Advances in Ophthalmology Practice and Research 3 (2023) 55–62

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Advances in Ophthalmology Practice and Research

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Review

Paediatric cornea crosslinking current strategies: A review

Pawan Prasher a, Ashok Sharma b, *, Rajan Sharma b, Vipan K. Vig c, Verinder S. Nirankari d
a
Department of Ophthalmology, Sri Guru Ram Das Institute of Medical Sciences and Research, Amritsar, Punjab, India
b
Cornea Centre, SCO 2463 - 2464, Sector 22 C, 160022, Chandigarh, India
c
Amritsar Eye Hospital, GNDU Shopping Complex, Amritsar, Punjab, India
d
Department of Ophthalmology, University of Maryland, USA

A R T I C L E I N F O A B S T R A C T

Keywords: Background: In the general population, 1 in 2000 people has keratoconus. Indians and other people from Southeast
Keratoconus Asia have a higher incidence of keratoconus. Children with keratoconus typically present earlier in life and with a
Corneal collagen cross-linking more severe disease. Rubbing the eyes has been identified as a risk factor. Children have a higher incidence and a
Corneal transplant
faster rate of keratoconus progression. Visual rehabilitation in children with keratoconus is challenging. They
Pediatric keratoconus
have a low compliance with contact lens use. Many of these children require penetrating keratoplasty at an early
age. Therefore, stopping the progression of keratoconus in children is of paramount importance.
Main text: Compared to treatment, keratoconus progression prophylaxis is not only preferable, but also easier.
Corneal collagen cross-linking has been shown to be safe and effective in stopping its progression in children. The
Dresden protocol, which involves central corneal deepithelization (7–9 mm), saturation of the stroma with
riboflavin (0.25%), and 30 min UV-A exposure, has proven to be the most successful. Two significant disad-
vantages of the typical Dresden regimen are the prolonged operating time and the significant post-operative pain.
Accelerated-CXL (9 mW/cm2 x 10 min) has been studied to reduce operative time and has been shown to be
equally effective in some studies. Compared to accelerated CXL or traditional CXL, epi-off procedures, trans-
epithelial treatment without the need for de-epithelialization and without postoperative discomfort, have been
shown to be safer but less effective. Corneal crosslinking should only be performed after treating children with
active vernal keratoconjunctivitis. Corneal opacity, chronic corneal edema, sterile infiltrates, and microbial
keratitis have been reported after cross-linking of corneal collagen.
Conclusions: The "Dresden protocol", also known as the conventional corneal cross-linking approach, should be
used to halt the progression of keratoconus in young patients. However, if the procedure needs to be completed
more rapidly, accelerated corneal crosslinking may be considered. Transepithelial corneal cross-linking has been
proven to be less effective at stabilizing keratoconus, although being more safer.

1. Introduction keratoplasty was needed for 11%–27% of kids with advanced keratoconus
who were not candidates for optical correction.7,8 Despite extensive
The term "keratoconus" refers to a gradual non-inflammatory thinning research on corneal cross-linking in adults, its use in the treatment of pe-
and ectasia of the cornea. Myopia, astigmatism, and higher-order aberra- diatric keratoconus is still under investigation. These concern the effec-
tions are traits of keratoconus. As the condition worsens, an irregular tiveness, the necessity of follow-up, repeat therapies, the management of
astigmatism develops, which can seriously impair vision.1–3 Typically, it is co-occurring allergy disorders, and the management of behavioral issues
thought to be an adolescent-only illness that worsens by the third or fourth such eye rubbing. The pediatric population is particularly sensitive in
decade of life. Historically, the early stages of keratoconus were commonly terms of psychological factors, where the illness and the surgical procedure
treated with spectacles and contact lenses, and the later stages with a have a major impact on attendance at school and learning, emphasising the
corneal transplant.4–6 Corneal cross-linking, which delays the advance- significance of special considerations in this demographic.
ment of illness, has grown in prominence in recent years as a way to
obviate the necessity for penetrating keratoplasty. In the past, penetrating

