ORIGINAL ARTICLE  
Comparison of High Intensity Accelerated  
Corneal Cross Linking Protocols in  
Treatment of Progressive Keratoconus  
Bushra Akbar1, Imran Basit2, Amjad Akram3, Maham Zahid4  
1,2Armed Forces Institute of Ophthalmology, Rawalpindi. 3Combined Military Hospital (CMH), Kharian  
4National University of Medical Sciences (NUMS), Rawalpindi – Pakistan  
ABSTRACT  
Purpose: To compare the safety and efficacy of Accelerated Corneal Cross Linking (AXL) protocols, 9 mW/cm2  
for 10 min with 18 mW/cm2 for 5 min in terms of refractive and topographic keratometric indices in patients with  
progressive Keratoconus.  
Study Design: Quasi experimental study.  
Place and Duration of Study: Armed Forces Institute of Ophthalmology, Rawalpindi Pakistan, from Nov 2016 to  
Jun 2018.  
Material and Methods: Sixty eyes, 30 in each group, of 55 consecutive patients diagnosed with progressive  
keratoconus were enrolled through convenience sampling and were subjected to AXL with irradiance protocols of  
18 mWatt/cm2 for 5 minutes in group 1 and 9 mW/cm2 for 10 minutes in group 2. All patients underwent a  
comprehensive ophthalmic examination at baseline and postoperative follow up visits at 3, 6, 12 and 18 months.  
Primary outcome parameter was disease stability defined as increase in maximum keratometry over baseline K  
max of no more than 1 diopter at 1 year after AXL. Statistical analysis of data was performed with IBM SPSS  
software (version 20.0 SPSS). P value of < 0.05 was considered as statistically significant.  
Results: Disease stability was 96 % in each group. At the final time point of 18 months, group 2 (AXL 9 mm  
watt/cm2 for 10 min) was superior as compared to group 1 (AXL 18 mm watt/cm2 for 5 min) in terms of flattening  
of steep and sim K (p = 0.007, 0.023 respectively).  
Conclusion: The two AXL protocols are safe and appear to show comparable efficacy in disease stability. They  
can be used alternatively in the treatment of progressive keratoconus.  
Key Words: Corneal Cross Linking, Keratoconus, Ultraviolet A, Accelerated Corneal Cross Linking.  
How to Cite this Article: Akbar B, Basit I, Akram A, Zahid Z. Comparison of High Intensity Accelerated Corneal  
Cross Linking Protocols in Treatment of Progressive Keratoconus. Pak J Ophthalmol. 2020, 36 (2): 96-102.  
Doi: 10.36351/pjo.v36i2.976  
INTRODUCTION  
progressive keratoconus. AXL protocols are in  
High intensity Accelerated corneal collagen cross  
linking protocols (AXL) with optimized beam profiles  
have been new options in treatment armamentarium of  
accordance with Bunsen-roscoe law of chemical  
reciprocity that states “same photochemical effect can  
be achieved by reducing the irradiation interval,  
provided that the total energy level is kept constant by  
a corresponding increase in irradiation intensity”1.  
Correspondence to: Bushra Akbar  
Armed Forces Institute of Ophthalmology, Rawalpindi–  
The classical CXL Dresden protocol included  
debridement of the corneal epithelium in the central 7  
Pakistan.  
Email:dr.bushra.akbar@gmail.com  
Pakistan Journal of Ophthalmology, 2020, Vol. 36 (2): 96-102  
96  
Bushra Akbar, et al  
to 9 mm area and a pre-soak of 30-minute, with  
riboflavin-5-phosphate and 20% dextran. It was  
followed by UVA irradiance of 3 mW/cm2 (365nm,  
total energy 5.4j/cm2) for 30 minutes2. AXL protocols  
incorporated a fraction of time of Dresden protocol,  
with a proportionate increase in irradiation intensity in  
order to achieve total energy levels of 5.4 j/cm2  
equivalent to that proposed by Dresden classical  
protocol i.e.9 mW/cm2 for 10 minutes, 18m W/cm2 for  
5 minutes and 30m W/cm2 for 3 minutes3. The reduced  
surgical time of AXL confers the benefit of increased  
patient and surgeon comfort, minimal corneal  
dehydration and a decreased risk of postoperative  
infection owing to less exposure of denuded corneal  
epithelium4. The same photochemical effect or photo-  
activated corneal covalent intra and interlamellar  
stromal cross linking achieved by AXL and  
conventional protocols promise comparable efficacy in  
over the previous 12 months; documented on a  
minimum of 2 corneal topographies over a period of 6  
months. Any active or previous ocular infections,  
corneal opacities, dry eyes, corneal pachymetry of less  
than 400 microns at thinnest point, previous CXL  
treatment or any ocular surgery, active autoimmune  
disorders, pregnancy and lactation were excluded from  
the study.  
