DR. Shreyas Ramamurthy, R14399, Dr. Umesh Sharma, Dr. Gitansha Sachdev
Abstract:
AIM:To compare the outcomes of Customised versus conventional cross linking in the management of Progressive Keratoconus.
METHODS: Prospective interventional study of consecutive patients with documented progression of Keratoconus were included. An accelerated 9mw/cm2 for 10 mins protocol was used in the conventional group(Group A). In the customized group (Group B), 3 concentric zones received 15, 10 & 5.4J/cm2 of energy centered on the highest point on the posterior float.
RESULTS:60 eyes (30 in each group) were included in the study. At 6 months follow up a mean maximal flattening of 2.9D was achieved in Group B as compared to 1.1D in Group A (p=0.02). The I-S index, which was the ratio of inferior to superior flattening, was also better in Group B (p = 0.032). Significant improvement in BDVA was achieved in Group B(p=0.03).Depth of demarcation line was 182u in Group A & 268u in Group B(p=0.021).
CONCLUSION:Customised cross linking provided superior visual & topographic outcomes.
Introduction
Roughly two decades ago, corneal collagen crosslinking (CXL) was first proposed as a treatment modality to stabilize the ectatic cornea.1 Apart from disease stabilization, an increase in the corneal biomechanical rigidity was associated with keratometric flattening in a high proportion of eyes.2 Recent understanding with finite element analysis model demonstrates greater reduction in keratometry and corneal aberrations following cone localized smaller diameter treatments in comparison to the conventional broad beam profile in keratoconic eyes.3 Clinical application of this principle entails ultraviolet irradiation in customized patterns localized on specific corneal zones, using the Mosaic delivery system (KXL II, AvedroInc, Waltham, MA, USA) or customized crosslinking.
We compared the outcomes following customized CXL versus conventional treatment in eyes with progressive keratoconus in an Indian population.
PATIENTS AND METHODS
Study population and design
This prospective interventional study was conducted at The Eye Foundation, a tertiary eye care hospital in South India. Written informed consent was obtained from all participants in accordance with the tenets of Declaration of Helsinki and approval was obtained from the Ethics Committee of The Eye Foundation, Coimbatore – Registration Number: ECR/934/Inst/TN/2017).
The study included patients with documented progression of keratoconus (increase in maximum keratometry by1 dioptre (or) decrease in thinnest pachymetry by greater than 20 microns).Soft and rigid gas permeable contact lens use was discontinued one to two weeks prior to screening respectively.
Eyes with prior ocular surgery, concurrent ocular inflammation, endothelial cell count less than 2,500 cells/mm2, thinnest pachmetry lower than 400 microns and conditions precluding steady fixation such as squint and nystagmus were excluded from the study. Other exclusion criteria included known sensitivity or allergy to riboflavin or ultraviolet-A irradiation.
Preoperative and postoperative assessments
All eyes underwent a detailed slit-lamp bio-microscopic and dilated fundus evaluation. Following parameters were measured at preoperative and at 1,3 and 6 and 12 months’ postoperative visits: CDVA in logarithm of the minimal angle of resolution (logMAR), log MAR uncorrected distance visual acuity (UDVA), mean refractive spherical equivalent, keratometry (ScheimpflungPentacam HR, Oculus Optikgerate), endothelial cell density (Topcon SP-1P specular microscope). Stromal demarcation line was measured at first postoperative month using anterior segment optical coherence tomography (Optovue, Heidelberg engineering, Fremont, USA).
Safety and efficacy Endpoints
The primary outcome parameter include improvement in the anterior corneal asymmetry (inferior-superior asymmetry). The secondary outcome parameters included flattening of Max keratometry & Mean keratometry, improvement in best corrected visual acuity & depth of demarcation line.
Safety endpoints included were endothelial cell count and extent of haze formation.
Surgical procedure
A written informed consent was obtained from all patients, after explaining the risks and benefits of the procedure. Topical anesthesia (proparacine hydrochloride 0.5%, Aurolab, India) was applied prior to the procedure to improve patient comfort. An epithelium off approach was used and the epithelium was debrided mechanically using a 15 number blade after the central cornea was soaked for 1 minute in a well using propracaine eye drops. Two drops of riboflavin (Vibex Rapid 0.1% riboflavin with HPMC) was instilled every 2 minutes for 10 minutes. For the conventional approach ultraviolet-A irradiation was delivered in an accelerated protocol of 9mw/cm2 for 10 minutes delivering a total fluence of 5.4J/cm2 in the central 9 mm zone. In the customized CXL group ultraviolet-A irradiation of 365nm was delivered using the Mosaic system (Avedro Inc.) in 3 concentric zones (3,5 and 7mm diameter) receiving 15, 10 and 5.4 J/cm2 of energy respectively, centered on the highest point of posterior float elevation.