* Corresponding author. Cornea Centre, 2463-2464, Sector 22c, Chandigarh, 160022, India.
E-mail address: [email protected] (A. Sharma).

https://doi.org/10.1016/j.aopr.2022.11.002
Received 8 July 2022; Received in revised form 13 November 2022; Accepted 16 November 2022
Available online 25 November 2022
2667-3762/© 2022 Published by Elsevier Inc. on behalf of Zhejiang University Press. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).
P. Prasher et al. Advances in Ophthalmology Practice and Research 3 (2023) 55–62

2. Main text strengthen restorative materials.40 The three main types of corneal
cross-linking responses are as follows: 1) physiological cross-linking
2.1. Epidemiology mediated by lysyl oxidase, which stabilizes collagen fibril structure and
may help reduce the risk of ectasia with age; 2) cross-linking mediated by
Keratoconus is more common than previously thought, with inci- advanced corneal glycation endproduct in diabetics thought to be
dence rates ranging from 0.9% to 3.3% in various populations world- responsible for protection against the development of keratoconus; and
wide. Recent improvements in early detection could contribute to this 3) riboflavin-mediated photooxidative crosslinking used as a treatment
increasing occurrence. One in 2000 people globally are thought to have option for various types of corneal ectasia.41
keratoconus.9–17 The prevalence of keratoconus seems to be higher in Corneal cross-linking was first described in 2003 as a new therapeutic
hot, arid nations like India and the Middle East than in colder nations like option for patients with progressive keratoconus.42 This technique uti-
the Netherlands and the UK.9–11 lizes a photochemical reaction induced by riboflavin in the corneal
The precise pathophysiology of keratoconus is unknown. However, it stroma upon exposure to ultraviolet light. Corneal crosslinking
is thought that various ethnic, genetic, environmental, and regional strengthens the corneal stroma by forming chemical bonds between
factors may have an impact on how it develops in certain demographic collagen fibrils.39,43 Corneal crosslinking has been extensively evaluated
groups. There have been numerous reports of ocular and systemic cor- in adult keratoconus and its efficacy and safety in adults has been
relations in juvenile patients, including allergic keratoconjunctivitis, demonstrated. However, the procedure in children is still being evalu-
vernal keratoconjunctivitis, atopy, eye rubbing, and atopic ated, and evidence of its safety and effectiveness has been accumulating
dermatitis.18–21 Contrary to the widespread perception that keratoconus in recent years.
is a non-inflammatory illness, recent research have revealed that in-
flammatory mediators may play a role in the development of the 2.3. Corneal crosslinking in children
condition.22,23
According to reports, keratoconus prevalence in many nations is Rapid decision-making is advisable in adolescents with keratoconus
significantly influenced by ethnicity. Patients with South Asian ancestry because the disease is advanced at the time of presentation and it pro-
in the UK showed a higher frequency (4.4 to 7.5-fold) than Cauca- gresses more quickly. According to Leoni-Mesplie et al.,44 a greater
sians.24,25 Genetic factors may play a role in the aetiology of keratoconus proportion (27.8%) of patients younger than 15 years had stage IV
due to its association with systemic disorders such Down syndrome, Amsler-Krumeich disease at presentation compared to those 27 years and
Marfan syndrome, retinitis pigmentosa, Leber congenital amourosis, older (7.8%). According to Soeters et al.,30 the keratoconus increased by
mitral valve prolapse, and collagen vascular diseases.26,27 Further evi- 2.6 D in 7 weeks and by about 5.0 D in one year. Chatzis and Hafezi36
dence for the significance of genetic variables comes from the observed reported progression in 88% of patients after one year of follow-up.
higher occurrence in patients of consanguineous descent and higher Therefore, it is important that children are treated at the time of diag-
probability (15%–67%) of developing ectasia in first-degree relatives.28 nosis without waiting for signs of progression.45
