Keratoconus (KC) is a degenerative, bilateral and asymmetrical condition characterised by mild-to-severe visual impairment (VI).^1,2 The reported prevalence of KC varies widely, ranging from approximately 0.17 per 1000 in the United States to as high as 40 per 1000 in Iran, with an overall estimated prevalence of 1.38 per 1000 in the general population.^1,3 This variability likely reflects differences in study design, genetic and environmental factors, geographic location and diagnostic criteria. Keratoconus usually starts during adolescence and progresses over the next 10–20 years, reaching a plateau in the late 30s or early 40s, with a few exceptions.⁴ Keratoconus affects men and women equally.¹

Although KC has an unknown pathogenesis, there is a strong association with vernal keratoconjunctivitis, reduced ocular rigidity, connective tissue abnormalities, protein inhibitors, genetics, atopy and eye rubbing.^5,6,7,8 Lysyl oxidase is a corneal crosslinking (CXL) enzyme that is found in very low concentration in KC corneas.² In 2015, KC ceased to be regarded as a non-inflammatory disease to more correctly considered an inflammatory-related or quasi-inflammatory disease.^5,6 Keratoconus is found not to be associated with systemic inflammation, but rather disruption of the homeostasis of the cornea due to variance between inflammatory and anti-inflammatory molecules.⁶ Genetic susceptibility, atopy, family history (autosomal dominant and sporadic pattern), ethnic differences and eye-rubbing are key factors that play a role in causing KC.^1,6,8 The diagnosis of KC relies on clinical examination and corneal imaging modalities such as slit-lamp biomicroscopy and corneal tomography, together with quantitative indices including maximum keratometry (Kmax) and simulated keratometry (SimK) values that characterise corneal curvature changes.^5,9 Keratoconus progression is typically defined by changes in multiple tomographic parameters rather than a single index. These include increases in maximum keratometry (Kmax), progressive corneal thinning and changes in anterior or posterior corneal curvature or elevation. Although an increase in Kmax of ≥ 1 dioptre (D) within 12 months is commonly used as a clinical indicator of progression, current consensus guidelines recommend evaluating several parameters simultaneously to confirm true disease progression.^9,10 In KC eyes, there is a decline in thickness and volume of the cornea, together with asymmetrical displacement of the anterior and posterior apex of the cornea. The posterior cornea exhibits KC changes first, underscoring the importance of early imaging.

Corneal thinning most commonly occurs in the inferior-temporal and central quadrants of the cornea, but it can also occur in the superior corneal quadrant.⁴ As KC progresses, the patient notices distorted vision. Clinical signs include steepening of the cornea, changing corneal curvature and an increase in coma-like aberrations.^5,6 Thinning of the cornea in the central and paracentral quadrants can result in nipple or oval cones. The most important clinical signs are the changes in the anterior and posterior curvatures of the cornea, as well as corneal thinning via pachymetry.

Pellucid marginal degeneration (PMD) is characterised by a marked steepening in the inferior corneal periphery along the vertical axis.¹¹ Not much is known about the aetiology of PMD and its incidence, but PMD is characterised by severe against-the-rule astigmatism, hydrops and the ‘lobster-claw pattern’ or ‘kissing doves’ sign, which is observed with corneal topography.¹¹ Pellucid marginal degeneration and post-refractive-surgery ectasia share overlapping features with KC but remain distinct in morphology and progression patterns.⁸ Collectively, ectatic disorders impose substantial visual, psychological and economic burdens, particularly in settings where access to speciality lenses and keratoplasty is limited.