All patients underwent  
a
comprehensive  
ophthalmic examination at baseline and postoperative  
follow up visits at 3, 6, 12 and 18 months, which  
included UDVA (uncorrected distance visual acuity),  
CDVA (corrected distance visual acuity) (Snellen  
visual acuity converted to log MAR notation), slit  
lamp biomicroscopy, dual scheimpflug corneal  
topography (Galilie G4), pachymetry (Galilie G4),  
specular microscopy (Topcon sp-3000, USA) for  
endothelial cell density analysis and dilated fundus  
examination. Rigid gas permeable contact lenses were  
discontinued for three weeks and soft contact lens for  
at least two weeks prior to baseline evaluation.  
terms of disease stabilization and  
a
relative  
improvement in topographic keratometric indices and  
refractive profiles by augmenting the biomechanical  
strength of cornea3-5.  
AXL was performed under topical anaesthesia  
0.05% proparacaine hydrochloride (Alkaine), in both  
groups as a day care procedure. Standard preoperative  
preparation with 5% povidine iodine solution was  
done. Central 9 mm of epithelium was scraped off,  
followed by instillation of one drop of isotonic  
riboflavin (0.1% riboflavin (Vit B2), HPMC 1.1%  
(Peschke M, PESCHKE Trade GmbH) every 2  
minutes for 20 minutes. Cornea with pachymetry of  
less than 400 microns after epithelium removal and  
isotonic riboflavin instillation were treated with  
hypotonic riboflavin drops Peschke H (PESCHKE  
Trade GmbH) one drop every 5 seconds till it reached  
400 microns. Cornea was exposed to UVA light of  
366-370 microns at a distance of 55 mm from the eye  
at an irradiance of 18 mW/cm2for 5 minutes in group 1  
and 9 mWatt/cm2 for 10 minutes in group 2, delivering  
a total energy of 5.4 joules/cm2 (CCL VARIO 365,  
PESCHKE Trade GmbH, Huenenberg Switzerland) in  
both groups, with continued instillation of riboflavin  
drops every 2 minutes. A bandage contact lens  
(Interojo, Korea) was applied and removed on 7thpost-  
operative day, if epithelium had healed.  
Previous comparative clinical trials conducted  
with variable beam profiles, with different riboflavin  
solutions, in different populations have claimed safety  
and comparable efficacy of conventional protocol vs.  
AXL algorithms5-13. We aimed to directly compare the  
safety and efficacy of AXL protocols, 9 mw/cm2 for  
10 minutes with 18 mW/cm2 for 5 minutes in terms of  
refractive and topographic keratometric indices, in  
patients with progressive keratoconus.  
MATERIAL AND METHODS  
This study was conducted at Armed Forces Institute of  
Ophthalmology, Rawalpindi Pakistan, from Nov 2016  
to Jun 2018 after approval from Hospital ethical  
committee and, in accordance with tenets of  
declaration of Helsinki. Sixty eyes of 55 consecutive  
patients diagnosed with progressive keratoconus were  
enrolled in this study after obtaining an informed  
written consent. Thirty eyes, each were randomized to  
AXL with irradiance protocols of 18 mWatt/cm2 for 5  
minutes in group 1 and 9 mWatt/cm2 for 10 minutes in  
group 2. Inclusion criteria were; clear cornea, age  
between 18 to 40 years, documented evidence or  
reported progression with reduced visual acuity by  
more than 0.50 Snellen lines, an increase in the  
spherical/cylinder refraction of more than 0.50 D, an  
increase in the maximum keratometry reading of more  
than 1 D and a reduction in CCT of more than 10 µm  
Post operatively cyclopentolate 1% eye drops were  
advised 8 hourly for 3 days and moxifloxacin  
(Vigamox 0.05%, Alcon) for 2 weeks respectively.  
Topical steroids Flourometholone (FML 0.1%,  
Allergen) were added after one week, if epithelium  
had healed and continued for 4 weeks along with  
97  
Pakistan Journal of Ophthalmology, 2020, Vol. 36 (2): 96-102  
Comparison of High Intensity Accelerated Corneal Cross Linking Protocols in Treatment of Progressive Keratoconus  
Table 1: Preoperative Comparison of Parameters.  
topical lubricants hypromellose, dextran (Tear Natural  
II, Alcon).  