Prevalence data for pediatric keratoconus (onset before age 18) have
not been widely reported in the literature. The median age of keratoco- 2.4. Protocols for corneal crosslinking in children
nus in the pediatric population is 15 years,29,30 with the youngest re-
ported case being a 4-year-old girl with Down syndrome.31 Keratoconus Corneal cross-linking procedures in children are not significantly
behaves differently in children than in adults, and children are more different from those in adults. However, with children, there may be
likely to present with advanced disease. Leoni-Mesplie et al.32 reported certain additional considerations that need to be made. In this vulnerable
that 27.8% of children had stage 4 disease compared to 7.8% of adults. demographic it may be prudent to stick with the traditional Dresdon
These children are more likely to be males with a history of associated protocol, which has been shown to have the maximum effectiveness, but
allergic diseases and a habit of rubbing their eyes. It has been suggested various protocols aimed at reducing the treatment duration, shortening
that eye rubbing, in addition to its mechanical effect on the cornea, is the recovery period and reducing discomfort are also being explored.46
associated with an increase in ocular surface inflammation, as evidenced
by higher levels of MMP-13, IL-6, TNF-alpha in the tear film, which may 2.5. Standard dresden protocol
play a role plays a key role in the pathogenesis of keratoconus.33 Younger
age may be associated with rapid progression and the eventual need for The standard Dresden protocol is the most commonly used technique
corneal transplant surgery.34,35 Chatzis and Hafezi reported progression to date for corneal cross-linking in adults and children. It was first re-
of keratoconus in 88% of children after a follow-up of one year.36 ported by Wollensak et al.42,47 To facilitate riboflavin penetration into
Compared to adults, children with keratoconus face unique challenges the stroma, the central 7–9 mm of the corneal epithelium is removed.
due to additional factors such as underdiagnosis, poor compliance, need Riboflavin drops are administered every 2 min for a total of 30 min after
for treatment of associated vernal keratoconjunctivitis, schooling, epithelial excision. This is followed by another 30-min exposure to
behavioral problems, and amblyopia. ultraviolet-A light (370.5 nm wavelength, 5.4 J/cm2 irradiance) for
Traditional therapies like eyeglasses, contact lenses, corneal trans- another 30 min along with instillation of the riboflavin solution every 5
plantation, and intracorneal ring segments have been used for treating min. Finally, a bandage contact lens is fitted. The patient is prescribed
keratoconus in both adults and children for a number of years. But there oral analgesics and antibiotic eye drops. Ucakhan et al.48 comparred 88
is a highrisk of rejection due to their hperactive immune system. In- pediatric eyes (54 patients) and 104 adult eyes (68 patients), and found
fections following keratoplasty, glaucoma, and poor compliance are that traditional crosslinking was equally effective in slowing the pro-
additional risk factors.37 The development of minimally invasive corneal gression of keratoconus in both groups. The treatment produced com-
cross-linking has changed the way keratoconus is treated in recent years. parable visual, refractive, aberrometry, and tomographic results at 3
To arrest the progression of ectasia and avois corneal transplant surgery, years follow-up. Numerous long-term studies have documented the
corneal cross-linking is used.38,39 effectiveness of the Dresdon protocol in stopping the progression of
keratoconus in children.36,49–54
2.2. Crosslinking Godefrooiz et al.49 reported results of standard crosslinking in 54 eyes
of 36 pediatric patients. They found an improvement in maximal kera-
Crosslinking is the process by which one polymer chain is joined to tometry, the best corrected visual acuity at any follow-up visit. Despite
another by bonds, which can be covalent or ionic, resulting in a change in crosslinking, however, 12 eyes (22%) showed a progression of 1.0 D or
physical properties.39 Crosslinking is commonly used in dentistry to more up to the last follow-up.

