% ) had complete follow - up from baseline up to 12 months after icl implantation ; only 10 ( 33% ) eyes of 10 patients had 24 months of follow - up . the visian toric icl was implanted in all eyes ; 11 patients underwent bilateral implantation while the remaining 8 patients had unilateral icl implantation . preoperative mean spherical power was 8.37  3.89  d ( range : 20.5 to 4  d ) and mean cylindrical power 2.95  1.40  d ( range : 1 to 5.25  d ) . according to the amsler - krumeich classification , 6 eyes had stage i , 14 eyes had stage ii , and 10 eyes had stage iii keratoconus at baseline . among the eyes that completed the 24 months of follow - up after icl implantation , 6/10 had stage i , 2/10 had stage ii , and 3/10 had stage iii keratoconus at baseline . the preoperative values were compared to values starting 6 months after cxl , because visual acuity and corneal keratometry vary significantly in the first few months after cxl . according to table 1 , both udva and cdva values at 6 months after cxl did not differ from baseline ( p = 1.000 and 0.231 , resp . ) . at 6 months after icl implantation , there was significant improvement in mean udva from 1.57 logmar to 0.17 logmar ( p < 0.001 ) and mild improvement in cdva from 0.17 logmar to 0.11 logmar ( p < 0.001 ) . both cdva and udva remained stable thereafter up to 24 months ( tables 1 and 2 ) . no eye lost 2 or more lines in cdva in the study ( figure 1 ) . at 12 months , 43% ( 13 of 30 ) of eyes gained 1 line in cdva , and in the smaller subset of eyes with 24 months follow - up 60% of eyes gained 1 line in cdva . overall , 60% ( 18 of 30 ) and 50% ( 5 of 10 ) of eyes had udva of 20/30 or better 12 months and 24 months after icl implantation , respectively . at 6 months after cxl , the small changes in se and the spherical component of refraction were not significant from baseline ( p = 0.611 and 1.000 , resp . ) , unlike the mean change of 0.21  d in cylindrical component ( p = 0.012 ) ( table 1 ) . however , the changes in se , sphere power and cylindrical power at 6 months after icl implantation were all clinically and statistically significant from baseline and their values remained relatively stable up to 12 months ( table 1 ) . however , in the smaller subset of 10 eyes with 24 months of follow - up ( table 2 ) , small hyperopic shifts of 0.25  d in se ( p = 0.012 ) and 0.20  d in spherical power ( p = 0.005 ) were noted after 6 months after icl visit . overall , 63.3% and 40% of eyes were within 1.0  d se at 12 and 24 months after icl implantation , respectively ( figure 2 ) . all keratometric values showed a gradual decrease after cxl , up to the 24 months of follow - up . according to table 1 , the decrease in mean k ( flat ) from baseline became statistically significant 6 months after icl implantation , while the decreases in mean k ( steep ) and mean k ( max ) from baseline were statistically significant starting 6 months after cxl . overall , the safety index = [ mean postoperative cdva ( logmar)/mean preoperative cdva ( logmar ) ] at 12 months and 24 months after icl implantation was 0.73  0.29 and 0.72  0.25 , respectively . the efficacy index = [ mean postoperative udva ( logmar)/mean preoperative cdva ( logmar ) ] at 12 months and 24 months after icl implantation was 1.03  0.26 and 1.04  0.26 , respectively ( figure 3 ) . all epithelial defects healed within 4 days after cxl . in this study , none of the patients had infectious keratitis , lens rotation , vaulting problem , cataract formation , pigment dispersion , or pupillary block . also , none had development of clinically significant haze at any of the follow - up periods . there was , however , a transient increase of intraocular pressure that was observed in most patients during the first week after icl implantation that was controlled with topical drops . providing optimal refractive and vision results to patients with progressive keratoconus remains challenging to the refractive surgeon . while corneal collagen cross - linking ( cxl ) can halt progressive disease , patients with high refractive error and poor vision at baseline would remain so , after cxl , even without keratoconus progression [ 10 , 18 , 19 ] . therefore , cxl is used to set the stage for other interventions to be performed . management after cxl is tailored according to the patient 's best - corrected visual acuity and refractive status . in patients with good - best corrected visual acuity and high residual refractive error after cxl , piol implantation provides adequate correction of ametropia . several types of toric piol were reported to be effective and safe in eyes with keratoconus , but only a handful of studies have evaluated their use following a cxl procedure [ 6 , 9 , 10 , 18 , 2024 ] . the visian toric icl has demonstrated good efficacy and safety profiles for the correction of high ametropia in patients without keratoconus [ 2532 ] . in our previous study , toric icl implantation 6 months after cxl was proven to be an effective and safe method of improving visual acuity and refraction in selected eyes with moderate to severe keratoconus . in this paper , we assess the long - term ( up to 24 months ) safety and efficacy of that same procedure in 30 eyes with mild - to - moderate progressive keratoconus . stability of keratoconus following cxl in preparation for icl implantation has been previously defined using stability of refraction data [ 5 , 9 , 10 ] . as such , icl implantation was performed 6 months after cxl , since most patients had a stable visual acuity and manifest refraction by 4 months . this flattening was not significant enough to alter the mean se manifest refraction at the time of icl implantation , or the outcome of the icl procedure at 12 months . in the small subset of 10 eyes with 24 months of follow - up , the small hyperopic shift in se might have resulted from the continuous flattening in k readings ; however , the change did not affect vision . the continuous flattening in k readings and its effect on se is most likely due to