Accelerated CXL  
Parameters  
P
value  
0.486  
0.090  
0.781  
0.540  
0.404  
0.379 b  
0.774  
0.442 b  
0.781  
GP 1 (n = 30)  
0.75 ± 0.51  
0.37 ± 0.27  
-6.05 V 3.08  
-4.15 ± 1.69  
50.4 ± 3.72  
48.37 ± 2.96  
53.97 ± 4.29  
471.20 ± 36.91  
GP 2 (n = 30)  
0.65 ± 0.58  
0.26 ± 0.22  
-6.2 ± 2.85  
-3.81 ± 5.52  
49.6 ± 3.53  
47.8 ± 2.92  
53.63 ± 4.80  
479 ± 37.7  
Primary outcome parameter was disease stability  
defined as increase in maximum keratometry over  
baseline Kmax of no more than 1 diopter at 1 year  
after AXL. Refractive outcome UDVA, CDVA,  
spherical equivalent SE, Refractive astigmatism,  
change in simulated K and steep K, corneal  
pachymetry (central corneal thickness) were additional  
outcome measures documented at 3, 6, 12 and 18  
months post AXL test points.  
UCVA  
CDVA  
SE  
Ast  
Steep K  
Sim K  
K max  
CCT  
ECD  
2566.19 ± 428.61 2516.88 ± 343.85  
aIndependent samples T-test, bMann-Whitney U test *P<0.05.  
UCVA = Uncorrected distance Visual acuity, CDVA = corrected  
distance visual acuity, SE = Spherical equivalent, Ast = Refractive  
astigmatism, Steep K = Steep keratometry, Sim K = Simulated  
Statistical analysis of data was performed with  
IBM SPSS software (version 20.0 SPSS). p value of  
< 0.05 was considered as statistically significant.  
Normality of data was established utilizing  
Kolmogorov smirnov test. Within the groups, related  
two samples comparisons at multiple points were  
performed with one way repeated measure ANOVA  
for normally distributing data and Wilcoxon matched  
pairs test for non-normally distributing data. Between  
the group comparisons for normally distributing data  
was done with independent sample t test and Mann -  
keratometry, Kmax  
=
Maximum or Apex Keratometry,  
CCT=central corneal thickness  
12 and 18 months follow-up (p = 0.000, 0.000)  
(Tables 2, 3). The change in SE and Astigmatism did  
not differ between two groups (Table 4).  
Disease stability that was the primary outcome  
measure was 96% in each group in present study.  
Similar trend of significant flattening of Kmax, sim K,  
steep K was observed in each group (p < 0.05) against  
baseline indices. At 6 and 12 months follow up, no  
significant differences in keratometric parameters  
Kmax, sim K, and steep K were ascertained comparing  
both procedures. At the final time point of 18 months,  
group 2 (AXL 9 mWatt/cm2 for 10 minutes) was  
superior as compared to group 1 (AXL 18mWatt/cm2  
for 5 minutes) in terms of flattening of steep and sim K  
(p = 0.007, 0.023 respectively) and Kmax, that barely  
missed statistical significance (Table 4). CCT in group  
2 showed reduction of 23.16 ± 21.77 microns in group  
1 and 25.06 ± 28.18 in group 2 with no statistically  
significant difference at any follow-up between  
the groups (p = 0.855, 0.351,0.771 respectively)  
(Table 4).  
Whitney  
U
test was applied to non-normal  
distributions.  
RESULTS  
The mean age was 24.47 ± 4.90 years in AXL group 1  
and 24.81 ± 6.39 in AXL group 2, with no statistically  
significant difference. Keratometric parameters  
(simulated K, steep K, Kmax), refractive data (UDVA,  
CDVA, refractive astigmatism, spherical equivalent  
SE) and pachymetry, central corneal thickness (CCT)  
were comparable at baseline between the two AXL  
groups (Table 1). The mean postoperative log MAR  
UDVA improved at test points of 6, 12 and 18 months  
in both AXL groups, however these differences were  
not statistically significant (p = 0.361 and p = 0.138  
respectively) (Table 2 and 3). The mean postoperative  
log MAR CDVA significantly improved over mean  
preoperative value in both the groups (p = 0.020 and  
p = 0.020). However, the difference in post-operative  
log MAR UDVA and CDVA was not statistically  
significant between the AXL groups at any time point  
(p = 0.979, 0.700, 0.873, 0.125, 0.072, 0.171  
respectively) (Table 4). The refractive Astigmatism  
and spherical equivalent SE showed significant  
reduction from baseline at all postoperative test points  
of 3, 6, 12 and 18 months in both groups (p < 0.05).  