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In the largest study to date by Padmanabhan et al.,50 194 eyes of 153 2.7. Transepithelial crosslinking
children aged 8–18 years with documented progressive keratoconus
were followed for up to 6.7 years after corneal crosslinking (142 with Epithelial debridement is a critical part of the traditional technique to
standard and 52 with hypoosmolar riboflavin). The authors observed a allow the riboflavin solution to penetrate into the stroma. This maneuver
significant improvement in mean best-corrected visual acuity, a reduc- has been reported to be associated with great pain, discomfort, and risk of
tion in topographical astigmatism, and a mean flattening of maximal infection.4 Transepithelial, or epithelial-on-crosslinking, is a newly
keratometry. However, after 4 years of follow-up, there were features in developed modification to improve the safety profile and reduce
some eyes that indicated that the cross-linking effect had reversed. post-operative discomfort. It does not require epithelial debridement. A
Zotta et al.51 reported stabilization of keratoconus using the standard number of delivery techniques have been explored to promote the
crosslinking Dresden protocol in 20 eyes of 10 patients during a mean diffusion of riboflavin across the intact epithelium. These include
follow-up of 7.6 years. They reported that stabilization of keratoconus chemical enhancers, epithelial disruption devices, intrastromal channels,
was evident from topographic indices and improvement in mean cor- microneedling, iontophoresis, ultrasound, and vacuum.39,46 In pediat-
rected distance visual acuity during follow-up. rics, where more patients are prone to infection, haze, surgical pain, and
In their prospective analysis, Uakhan et al.52 recruited 40 eyes from transient visual impairment, epithelium-on-crosslinking appears even
40 consecutive patients with progressive keratoconus aged 10–18 years. more tempting.
During the four-year follow-up, they documented improvements in Henriquez et al.60 reported a comparison of the results of epi-on
topographic indices, reductions in maximal keratometry, and improve- crosslinking involving 36 eyes with a 30-min impregnation (0.25%
ments in both uncorrected and best-corrected television acuity. There riboflavin, 1.0% phosphate hydroxypropyl methylcellulose and 0.007%
was no progression or complication that compromised vision. benzalkonium chloride) and one 5 min irradiation (18 mW/cm), with
In a prospective study by Mazotta et al.53 62 eyes of 47 keratoconus epi-off crosslinking involving 25 eyes, using 30 min impregnation
patients underwent epithelium-off-CXL. It was found that the majority of (riboflavin 0.1% solution plus 20% dextran 500) and 30 min irradiation
patients had improved uncorrected and corrected teleacuity and kera- (3rd mW/cm2). After one year of follow-up, they found no significant
toconus stability after 10 years of follow-up. Final follow-up revealed an difference between the two groups in terms of changes in pachymetry
overall progression rate of 24%. Two of the subjects required a corneal and posterior height scores. The progression in the epi-on and epi-off
transplant due to progressive disease. groups was 5.6% and 12%, respectively.
In their comparative study of epi-on versus epi-off (18 patients in each
2.6. Accelerated CXL protocols group), Erlasan et al.61 reported that all keratometry readings in the
epi-off group improved but remained unchanged or deteriorated in
One focus was on reducing treatment time, as the traditional epi-on group during the 24-month follow-up. While there were no
method requires patient cooperation over a significant period of time, complications in the epi-on group, slight corneal opacities occurred in the
which can be quite challenging in children. The possibility that epi-off group 5(28%). Keratoconus stabilized or improved in 94.4% of
accelerated cross-linking has the potential to be as effective in children patients in the epi-off group compared to 66.6% in the epi-on group. Nath
as it is in adults needs to be evaluated. The concept of an accelerated et al.62 reviewed twelve studies (966 eyes) and found statistically sig-