the effect of cxl . it is unlikely that the 3.2  mm clear corneal incision at the time of icl implantation ( surgically induced astigmatism ) would have contributed to the change in se ; the incisions were placed at the temporal site according to the surgeon 's preference , regardless of the axis of manifest astigmatism . another possible yet unlikely culprit of the change in se is the rotation of the toric visian icl with loss in the refractive corrective effect . although possible , the effect of a rotation on refraction and visual acuity would have been uncovered earlier , and all our patients were happy with the end - result . after stabilization of keratoconus with cxl and icl implantation , 60% ( 18 of 30 ) and 50% ( 5 of 10 ) of eyes had udva of 20/30 or better at 12 months and 24 months , respectively . results of our study compare favorably to other reports in terms of gain in udva and cdva [ 9 , 10 , 21 ] , as reflected by the safety and efficacy indices . in our study , the slight myopic se refraction at post - icl implantation was related to 2 factors . first , there is no way to customize the icl to exactly fit the patient 's refraction , and in most cases we had to use what was available ( undershoot the target refraction of plano ) . second , one patient had a high refractive power that exceeds the capacity of the icl ( which is limited to 18.0  d of manifest refraction at the eyeglasses plane ) . only 2 other studies have evaluated the safety and efficacy of visian toric icl following cxl [ 6 , 10 ] . both kymionis et al . and shafik shaheen et al . in a case report published encouraging results of this procedure ; at 3 months , udva improved from counting fingers to 20/40 and cdva improved from 20/100 to 20/30 . shafik shaheen et al . , in a case series of 16 eyes with early - stage ( undefined ) keratoconus , showed a favorable outcome in terms of visual acuity and se at 3 years of follow - up ; mean cdva improved from 20/35 to 20/22 , mean udva improving to 20/23 and mean se improving from 8.5  d to 0.25  d. in our previous study on mild to severe keratoconus , the 6-month results revealed that mean cdva improved from 0.15 logmar to 0.12 logmar , mean udva decreased from 1.67 logmar to 0.15 logmar , and mean se decreased to 0.89  d with no complication . izquierdo jr et al .   employed the iris - fixated artiflex phakic iol ( ophtec , usa ) in 11 eyes with progressive keratoconus . results were favorable in terms of visual acuity , sphere , and cylinder at 12 months . employed the toric artiflex / artisan phakic iol in 17 keratoconic eyes ; at 24 months , 14 eyes were within 0.50  d of the attempted se correction and 13 eyes were within 1.00  d of the attempted cylinder correction . icl implantation after cxl depends on the stability of keratoconus ( both refraction and keratometry ) since progression would lead to refractive changes and drop of visual acuity . a continuous flattening in k readings after cxl occurred in our study with no significant effect on se , udva , nor cdva at 1 year ; in the smaller subset of 10 eyes a statistically but nonclinically significant change in se was observed following cxl at the 2-year follow - up , but both udva and cdva were not affected . although we do believe that a longer time interval would possibly show a greater change in keratometry , we are still uncertain whether an equivalent amount of change in refractive error would accompany this flattening , possibly related to the altered biomechanics of cross - linked corneas . as demonstrated in our results , the change in keratometry did not significantly alter the se and more importantly did not alter the udva and cdva . the small hyperopic shift observed in our study deserves further investigation with long - term studies to assess its long - term impact on vision , but it does not warrant delaying icl implantation . the continuous flattening effect of cxl with the accompanying risk for a hyperopic shift can last more than 2 years [ 35 , 36 ] ; therefore , targeting mild undercorrection rather than delaying the icl implantation for 12 months would improve predictability and may be a solution . moreover , implanting an icl at 6 months as opposed to 12 months offers the patient the benefit of earlier functional visual recovery . in conclusion , the results of toric icl implantation 6 months after cxl at 1 year and at 2 years compare to the outcomes at 6 months in a previous study ; it is an effective and safe method of improving visual acuity and refraction in keratoconus eyes with high myopia and astigmatism and good best corrected visual acuity .
purpose . to evaluate the long - term safety and clinical outcome of phakic visian toric implantable collamer lens ( icl ) insertion after corneal collagen cross - linking ( cxl ) in progressive keratoconus 
 . methods . 
 this was a retrospective study of 30 eyes ( 19 patients ) , with progressive keratoconus , who underwent sequential cxl followed by visian toric icl implantation after 6 months . 
 results . at baseline , 
 6 eyes had stage i , 14 eyes stage ii , and 10 eyes stage iii keratoconus graded by amsler - krumeich classification . at 6 months after cxl , 
 only k ( steep ) and k ( max ) decreased significantly from baseline , with no change in visual acuity or refraction . 
 flattening in keratometric readings was stable thereafter . 
 there was significant improvement in mean uncorrected distance visual acuity ( 1.57    0.56 to 0.17    0.06  logmar , p < 0.001 ) and mean corrected distance visual acuity ( 0.17    0.08 to 0.11    0.05  logmar , p < 0.001 ) at 12 months after icl implantation that was maintained at the 2-year follow - up . 
 mean cylinder power and mean spherical equivalent ( se ) also decreased significantly after icl implantation . 
 a small hyperopic shift in se ( + 0.25  d ) was observed at 2 years that did not alter visual outcomes . 
 conclusions . 
 visian toric icl implantation following cxl is an effective option for improving visual acuity in patients with keratoconus up to 2 years .