Astigmatism reached significance in group 2 only at  
Intra-group analysis showed significant reduction  
in endothelial cell count at the end of six, twelve and  
eighteen months in all groups (p < 0.05 in all groups).  
However, between the groups, the reduction in  
endothelial cells was not statistically significant at any  
time point.  
In group 2, one eye had a mild stromal haze that  
resolved with corticosteroid treatment by 6 weeks. No  
incidence of corneal endothelial de-compensation or  
any other adverse effect was recorded in any treatment  
group during follow-up. One eye (4%) in each group  
exhibited continued ectatic progression in terms of  
increase in Kmax of more than 1 dioptre.  
Pakistan Journal of Ophthalmology, 2020, Vol. 36 (2): 96-102  
98  
Bushra Akbar, et al  
Table 2: Comparison of Pre and Post-operative refractive and topographical measurements in AXL Group 1 - (18  
mWatt/cm2 for 5 min).  
Postoperative Follow-up Time Period  
Parameters  
P value  
Pre-operative  
(n = 30)  
3 Months  
(n = 30)  
6 Months  
(n = 30)  
12 Months  
(n = 30)  
18 Months  
(n = 30)  
UCVA  
CDVA  
SE  
0.75 ± 0.51  
0.37 ± 0.27  
-6.05 ±3.08  
-4.15 ± 1.69  
50.48 ± 3.72  
48.37 ± 2.96  
53.97 ± 4.29  
471.20 ± 36.91  
0.71 ± 0.47  
0.34 ± 0.20  
-5.05 ± 2.67  
-3.79 ± 1.61  
49.95 ± 3.76  
48.02 ± 3.20  
53.45 ± 4.09  
452.60 ± 43.57  
0.73 ± 0.46  
0.38 ± 0.25  
-4.12 ± 2.57  
-3.48 ± 1.11  
49.71 ± 3.67  
48.09 ± 3.18  
53.26 ± 3.74  
456.96 ± 44.38  
0.67 ± 0.45  
0.32 ± 0.27  
-4.66 ± 3.03  
-3.03 ± 1.20  
49.31 ± 3.62  
47.64 ± 3.18  
52.22 ± 3.92  
447.40 ± 43.24  
0.65 ± 0.43  
0.31 ± 0.27  
-4.60 ± 2.96  
-2.97 ± 1.18  
49.18 ± 3.59  
47.57 ± 3.20  
52.27 ± 3.94  
446.50 ± 44.25  
0.361  
0.020*  
0.000*  
0.000*  
0.000*  
0.001*  
0.000*  
0.000*  
Ast  
Steep K  
Sim K  
K max  
CCT  
One-way ANOVA repeated measures test, *P < 0.05. AXL = Accelerated CXL, UCVA = Visual acuity, CDVA = Corrected distance visual  
acuity, SE = Spherical equivalent, Ast = Refractive astigmatism, Steep K = Steep keratometry, Sim K = Simulated keratometry, Kmax =  
Maximum or Apex Keratometry, CCT=central corneal thickness  
Table 3: Comparison of Pre and Post-operative refractive and topographical measurements in AXL Group 2 - (9 mwatt/cm2  
for 10 min).  
Postoperative Follow-up Time Period  
Parameters  
P value  
Preoperative  
(n = 30)  
3 Months  
(n = 30)  
6 Months  
(n = 30)  
1 Year  
(n = 30)  
18 Months  
(n = 30)  
UCVA  
CDVA  
SE  
0.65 ± 0.58  
0.26 ± 0.22  
-6.27 ± 2.85  
-3.81 ± 2.52  
49.69 ± 3.53  
47.84 ± 2.92  
53.63 ± 4.80  
479.80 ± 37.75  
0.73 ± 0.49  
0.27 ± 0.20  
-5.68 ± 2.80  
-3.98 ± 1.87  
49.17 ± 3.44  
47.36 ± 2.94  
52.95 ± 4.37  
455.10 ± 44.72  
0.62 ± 0.53  
0.32 ± 0.25  
-4.52 ± 2.18  
-3.68 ± 1.49  
48.78 ± 3.49  
47.10 ± 3.09  
52.94 ± 4.39  
467.26 ± 45.97  
0.60 ± 0.51  
0.28 ± 0.27  
-4.96 ± 2.84  
-2.62 ± 2.32  
48.40 ± 3.47  
46.72 ± 2.95  
51.70 ± 4.38  
461.93 ± 47.99  
0.56 ± 0.45  
0.26 ± 0.25  
-4.27 ± 2.25  
-2.50 ± 1.26  
47.56 ± 3.41  
46.07 ± 3.00  
50.92 ± 4.33  
454.73 ± 47.05  
0.138  
0.022*  
0.000*  
0.000*  
0.000*  
0.000*  
0.001*  
0.000*  
Ast  
Steep K  
Sim K  
K max  
CCT  
ANOVA repeated measures test, *P < 0.05. AXL = Accelerated CXL, UCVA = Uncorrected distance Visual acuity, CDVA = Corrected  
distance visual acuity, SE = Spherical equivalent, Ast = Refractive astigmatism, Steep K = Steep keratometry, Sim K = Simulated  
keratometry, Kmax = Maximum or Apex Keratometry, CCT =central corneal thickness  
Table 4: Comparison of Post-operative changes in refractive data, keratometry and pachymetry between two study groups.  