protocol originates from the Bunsen-Roscoe rule of reciprocity, which nificant difference between transepithelial and epithelium-off cross--
stipulates that a combination of higher intensity and shorter exposure linking groups in K max change at 12 months (MD, 0.75; 95% CI,
time should theoretically result in a total dosage to tissue that is 0.23–1.28; P ¼ 0.004; primary outcome) and at longest follow-up (MD,
equivalent to that applied with standard treatment. In recent years, 1.20; 95% CI, 0.62–1.77; P < 0.001; secondary outcome) after treatment.
numerous surgeons have investigated accelerated cross-linking for the The effectiveness of transepithelial cross-linking is lower compared to the
pediatric population using a variety of therapies, including UVA irra- epithelium-off method, although it is significantly safer.
diation at 30 mW/cm2 for 3 min, 10 mW/cm2 for 9 min, or 9 mW/cm2
for 10 min.55–59 2.8. Iontophoretic crosslinking protocols
Nicula et al.55 compared the results of accelerated CXL performed on
27 eyes (A-CXL group) with the conventional CXL Epi-Off procedure The process of iontophoresis uses a small electrical current to help
performed on 37 eyes (S-CXL group) over a follow-up period of 4 years. chemicals penetrate tissue. Iontophoresis increases the penetration of
They noted an improvement in visual acuity and a statistically significant riboflavin, a negatively charged, water-soluble molecule with a molec-
decrease in keratometry measurements in all patients; however, there ular weight of 376.40 g/mol.63 In a study evaluating the effects of
was no difference in improvements between the two groups. They iontophoretic cross-linking in 20 eyes (15 patients) and using the stan-
concluded that both traditional and accelerated procedures are effective dard epi-off cross-linking in 20 patients (13 eyes), Buzonetti et al.64 re-
and viable treatments for pediatric patients with progressive keratoconus ported that iontophoresis CXL halted progression in only 50% of the eyes,
with comparable outcomes. but epi-off-crosslinking in 75% of the eyes.
Eissa et al.58 recruited 68 eyes (34 patients), randomly assigned them Thirteen children (13 eyes) with progressive keratoconus treated with
to groups A and B. Group A had standard cross-linking while Group B corneal iontophoretic transepithelial crosslinking were followed up for
received rapid cross-linking. They did not discover any statistically sig- 18 months by Magli et al.65 They noted a stabilization of keratometry
nificant difference between the two groups in terms of simulated kera- measurements as well as a stabilization of uncorrected and best-corrected
tometry, corneal densitometry, endothelial density or wavefront visual acuity. They concluded that this technique was successful in
aberrations during three years follow-up. There was no progression over halting the progression of keratoconus over the course of the study.
the 36-month follow-up period. Table 1 summarizes the results of numerous studies of pediatric kerato-
Sarac et al.59 reported the results of their comparative study in which conus using different procedures and treatment settings.66–90
38 eyes received standard cross-linking (3 MW/cm2, 30 min) while 49
eyes received accelerated cross-linking (9 mW/cm2, 10 min) for pediatric 2.9. Novel cross-linking protocols
keratoconus received over a follow-up period of two years. There was no
difference between the two groups in terms of keratometry, higher-order Crosslinking of corneal collagen is a photoactive process using ribo-
aberration, or uncorrected and best-corrected visual acuity. They flavin and exposure to UV light that increases the biomechanical strength
concluded that efficacy and safety were similar for both protocols; of the cornea. The underlying biochemical changes are similar to
accelerated cross-linking appeared to be more beneficial for pediatric photodynamic therapy. Both of these treatments produce highly reactive
patients because it is a shorter procedure. oxygen species that lead to the formation of new cross-links in the