In the early stages, patients with KC are asymptomatic, thus making it difficult to diagnose the condition. Initially, only spectacles or soft or rigid gas permeable (RGP) corneal lenses may be required for adequate vision; however, the gradual progression of KC cannot be prevented by spectacles or contact lenses.^12,13,14 Reduced corneal thickness results in myopia, irregular astigmatism and visual disturbances such as ghosting and glare.⁹ As the disease progresses, spectacle or soft contact lenses do not improve vision adequately. Once the better eye is significantly affected, patients will start to notice diminishing visual acuity (VA). Keratoconus in the more severely affected eye would then be at a more advanced stage by the time the patient presents to the optometrist or ophthalmologist. At that point, patients with KC who are not already wearing corneal RGP lenses are typically fitted with them to improve vision. Such RGP corneal lenses create a new uniform optical surface, thereby improving vision more than soft contact lenses while allowing good tear exchange.⁷ In progressive KC, corneal opacities or hydrops due to previous rupture of the Descemet membrane may reduce VA with contact lenses.^9,15 Eventually, some patients will be unable to see with either eye, and RGP corneal lenses may not be well tolerated.^16,17 In advanced cases of KC, where RGP corneal lenses or scleral lenses cannot be fitted, medical procedures such as intracorneal ring segments (ICRS), deep anterior lamellar keratoplasty (DALK), phakic intraocular lenses, photorefractive keratectomy (PRK) or penetrating keratoplasty (PK) become the primary options for patients.^6,10 Such medical treatment options can be expensive and rely on the surgeon’s skill for success.¹⁸ These techniques can present with graft failure and rejection or surgically induced high postoperative astigmatism.¹⁸ In some patients, KC eventually stabilises, and invasive surgery (such as DALK or PK) may not be required.

Keratoconus and other corneal ectatic disorders are progressive conditions that distort corneal architecture, degrade visual quality, and, when advanced, often necessitate keratoplasty.^1,2,3 For decades, management has been centred on optical rehabilitation, spectacles, RGP corneal lenses or scleral lenses, and, in severe cases, surgical intervention. These approaches, however, did little to arrest biomechanical weakening of the cornea. The advent of riboflavin/ultraviolet A (UVA)–mediated CXL fundamentally changed this paradigm by biologically strengthening stromal collagen and thereby slowing or halting ectatic progression.^9,19,20,21

Crosslinking was originally described as the formation of covalent bonds between long-chain polymers in industrial and biomedical applications.²² Its ophthalmic translation, photochemically induced corneal collagen crosslinking, relies on riboflavin as a photosensitiser and UVA light to generate reactive oxygen species that form additional intrafibrillar and interfibrillar bonds within the corneal stroma.^4,19 Early laboratory work established safety thresholds, tissue penetration characteristics and the pivotal role of oxygen, laying the groundwork for human application. The seminal ‘Dresden protocol’, introduced in the early 2000s, standardised the parameters for an epithelium-off procedure and rapidly became the clinical gold standard.^23,24

Since its introduction, CXL has diversified. Variants include accelerated protocols applying Bunsen–Roscoe reciprocity to shorten treatment time, transepithelial (‘epi-on’) techniques aimed at reducing discomfort and infection risk, iontophoresis-assisted delivery to enhance riboflavin penetration and customised or ‘CXL Plus’ approaches that combine CXL with refractive procedures to optimise visual outcomes.^5,6,7,8 Parallel innovations address the perennial challenge of thin corneas, traditionally excluded because of endothelial safety thresholds, through hypo-osmolar riboflavin swelling, contact lens-assisted corneal crosslinking (CACXL) and spatially modulated irradiation.^4,11,12 Collectively, these developments reflect a shift from a single, lengthy protocol to a spectrum of tailored interventions balancing efficacy, safety and patient comfort.

The incidence of KC, its often-early onset and its potential to impose lifelong visual disability underscore the importance of timely detection and intervention.^5,6 With accumulating long-term data demonstrating sustained corneal stability and reduced need for keratoplasty, CXL has emerged as a cornerstone in modern ectasia management.^14,15 Nevertheless, questions remain regarding optimal energy dosing, depth of effect, paediatric applications and long-term outcomes of newer protocols.

The aim of this paper is to critically synthesise three decades of evidence on CXL, from the original Dresden protocol to contemporary accelerated, transepithelial, thin-cornea and ‘CXL Plus’ variants, highlighting the relative advantages, limitations and clinical outcomes of epi-off versus epi-on techniques in order to guide current practice and future research in the management of KC and other ectatic corneal disorders.

The 57 included publications collectively describe the progressive evolution of CXL from a single standardised protocol to a spectrum of individualised treatment approaches. Across the reviewed studies, the evidence synthesised can be grouped into five major themes: (1) biomechanical efficacy and safety of the standard epithelium-off Dresden protocol; (2) development of accelerated protocols to reduce treatment time and postoperative morbidity; (3) emergence of transepithelial and iontophoresis-assisted techniques to improve patient comfort and epithelial safety; (4) modified strategies to enable treatment of thin corneas previously considered unsuitable for CXL; and (5) combined or ‘CXL Plus’ procedures aimed at simultaneous biomechanical stabilisation and visual rehabilitation.