Follow-up Time period  
Group 1  
Group 2  
Parameters  
6 Months  
(n = 30)  
12 Months  
(n = 30)  
18 Months  
(n = 30)  
6 Months  
(n = 30)  
12 Months  
(n = 30)  
18 Months  
(n = 30)  
UCVA  
CDVA  
SE  
-0.29 ± 0.27  
0.11 ± 0.15  
1.93 ± 3.29  
0.67 ± 1.02  
-0.77 ± 1.10  
-0.28 ± 1.15  
-0.70 ± 2.04  
-0.82 ± 0.29  
-0.045 ± 1.56 -0.45 ± 0.15  
-0.82 ± 0.29  
-0.31 ± 0.40  
0.06 ± 0.12  
1.74 ± 2.45  
0.12 ± 1.98  
-0.91 ± 1.68  
-0.73 ± 1.13  
-0.68 ± 1.32  
-0.05 ± 0.28  
0.22 ± 0.12  
1.30 ± 1.54  
1.18 ± 3.25  
-0.91 ± 1.68  
1.11 ± 1.30  
-1.93 ± 1.51  
-0.94 ± 0.29 0.979 0.700 0.873  
0.01 ± 0.11 0.125 0.072 0.171  
-4.93 ± 2.69 0.803 0.793 0.548  
1.31 ± 2.10 0.189 0.922 0.660  
-2.13 ± 1.77 0.694 0.694 0.023*  
-1.77 ± 1.42 0.130 0.283 0.007*  
-2.71 ± 1.43 0.967 0.723 0.058  
1.39 ± 1.04  
1.12 ± 0.99  
-0.77 ± 1.10  
-0.73 ± 1.44  
-1.74 ± 2.34  
-5.42 ± 3.46  
1.12 ± 0.99  
-1.16 ± 1.40  
-0.73 ± 1.44  
-1.70 ± 2.48  
Ast  
Steep K  
Sim K  
K max  
CCT  
-14.23 ± 35.45 -23.80 ± 21.99 -23.16 ± 21.77 -12.53 ± 36.27 -17.86 ± 26.62 -25.06 ± 28.18 0.855 0.351 0.771  
-3.66 ± 6.00 -4.16 ± 6.28 -4.16 ± 6.28 -3.52 ± 5.99 -4.01 ± 6.30 -3.44 ± 6.58 0.926 0.929 0.670  
ECD  
Independent samples T test. *P < 0.05. AXL = Accelerated CXL, UCVA = Visual acuity, CDVA = Corrected distance visual acuity, SE =  
Spherical equivalent, Ast = Refractive astigmatism, Steep K = Steep keratometry, Sim K = Simulated keratometry, Kmax = Maximum or  
Apex Keratometry, CCT =central corneal thickness, ECD = Endothelial cell count  
99  
Pakistan Journal of Ophthalmology, 2020, Vol. 36 (2): 96-102  
Comparison of High Intensity Accelerated Corneal Cross Linking Protocols in Treatment of Progressive Keratoconus  
Table 5: Previous Clinical Trials of AXL.  
Conventional  
Cross Linking  
Accelerated Cross Linking  
N Protocol/Platform  
Follow-up  
(Months)  
Study  
Study Design  
Findings  
Protocol/  
Platform  
N
Prospective  
comparative case  
series  
Comparable visual and refractive  
results, decrease in Km and  
Kmax in both groups  
Cinar et al.  
3 mW/cm2  
for 30 mins  
13  
13 9mW/cm2 for 10 mins  
6
6
20147  
Prospective  
randomized  
3 mW/cm2  
31 for 30 mins  
UV-X  
Comparable visual acuity,  
refractive, keratometric and  
biomechanical outcomes  
Hashemi  
18mW/cm2 for 5 mins  
31  
et al. 20158 comparative case  
UV-X  
series  
18 mW/cm2  
31 for 5 mins  
UV-X  
Comparable visual acuity,  
refractive, keratometric and  
biomechanical outcomes  
Hashemi  
Prospective  
3mW/cm2 for 30 mins  
UV-X  
31  
18  
et al. 20159 randomized  
Comparable visual acuity and  
refractive outcomes. More  
topographic flattening in the  
conventional group compared to  
accelerated group  
Prospective  
comparative case  
series  
3 mW/cm2  
19 for 30 mins  
UV-X  
Chow et al.  