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Table 1
Pediatric corneal crosslinking: Outcome of various protocols.
Study Design Age No. of Protocol Vehicle UVA irradiation Outcome Follow-up
(years) eyes (mW/cm2) x period (months)
(min)

Arora et al. 2012 [70] P 10–15 15 C Dx 3  30 Stabilization 12

Safe & Effective
Vinciguerra P 9–18 40 C Dx 3  30 Stabilization 24
et al.2012 [71] Improved UCVA, BSCVA
Caporossi et al.2012 P 10–18 56 C Dx 3  30 Stabilization. No stat sig diff b/w < 450, >450 μm. 36
[72]
Viswanathan P 8–17 25 C Dx 3  30 Stabilization þ Effective 20
et al.2014 [73]
Kodavoor et al. 2014 R 9–16 35 C Dx 3  30 Stabilization (86%) 12
[74]
Soeters et al.2014 R 12–17 31 C – 3  30 Improvement, 12
[30] Pediatric & Adults equally safe
Godefrooij et al.2016 P 11–17 54 C Dx 3  30 Safe & Effective 60
[49] Progression in 22% eyes (Paracentral Cone)
Sarac et al.2016 [75] R 9–17 72 C Dx 3  30 In Paracentral cone, Thin CCT<450 μm; -Kmax more 24
likely to progress
Ucakhan et al.2016 P 10–18 40 C Dx 3  30 Kmax decreased from 58.4  5.5D to 57  5.3D 48
[52]
Wise et al.2016 [76] R 11–18 39 C – 3  30 Safe, Halts Progression 12
Zotta et al.2017 [51] P 10–17 20 C Dx 3  30 Safe, Halts Progression 96
Padmanabhan R 8–18 194 C – 3  30 Kmax decreased at 4 yrs in 76%, CDVA stabilization/ 80
et al.2017 [50] improve in 69.1%
Henriquez et al.2018. P 10–17 26 C Dx 3  30 Safe, Halts Progression. Progress in 23.07% 36
[77]
Mazzotta et al.2018 P 8–18 62 C Dx 3  30 KC stabilization in 80% 120
[53]
Barbisan et al. 2020 R 10–16 105 C – 3  30 No diff pediatric & elder group. 12
[79]
Shetty et al. 2014 P 11–14 30 A Dx 9  10 ACXL safe & effective. Careful management of VKC 24
[81] for progression.
Badawi 2017[82] P 8–15 33 A HP 10  9 ACXL safe & effective. 12
Improvement in UCVA, BCVA, K reading.
Agca et al. [83] R 12–17 30/ A Dx 30  4/18  5 ACXL safe & effective 60
113 Increased Irradiation, Decreased Time > Decreased
Effect on Topography
McAnena & O'Keefe R 13–18 25 C/A Dx/HP 3  30/30  4 Stable UCVA, K values, Refractive indices 36
2015 [84] Improved BCVA
Henriquez et al.2017 P 8–16 25/36 C/A Dx/HP 3  30/18  5 Both Epi-On & Epi-Off Safe & Effective for stopping 12
[60] progression
Sarac et al.2018 [59] R 10–17 38/49 C/A Dx/Dx 3  30/9  10 ACXL more beneficial than Standard CXL 24
Eissa et al.2019 [58] P 9–16 68/68 C/A Dx/Dx 3  30/18  5 Both ACXL, Std. CXL beneficial, No progression seen 36
Amer et al.2020 [85] P 12–18 34/34 C/A HPMC 3  30/9  10 Std. CXL > Better than ACXL in K reading, post Op. 36
thinnest CT
Buzzonetti & P 8–18 13 TE Trom 3  30 TE-CXL Safe. Not as effective as Std. CXL 18
Petrocelli 2012.
[86]
Tian et al. 2018[87] R 12–17 18 TE HP 45  5/45  3 ATE-CXL safe & effective. 12
Magli et al.2013 [88] P 12–17 23/16 C / TE Dx 3  30/3  30 TE-CXL safer, similar effectiveness, less painful, less 12
complications than Std. CXL.
Eraslan et al. 2017 P 12–18 18/18 C / TE Dx/Dx 3  30/3  30 Efficacy of Epi-on 0.70 of the efficacy of epi-off CXL 24
[61]
Henriquez et al.2020 P 8–17 46/32 C / TE Dx/HP 3  30/18  5 Epi-off CXL safer and more effective compared to A- 60
[89] epi-on CXL
Buzzonetti 2019 [64] R 9–18 20/20 C / I-ON Dx/ 3  30/10  9 Epi-off CXL halted KC progression in 75% eyes, 36
TE Trom whereas I-ON CXL in 50% of eyes,
Iqbal et al.2020 [90] P 9–17 91/ C / TE Dx/HP/ 3  30/30  4/45  2 SCXL was more effective for pediatric KC and 24
92/88 HP achieved greater stability than ACXL or TE-CXL, and
ACXL was superior to TE-CXL

(Study design: Prospective ¼ P, Retrospective ¼ R, Not described ‘-’; Vehicles: Dx ¼ dextran, HP¼ HPMC, Trom ¼ Trometamol. Protocols: Conventional ¼ C, Accelerated
CXL ¼ A, Trans-Epithelial CXL ¼ TE, Accelerated Trans-Epithelial CXL ¼ ATE, Iontophoretic transepithelial corneal cross-linking ¼ I-ON).