Corneal crosslinking pioneers, Wollensak et al.¹⁹ found an increase in the rigidity of the cornea by 328.9% and in Young’s modulus by a factor of 4.5 after CXL. Corneal crosslinking has been approved by the Food and Drug Administration (FDA) to modify the corneal stroma in the management of KC and other corneal disorders.³ Riboflavin or vitamin B2 is important for maintaining health in humans and animals and is a readily absorbed micronutrient. Topical iso-osmolar riboflavin interacts with UVA of wavelength 370 nm to induce CXL of the cornea. The riboflavin molecule, upon exposure to UV light, becomes excited to higher energy states and acts as a photosensitiser, producing singlet oxygen. These free radicals activate the natural lysyl oxidase pathway. In this excited state, riboflavin can induce covalent bonds, thus causing collagen fibres in the collagen stroma to crosslink with each other. Corneal crosslinking with UV makes the cornea more rigid and stable by linking collagen and non-collagen molecules.² For this reason, the term ‘corneal collagen’ crosslinking is not entirely accurate.¹⁹

While keratocyte aptosis in the corneal stroma occurs during CXL, it does not affect corneal transparency and thickness.^19,20 Corneal crosslinking appears to be effective for KC as well as infectious and non-infectious keratitis and keratectasia, while its use in the treatment of bullous keratopathy is indefinite.^9,21 Previous studies have shown that stabilisation and flattening (an increase in keratometry readings) of the cornea in both paediatric and adult populations take place after CXL.²¹ Corneal crosslinking occurs naturally with age due to natural lysyl oxidase pathways.²³

Corneal crosslinking treatment is a minimally invasive option in the treatment to halt the progression of keratectasia.¹⁵ It has also been used to manage other conditions such as ulcerative keratitis, infectious ulcers and bullous keratopathy. Laser-assisted in situ keratomileusis (LASIK), PRK and radial keratotomy (RK) have all been shown to produce keratectasia. Keratectasia secondary to refractive surgery is seen in only 0.04% – 0.6% of post-LASIK cases but is visually devastating.²¹ Risk factors such as thin corneas, high myopic and/or astigmatic corrections, pre-existing KC, PMD and young age should be ruled out during pre-operative screening for refractive surgery to reduce the risk of corneal ectasia. Post-LASIK ectasia exhibits abnormal, asymmetric topographic findings with progression that is unpredictable. Corneal crosslinking has also been administered prophylactically before PRK to prevent complications.^15,25 Once again, management of keratectasia with CXL depends on the severity of the condition. Current CXL protocols have been shown to be safe and effective in halting keratectasia.^13,26,27,28

The chronological synthesis of the literature demonstrates a clear evolution from a single, standardised protocol to a spectrum of individualised approaches. Early studies established the biomechanical efficacy and safety margins of the Dresden protocol, which explains its continued role as the benchmark technique. Subsequent innovations: accelerated, transepithelial and thin-cornea protocols did not arise from inadequacy of the standard approach, but rather from clinical pressures to reduce treatment time, postoperative morbidity and exclusion of advanced cases. The persistence of epi-off CXL as the comparator in modern trials underscores that newer techniques represent strategic compromises rather than outright replacements. This evolution reflects a broader shift in KC management towards personalised care, in which biomechanical stability, visual rehabilitation, patient comfort and resource availability must be balanced.

Corneal crosslinking has shifted the management of KC and other ectasias from predominantly rehabilitative strategies to proactive biomechanical stabilisation. The demonstrable reduction in progression rates and consequent decline in keratoplasty demand underscore CXL’s public-health relevance, particularly in regions with limited access to donor tissue and subspeciality surgical care. Early identification of progression and timely referral for CXL are therefore critical clinical imperatives for optometrists and ophthalmologists alike.

Pre-operative screening is fundamental to the selection of an appropriate CXL protocol and must precede any intervention. Screening includes confirmation of ectatic diagnosis, documentation of disease progression, assessment of stromal thickness at the thinnest point, ocular surface status, patient age, atopic history and tolerance for postoperative discomfort. Tomographic evidence of progression, commonly defined as an increase in maximum keratometry (Kmax) of ≥ 1.0 D over 12 months with alterations in corneal thickness and posterior elevation, remains a key trigger for intervention.