18mW/cm2 for 5 mins  
CCL-VARIO  
19  
12  
12  
201510  
Prospective  
randomized  
interventional study  
3 mW/cm2  
36 for 30 mins  
Avedro KXL  
Conventional group and  
accelerated groups with  
irradiance of 9mW/cm2 and  
18mW/cm2 showed better visual,  
refractive and tomographic  
Shetty et al.  
36 9mW/cm2 for 10 mins  
33 18mW/cm2 for 5 mins  
201511  
Accelerated corneal CXL is  
effective in stabilizing  
Cummings  
Retrospective  
3mW/cm2  
66  
36 9mW/cm2 for 10 mins  
72 30mW/cm2 for 3 mins  
12  
12  
et al 201612 interventional study  
for 30 mins  
topographic parameters better  
after 12 months 9mW/cm2  
Yildrim et al prospective  
18mW/cm2  
74  
Comparable visual acuity,  
refractive, keratometric  
201713  
comparative study  
for 5 mins  
UCVA = Uncorrected distance Visual acuity, CDVA = Corrected distance visual acuity, SE = Spherical equivalent, Ast = Refractive  
astigmatism, Steep K = Steep keratometry, Sim K = Simulated keratometry, Kmax = Maximum or Apex Keratometry, CCT = Central  
corneal thickness  
with no other adverse effects were documented in our  
study.  
DISCUSSION  
The promising effects of AXL in halting disease  
Significant improvements in our study in UDVA,  
CDVA along with reduction in SE and Ast at 6 and 12  
months over baseline were consistent with refractive  
outcomes of prospective well designed interventional  
trials that recruited one arm of cohort to receive CXL  
irradiance protocol similar to our study6,11,12. Hashemi  
et al8,9 and Al-Nawaeiseh et al14 in contrast to our  
results reported no significant improvements in  
refractive parameters at 12 months in patient receiving  
5 minutes accelerated protocol. CXL alone without  
excimer laser is not considered a refractive procedure  
albeit, the effect on refractive parameters in different  
studies may be attributed to variable grades of  
keratoconus and associated difficult non repeatable  
subjective manifest refractions due to distorted multi  
focal optics of ectatic steep corneas12.  
progression by augmenting corneal strength and  
halving the surgical time with increased patient  
comfort have excited ophthalmologic researchers.  
Modified higher UVA irradiation intensity protocols  
with different time settings utilizing variable riboflavin  
solutions, soak time and CXL devices have been tested  
with the aim of achieving a short and equally effective  
procedure to date3-13. In this particular study, both  
AXL showed equivalent improvement in UDVA,  
CDVA and topographic indices at 3, 6, 12 and 18  
months follow-up except for flattening of keratometry  
(sim K, Steep K) that was significantly superior in  
AXL group 2 (p < 0.007, 0.023) at 18 months follow-  
up. Comparable clinical stabilization of disease (96%)  
was achieved with optimum safety in each group.  
Failure rate of 4% in terms of continued progression,  
Pakistan Journal of Ophthalmology, 2020, Vol. 36 (2): 96-102  
100  
Bushra Akbar, et al  
In present study, AXL groups demonstrated  
in disease stability, and change in refractive  
parameters and topographic indices in progressive  
Keratoconus. These two modified high intensity  
protocols may be recommended alternatively in  
treatment of progressive keratoconus, considered fit  
for epithelium off CXL.  
significant trend of flattening of keratometric indices  
Kmax, steep K, sim K within groups, with no  
superiority between the groups, except for sim K and  
steep K at 18 months follow-up. Although K max only  
just missed statistical significance at 18 months, a  
marked flattening of 2.7D was attained with 9  
mWatt/cm2 for 10 minutes regimen as compared to  
1.5D in group 1. This trend of decrease in keratometric  
values was generally in accordance with results of  
previous studies of accelerated protocols. Shetty et al11  
in a prospective interventional study on 138  
keratoconic eyes, with randomization at radiance of 3,  
9, 18 or 30 mWatt/cm2 found that cross linking,  
flattening effect was abridged in higher irradiance and  
shorter duration treatments, in conformation with our  
results. However, the disease stability with AXL in  
each group in our study with no further corneal  
steeping at a long term follow up of 18 months is a  
significant clinical finding, even if it misses statistical  
significance between the groups.  