Postoperative treatment regimen included steroids (L-Pred, loteprednol 0.5%, Allergan) in tapering doses, antibiotic drops (Vigamox, Moxifloxacin ophthalmic solution 0.5%, Alcon, Novartis AG) and lubricant eye drops (Systane Ultra, Polyethylene Glycol 0.4% and propylene Glycol 0.3%, Alcon, Novartis AG).
Statistical analysis
IBM SPSS version 22 was used for statistical analysis. Snellen best-corrected visual acuity measurements were converted to logarithm of the minimum angle of resolution (logMAR) equivalents for the purpose of data analysis. Data was checked for normal distribution within each category of study group by using visual inspection of histograms and normality Q-Q plots. Shapiro- Wilk test was also conducted to assess normal distribution, wherein a test p value of >0.05 was considered as normal distribution. Categorical outcomes were compared between study groups using paired t-test.Association between quantitative explanatory and outcome variables was assessed by calculating person correlation coefficient and the data was represented in a scatter diagram. P value < 0.05 was considered statistically significant.
RESULTS
60 eyes of 42 were included with 30 eyes in each group. The baseline characteristics including Age, pre operative spherical equivalent, pre operative Maximum keratometry, Mean Keratometry, thinnest pachymetry and best corrected visual acuity (BCVA) were similar in both groups as shown in Table 1.
TABLE 1: BASELINE DEMOGRAPHICS
| CXL: Mean (SD) | Customized CXL : Mean (SD) | P Value | |
| Age (years) | 21.9(3.82) | 23.86(5.47) | 0.23 |
| Spherical Equivalent (D) | -2.51(1.92) | -2.85(2.30) | 0.66 |
| BCVA (Log Mar) | 0.10(0.13) | 0.12(0.12) | 0.85 |
| K-mean (D) | 46.39(2.49) | 47.36(2.43) | 0.30 |
| K-max (D) | 51.73(3.99) | 52.25(3.73) | 0.35 |
| Pachymetry Thinnest
(microns) |
468.08(30.77) | 453.36(23.96) | 0.19 |
The customized cross linking had a statistically significant improvement in inferior superior asymmetry , mean keratometry, maximum keratometry (Table 2). Improvement was noted in BCVA as well although it did not achieve statistical significiance.
| CUSTOMISED CXL | PRE-OP | POST OP | P VALUE |
| I-S Asymmetry | 5.41(3.08) | 2.18(3.25) | 0.0014 |
| K-mean | 47.322(2.46) | 45.21(2.52) | <0.00001 |
| K-max | 53.25(3.73) | 50.92(3.39) | <0.0001 |
| BCVA | 0.12(0.12) | 0.08(0.07) | 0.06 |
TABLE 2: CUSTOMISED CXL – PRE & POST OP COMPARISON
In the standard cross linking improvement there was no improvement in any of the above parameters as denoted in Table 3.
| STANDARD CXL | PRE-OP | POST OP | P VALUE |
| I-S Asymmetry | 3.75(2.94) | 3.66(3.62) | 0.78 |
| K-mean | 46.39(2.49) | 46.12(2.78) | 0.755 |
| K-Max | 51.72(3.98) | 51.12(4.26) | 0.3 |
| BCVA | 0.1(0.13) | 0.083(0.08) | 0.38 |
TABLE 3: STANDARD CXL – PRE & POST OP COMPARISON
An inter group comparison was also done which show statistical difference between the two groups in the extent of improvement in I-S Asymmetry, mean flattening of K max and K mean. (Table 4).
TABLE 4: INTER GROUP COMPARISON – STANDARD CXL VS CUSTOMISED CXL
| STANDARD CXL | CUSTOM CXL | P VALUE | |
| ∆ I-S | 0.09(1.56) | 3.56(0.42) | 0.005 |
| ∆ K-MAX | 0.21(0.9) | 1.95(0.34) | 0.0001 |
| ∆ K-MEAN | 0.03(0.45) | 1.02(0.22) | <0.001 |
On anterior segment OCT, the demarcation line in the customized cross linking group was seen in varying levels with deepest line in the area of maximum energy delivery and becoming progressively shallower moving out to the periphery. The deepest demarcation line was measured and the mean depth was 268u which was significantly deeper than mean depth of demarcation line in the standard cross linking group which was 182u (p=0.021).