Clinical implications include a move towards earlier intervention, the need for protocol individualisation (standard Dresden vs. accelerated regimens; epi-off vs. epi-on; modified approaches for thin corneas) and long-term follow-up to verify stability. The evidence base supports epi-off CXL as the benchmark for efficacy,^{8,14,32,38,39} but patient comfort, healing time and risk profiles justify selective use of alternative protocols.

Selection of an appropriate CXL protocol is intrinsically linked to pre-operative screening and should be individualised rather than uniform. The initial decision point is confirmation of progressive KC, typically defined by documented tomographic or keratometric progression over time. Corneal thickness at the thinnest point then becomes the primary determinant of protocol eligibility. In corneas with a minimum stromal thickness of ≥ 400 µm, the epithelium-off Dresden protocol remains the reference standard owing to its well-established biomechanical efficacy, predictable treatment depth and long-term stability.

Accelerated protocols have emerged primarily in response to the prolonged treatment time and postoperative discomfort associated with the standard protocol. While these regimens reduce procedure duration and improve patient tolerance, the shallower demarcation lines reported in several studies suggest reduced crosslinking depth, which may have implications for long-term biomechanical stability, particularly in rapidly progressive disease.

For patients with thin corneas (< 400 µm), pre-operative screening necessitates careful risk stratification, as endothelial safety becomes the dominant concern. Modified approaches such as hypo-osmolar riboflavin swelling, CACXL and customised irradiation protocols expand treatment eligibility but require meticulous intraoperative pachymetry and acceptance of potentially reduced stiffening effects.

Similarly, transepithelial and iontophoresis-assisted techniques may be preferentially selected in paediatric patients, individuals with significant pain sensitivity or those at higher risk of epithelial healing complications, despite their comparatively lower biomechanical impact. ‘CXL Plus’ strategies promise refractive gains but raise concerns about haze and require careful case selection and informed consent.

Thus, protocol selection is not algorithmic in isolation, but is intrinsically linked to pre-operative screening findings. Optimal outcomes depend on matching disease severity, corneal thickness, patient factors and rate of progression to the most appropriate CXL technique, rather than applying a uniform approach.

Over the last 100 years, the treatment and management of KC have substantially evolved. While it would be ideal to offer a quick, pain-free CXL procedure, the slow irradiation time of the Dresden protocol has been found to be the most successful. Currently, the epi-off procedure with 9 mW/cm² for 10 min using constant light appears to work best.³¹ The effect of treatment has been observed to remain stable for up to 10 years in the original Dresden cohort.⁴¹

Early detection and assessment of KC progression are vital. If it is progressive, the progression of KC needs to be halted. Corneal crosslinking has played a phenomenal role in changing the way we prevent the progression of KC. If corneas are more than 400 µm thick at their thinnest point (when KC is in its early or moderate phase), CXL can be implemented to prevent progression. Thereafter, patients can be referred to an optometrist for the fitting of RGP corneal lenses or scleral lenses to improve VA.⁵⁷ Corneal crosslinking is significant because it reduces the need for surgical interventions such as a keratoplasty.⁴¹ However, if KC is detected in the advanced stage, keratoplasty may sometimes be the only option.

This narrative review synthesises evidence from 58 publications and demonstrates a clear evolution from the standard epi-off Dresden protocol to a diverse range of accelerated, transepithelial, thin-cornea and combined treatment strategies. While newer protocols improve patient comfort, reduce treatment time and expand eligibility, the Dresden protocol remains the benchmark against which efficacy is measured.

Despite substantial progress, important research gaps remain. Long-term comparative data beyond 5–10 years are limited for accelerated, transepithelial and thin-cornea techniques.

The biomechanical durability of reduced-fluence or epithelial-on protocols in rapidly progressive disease, particularly in paediatric populations, requires further investigation. In addition, standardised outcome measures and consensus definitions of treatment success would strengthen inter-study comparability. Future research should focus on well-designed prospective trials, longer follow-up periods and the development of validated clinical algorithms to guide protocol selection. Addressing these gaps will further refine CXL as a personalised, evidence-based intervention in the management of KC.