ACKNOWLEDGEMENTS  
Mr Kashif Siddique, King Salman armed forces  
hospital, KSA Academic affairs (Research Unit) for  
helping in data analysis. Miss Paree Chera, Ex  
Optometrist, Armed forces institute of ophthalmology  
for helping in collection of data.  
Ethical Approval  
The study was approved by the Institutional review  
board/Ethical review board.  
Conflict of Interest  
The decrease in CCT is an indirect marker of  
efficacy of AXL, confirming compactness of collagen  
fibrils, apoptosis of stromal keratocytes and improved  
biomechanical stability8,9,15. Hashemi et al8,9 identified  
a statistically significant decrease in CCT at 18 months  
following AXL with 18 mWatt/cm2 for 5minutes. We  
also observed a parallel decrease in CCT for both  
groups, without significance between the protocols at  
18 months. Significant decrease in thinnest  
pachymetry was also reported for AXL 9 mWatt/cm2  
in comparison against conventional CXL in  
literature.12,16,17  
Authors declared no conflict of interest  
Authors’ Designation and Contribution  
Dr. Bushra Akbar; Registrar: Study design, analysis of  
data, manuscript drafting and critical revision of final  
draft.  
Dr. Imran Basit; Assistant Professor: Study design,  
analysis of data, manuscript drafting and critical  
revision of final draft.  
Dr. Amjad Akram; Research Advisor: Critical revision  
of manuscript, final approval of draft for publication.  
We lack the evidence of AXL induced structural  
change in anterior corneal stroma as anterior segment  
optical coherence tomography was not done in our  
study to assess the depth of demarcation line. In  
addition to this, the major limitation of this study was  
a relatively small sample size. We intend to follow our  
patients and publish our long term results to further  
validate efficacy of our procedures. We had 4% eyes  
in each group that experienced ectatic progression at  
12 and 18 months, in terms of increase in Kmax, with  
no incidence of sterile infiltrates, persistent corneal  
haze and damage or loss of endothelial cells  
succumbing to corneal endothelial decompensation,  
Dr. Maham Zahid; Research Associate: Data  
collection, analysis of data, interpretation of data,  
manuscript drafting and final approval of draft.  
REFERENCES  
1. Bunsen RW, Roscoe HE. Photochemical researches–  
Part V. On the measurement of the chemical action of  
direct and diffuse sunlight. Proc R Soc Lond. 1862; 12:  
306–12.  
http://rspl.royalsocietypublishing.org/content/12/306.  
2. Wollensak  
G,  
Spoerl  
E,  
Seiler  
T.  
Riboflavin/ultraviolet-A– induced collagen cross  
linking for the treatment of keratoconus. Am J  
Ophthalmol. 2003; 135 (5): 620–7.  
akin to previous AXL trials13,12,18,19,20  
.
https://doi.org/10.1016/S0002-9394(02)02220-1.  
3. Krueger RR, Herekar S, Spoerl E. First proposed  
efficacy study of high versus standard irradiance and  
fractionated riboflavin/ultraviolet a cross-linking with  
CONCLUSION  
AXL protocols are safe and comparable  
101  
Pakistan Journal of Ophthalmology, 2020, Vol. 36 (2): 96-102  
Comparison of High Intensity Accelerated Corneal Cross Linking Protocols in Treatment of Progressive Keratoconus  
equivalent energy exposure. Eye & Contact Lens, 2014;  
treatment of keratoconus: a comparison of outcomes  
after standard- and high-intensity protocols. Cornea,  
2016; 35 (6): 814–22.  
40 (6): 353–7. Doi: 10.1097/ICL.0000000000000095.  
4. Schumacher S, Oeftiger L, Mrochen M. Equivalence  
of biomechanical changes induced by rapid and  
standard corneal cross linking, using riboflavin and  
ultraviolet radiation. Invest. Ophthalmol. Vis. Sci.,  
2011; 52 (12): 9048-52.  
Doi: 10.1097/ICO.0000000000000823.  
13. Yıldırım Y, Olcucu O, Gunaydin ZK, Aqca A,  
Ozgurhan EB, Alagoz C, et al. Comparison of  
accelerated corneal collagen cross-linking types for  
treating keratoconus. Current eye research, 2017; 42  
(7): 971-5.  
https://doi.org/10.1080/02713683.2017.1284241.  