The safety parameters included endothelial cell count & the extent of haze formation which was comparable between both groups.
| Baseline
(cells/cm2) |
6 months post op
(cells/cm2) |
P value | |
| CXL | 2459 | 2398 | 0.46 |
| Custom CXL | 2562 | 2439 | 0.39 |
Discussion:
Over the last decade collagen cross linking in Keratoconus has seen rapid advancements which have tried to improve efficacy and safety of the procedure. By using Bunsen Roscoe law of reciprocity, Accelerated cross linking has become the mainstay in various forms. Although there is no accepted single format for cross linking, each method has been proven efficacious in arresting Keratoconus.
By using accelerated cross linking and the advent of the Mosaic Avedro cross linking system, which has a built in eye tracker, has paved the way for customized cross linking. The need of an active eye tracker is an integral part as it actively controls the location of the energy delivery in relation to the cone.
The concept of customized cross linking has come into vogue based on Brilliouin microscopy studies which have shown the corneal tissue outside the location of cone in keratoconic corneas behave similarly to that of normal corneas. Additionally computational models have also shown that selective stiffening & flattening of the cone can improve visual function.
Customised cross linking can be delivered in various customizable patterns, from arcuate patterns, sector patterns or concentric circles. There is yet no consensus on which pattern works best. A study comparing different beam profiles for customized cross linking showed that the concentric circle based on tangential map gave best results. However the limitation of this study was that they did not compare results based on centration of treatment on posterior float9.
In our study we based the treatment by identifying cone location on the posterior float. The reason is the posterior float is unaffected by variations in epithelial thickness which can affect treatment patterns based on curvature maps or pachymetry maps. A study by Seiler et al also showed good efficacy by using customized patterns based on posterior elevation maps6.
Additionally in our study we standardized the size of circles and only altered the location of treatment based on cones. These gave standardized and superior outcomes than in previous published literature4-7.
An important area of concern was that we are delivering maximum energy in the area of cone which is also the thinnest part of the cornea. So concerns of safety in terms of endothelial count and haze formation were addressed in our study and were found to be comparable to that of standard cross linking.
A confocal microscopy study has also shown that the corneal nerve regeneration was better and extent of keratocyte apoptosis was lesser in the customized cross linking as compared to standard cross linking8.
CONCLUSION:
Customised cross linking using standardized size of concentric circles based on posterior float provided anterior corneal regularization & gave superior refractive &keratometric outcomes with excellent safety profile. Future studies are required to look at combination of customized cross linking with topography guided ablation to further augment topographic and refractive outcomes.
References:
- Spoerl E, Huhle M, Seiler T. Induction of cross-links in corneal tissue. Exp Eye Res 1998; 66:97-103.
- Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet A- induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol 2003; 135: 620-627.
- Roy AS, Dupps WJ. Patient specific computational modelling of keratoconus progression and differential response to collagen cross-linking. Cornea 2011 (52): 9174-9187
- Kanellopoulos AJ, Dupps WJ, Seven I, Asimellis G. Torictopographically customized transepithelial, pulsed, veryhigh‑fluence, higher energy and higher riboflavin concentration collagen cross‑linking in keratoconus. Case Rep Ophthalmol2014;5:172‑80.
- Nordström M, Schiller M, Fredriksson A, Behndig A. Refractiveimprovements and safety with topography‑guided cornealcrosslinking for keratoconus: 1‑year results. Br J Ophthalmol2017;101:920‑5.
- Seiler TG, Fischinger I, Koller T, Zapp D, Frueh BE, Seiler T,et al. Customized corneal cross‑linking: One‑year results. Am JOphthalmol2016;166:14‑21.
- Mazzotta C, Moramarco A, Traversi C, Baiocchi S, IovienoA,Fontana L, et al. Accelerated corneal collagen cross‑linking usingtopography‑guided UV‑A energy emission: Preliminary clinicaland morphological outcomes. J Ophthalmol2016;2016:2031031.
- Cassagne M, Pierné K, Galiacy SD, Asfaux‑Marfaing MP, Fournié P,Malecaze F, et al. Customized topography‑guided corneal collagencross‑linking for keratoconus. J Refract Surg 2017;33:290‑7.
- Customised cross linking using different UVA beam profiles. Shetty R, Pahuja N, Roshan T et al. J Refract Surg. 2017 Oct 1;33(10):676-682.
EXAMPLES OF PRE & POST OP TOPOGRAPHY OF EYES UNDERGOING CUSTOMISED CROSS LINKING: SHOWING ANTERIOR CURVATURE REGULARISATION
PRE OP POST OP
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