extracellular matrix. The increased number of cross-links improves the Partial de-epithelialization method in which central 3.0 mm of
mechanical strength and stability of the corneal tissue.91 Supplemental corneal epithelium was kept intact and paracentral corneal epithelium
oxygen increases oxygen availability during the corneal cross-linking was removed. The authors found that keeping the central corneal
process. At higher irradiance levels, supplemental oxygen is beneficial epithelium intact was not beneficial for reducing corneal opacity, but this
and eliminates relative oxygen starvation, allowing for potentially more method resulted in better improvement in corrected vision. The total
efficient crosslinking.92 The higher oxygen availability in thin corneas epithelium off technique resulted in better improvement in K-max and Q-
may increase the overall efficacy of riboflavin UV-A CXL compared to value.94
standard thickness corneas. Clinical protocols for thin corneas should be Accelerated CXL was developed to achieve shorter treatment times by
revised to implement these results.93 increasing the intensity of the U V light accordingly. Another way to

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compensate for the relative lack of oxygen at high irradiance is to use 6-year period. They reported complications in 2 eyes, both in pediatric
pulsed light.95 The authors found that the pulsed light accelerated CXL groups: severe bacterial keratitis 3 days postoperatively in a 15-year-old
protocol was less harmful and more effective in inducing changes than and infectious crystalline keratopathy 3 weeks postoperatively in a
the continuous light accelerated CXL protocol in rabbit corneas.96 16-year-old patient. None of the adult patients developed infectious
SimLC is an acronym for Simultaneous Laser Cross-linking, intro- keratitis. Therefore, it is important to emphasize this issue to parents or
duced to distinguish it from Topography-Guided Photorefractive Kera- caregivers as they are believed to be linked to compliance-related con-
tectomy plus CXL (CXL Extra). The main difference is that in SimLC, the cerns in this demographic. The parents should be shown the exact
topography-guided element is always the only treatment given with no method of drop instillation. Parents need to be warned that they should
intention of correcting refractive errors. It is made very clear to the pa- ensure that the child does not touch or rub the eyes. After various ther-
tient that the treatment is not aimed at eliminating their need to wear apies, it has been observed that children may experience a transient
glasses or improving their uncorrected vision. The treatment aims to moderate opacity that resolves with topical steroid treatment in most
improve the corneal shape before it is stabilized with CXL and thus cases, while it may persist in 3% of patients.49
improve best corrected visual acuity (BCVA) and quality of vision.97 In 532 eyes subjected to rapid crosslinking, Maharana et al.69 re-
The newer protocols using hypoosmolar riboflavin and accelerated ported 7 (0.01%) subjects with a mean age of 11 years (range 8–17) who
CXL can be used reliably with reasonable results and are on par with the developed microbial keratitis. Vernal keratoconjunctivitis was also pre-
conventional technique.98 sent in 3 of the cases, and the median time to onset of infection was three
Contact lens-assisted corneal cross-linking (CACXL) has been intro- days after surgery. First, they were treated empirically using a
duced to treat thin keratoconic corneas with riboflavin-impregnated soft tailor-made approach and later treatment was modified based on the
contact lenses to artificially increase functional corneal thickness. It is microbiological findings. However, one of the patients required thera-
advantageous over other thin corneal cross-linking protocols because it peutic penetrating keratoplasty due to a corneal perforation.
works independently of corneal swelling. Because it is an epi-off tech- The potential effects of cross-linking treatment on the limbus (limbal
nique, no additional time, expensive equipment, or special riboflavin stem cells and limbal niche) are not fully understood. It is important to
solutions are required.99 study the effect of UV exposure on the limbal niche, particularly since UV
Intraoperative increase in corneal thickness using a lenticle obtained is known to be mutagenic to cellular DNA and ocular surface tumors can
from the SMILE procedure allows for safe and effective CXL. This pro- develop in the limbus.102 Protection of the limbus from UV rays during