14. Alnawaiseh M, Rosentreter A, Böhm MR, Eveslage  
M, Eter N, Zumhagen L. Accelerated (18 mW/cm2)  
corneal collagen cross linking for progressive  
keratoconus. Cornea, 2015; 34 (11): 1427–31.  
Doi: 10.1097/ICO.0000000000000578.  
Doi:10.1167/iovs.11-7818.  
5. Raiskup-Wolf F, Hoyer A, Spoerl E, Pillunat LE.  
Collagen cross linking with riboflavin and ultraviolet-A  
light in keratoconus: long-term results. J Cataract  
Refract Surg. 2008; 34 (5): 796–801.  
https://doi.org/10.1016/j.jcrs.2007.12.039.  
6. O’Brart DPS. Corneal collagen cross-linking: a  
review. J Optom. 2014; 7 (3): 113–24.  
https://doi.org/10.1016/j.optom.2013.12.001.  
15. Woo JH, Iyer JV, Lim L, Hla MH, Mehta JS, Chan  
CM, et al. Conventional versus accelerated collagen  
cross-linking for keratoconus: a comparison of visual,  
refractive, topographic and biomechanical outcomes.  
The Open Ophthalmology Journal, 2017; 11: 262.Doi:  
[10.2174/1874364101711010262].  
7. Cınar Y, Cingü AK, Türkcü FM, Cınar T, Yüksel  
H, Ozkurt ZG, et al. Comparison of accelerated and  
conventional corneal collagen cross-linking for  
progressive keratoconus. Cutan Ocul Toxicol. 2014; 33  
(3): 218-22.  
https://doi.org/10.3109/15569527.2013.834497.  
8. Hashemi H, Fotouhi A, Miraftab M, Bahrmandy H,  
Seyedian MA, Amanzadeh K, et al. Short-term  
comparison of accelerated and standard methods of  
corneal collagen crosslinking. J Cataract Refract Surg.  
2015; 41 (3): 533-40.  
16. Akbar B, Intisar-ul-Haq R, Ishaq M, Fawad A,  
Arzoo S, Siddique K. Comparison of transepithelial  
corneal cross linking with epithelium-off crosslinking  
(epithelium-off CXL) in adult Pakistani population with  
progressive keratoconus. Taiwan J Ophthalmol, 2017; 7  
(4):185.  
https://doi.org/10.1016/j.jcrs.2014.07.030  
Doi: [10.4103/tjo.tjo_38_17].  
9. Hashemi H, Miraftab M, Seyedian MA, Hafezi F,  
Bahrmandy H, Heidarian S, et al. Long-term results  
of an accelerated corneal cross-linking protocol (18  
mW/cm2) for the treatment of progressive keratoconus.  
17. Haq I, Fawad A, Saeed M, Humayun S, Islam Q,  
Arzoo S, et al. Comparison of rapid and conventional  
corneal collagen cross linking in patients having  
keratoconus. Pakistan Armed Forces Medical Journal,  
2015; 1 (1): 105-9.  
Am  
J
Ophthalmol. 2015; 160 (6): 1164–70.  
https://doi.org/10.1016/j.ajo.2015.08.027.  
18. Koller T, Mrochen M, Seiler T. Complication and  
failure rates after corneal cross linking. J Cataract  
Refract Surg. 2009; 35 (8): 1358–62.  
10. Chow VW, Chan TC, Yu M, Wong VW, Jhanji V.  
One-year outcomes of conventional and accelerated  
collagen cross linking in progressive keratoconus. Sci  
Rep. 2015; 5: 14425. Doi: 10.1038/srep14425 (2015).  
11. Shetty R, Pahuja NK, Nuijts RM, Ajani A, Jayadev  
C, Sharma C, et al. Current protocols of corneal  
collagen cross-linking: Visual, refractive, and  
tomographic outcomes. Am J Ophthalmol. 2015; 160  
(2): 243-9. https://doi.org/10.1016/j.ajo.2015.05.019.  
12. Cummings AB, McQuaid R, Naughton S, Brennan  
E, Mrochen M. Optimizing corneal cross linking in the  
https://doi.org/10.1016/j.jcrs.2009.03.035.  
19. Cerman E, Toker E, Ozarslan Ozcan D.  
Transepithelial versus epithelium off cross linking in  
adults with progressive Keratoconus. J cataract Refract  
Surg. 2015; 41 (7): 1416-25.  
20. Lesniak SP, Hersh PS. Transepithelial corneal  
collagen cross linking for Keratoconus: six months  
results. J Cataract Refract Surg. 2014 Dec; 40 (12):  
1971-9.  
.…….  
Pakistan Journal of Ophthalmology, 2020, Vol. 36 (2): 96-102  
102