cedure has been successfully performed in combination with intracorneal CXL surgery has been a concern.103 The use of a PMMA shield to protect
ring segments in ultrathin corneas. This allows the corneal surgeon to the limbal stem cells has not been included as a standard of care in the
avoid, or at least postpone, more invasive surgical procedures, lamellar corneal collagen cross-linking procedure.
keratoplasty for visual rehabilitation in such eyes.100 Sharma et al.104 reported persistent corneal edema in 10 patients
requiring penetrating keratoplasty. Other findings were: deep vascular-
2.10. Crosslinking combined with refractive surgery ization (2 eyes; 20%), iris atrophy (6 eyes; 60%), pigment dispersion (5
eyes; 50%), persistent epithelial defect (3 eyes; 30%), and infectious
Crosslinking is used in conjunction with refractive surgery to halt the keratitis (1 eye; 10%). Penetrating keratoplasty was offered to 5 patients
progression of keratoconus and improve visual and refractive outcomes. when improvement plateaued at 3 months, but only 2 patients under-
Kanellopoulos et al.66 reported 4-year follow-up results of went penetrating keratoplasty. CXL is a safe and effective procedure with
topography-guided photorefractive keratectomy combined with cross- few known side effects. This case series reports the possibility of damage
linking (Athens Protocol) in 39 eyes of 21 pediatric patients. Uncorrected to the corneal endothelium with visually significant corneal edema after
and corrected distance vision improved significantly while keratometer CXL treatment.
readings decreased. They concluded that the Athens regimen is a safe and
effective long-term treatment option for children with keratoconus. 3. Conclusions
In a study, 67 eyes of 37 children with pediatric keratoconus, were
treated with combined crosslinking with intracorneal ring segments In children with keratoconus, progression is more likely and pro-
using a femtosecond laser. They reported a significant improvement in gression occurs more quickly. Due to the aggressive nature of the disease
uncorrected and best-corrected visual acuity and mean spherical equiv- in pediatric patients, early and efficient therapy is required to halt its
alent refraction. There were 4 cases (6.4%) of keratoconus progression. progression. Therefore, CXL should be considered immediately. The
They advocated epi-off as the preferred treatment for the future.67 usual CXL "Dresden Protocol" should be applied with the epithelium off.
For kids who are less cooperative, accelerated CXL may be recom-
2.11. Status of Re-corneal collagen crosslinking in children mended. Even though it is less effective, trans-epithelial CXL is safer and
may be performed on patients who require repeated corneal collagen
Repeated collagen cross-linking has been reported to be successful for crosslinking. Parents of children with aggressive keratoconus should get
progression of keratoconus after primary collagen crosslinking. Wu counselling regarding side effects, temporary challenges, and the need
et al.101 evaluated the safety and efficacy of repeat corneal collagen for repeat therapy.
cross-linking assisted by double-cycle transepithelial iontophoresis
(DI-CXL) in the treatment of keratoconus progression after primary CXL. 4. Intellectual property
They excluded patients with a thinnest pachmeter reading of less than
380 μm. They found DI-CXL to be a safe and effective alternative for We confirm that we have given due consideration to the protection of
stabilizing keratoconus progression after primary CXL.101 intellectual property associated with this work and that there are no
impediments to publication, including the timing of publication, with
2.12. Complications respect to intellectual property. In so doing we confirm that we have
followed the regulations of our institutions concerning intellectual
Cross-linking collagen seems to have a favourable safety profile, and property.
there have not been many reports of problems in children with kerato-
conus. Microbial keratitis, one of the more devastating complications, Study approval
has been reported in epi-off crosslinking, transepithelial and accelerated
protocols. Steinwender et al.68 reported a comparable complication rate The authors confirm that any aspect of the work covered in this
for keratoconus in adults (103 eyes) versus children (30 eyes) over a manuscript that involved human patients or animals was conducted with

59
P. Prasher et al. Advances in Ophthalmology Practice and Research 3 (2023) 55–62

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and design of study: AS, RS, VSN; Data collection: RS, PP, VKV; Analysis https://doi.org/10.5005/jp-journals-10025-1070.
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