Keratoconus: A historical and prospective review

Abstract

This article is a historical and prospective review of keratoconus and ectatic corneal diseases. It covers definitions and terminology, the prevalence of keratoconus, predisposing factors, diagnosis, differential diagnosis, management, classifications, and progression criteria. It highlights other aspects of the disease that are usually over-missed, including the psychological, social, and economic impact. This review presents the information chronically in terms of the first author. It concludes by possessing the challenges and difficulties that are still to be overcome and suggests a plan.

Introduction

There are thousands of researches on keratoconus disease in terms of prevalence and management. During our review of the literature, we found a deficiency in the number of reviews, especially those documenting the sequence of events, mentioning the challenges of the disease, or foreseeing the future of prevention and management.

The PubMed search was the main engine used to track the earliest documented events.

Definition and Terminology

In 1748, the first physician who described keratoconus was German professor Burchard Mauchart. He described it as “Staphyloma Diaphanum.” In 1854, the British physician John Nottingham was the first to name it “Conical Cornea.” However, the Swiss physician John Horner was the first to give the term “Keratoconus” to the disease in 1869.

For over 150 years, keratoconus has been defined as a bilateral noninflammatory corneal ectasia.[1,2]

The term “ectasia” was vague and defined in most medical dictionaries as a dilation or distention of a tubular structure.[1] In 2015, the global consensus on keratoconus and ectatic corneal diseases defined ectasia as a thinning corneal disorder but excluded Terrien and Dellen.[3]

Recently, the inflammatory nature of the disease has been defined.[4]

Different entities share keratoconus in the ectatic nature. They include pellucid marginal degeneration, pellucid-like keratoconus, keratoglobus, and postlaser ectasia. In addition, some entities may share keratoconus in the ectatic nature, such as forme fruste keratoconus, keratoconus suspect, and posterior keratoconus. The differentiation between all those entities will be mentioned in the differential diagnosis.

Prevalence of Keratoconus

For long years, keratoconus was classified as a rare disease. That can be attributed to several factors affecting the disease's actual prevalence.

Regional

Studies were confined to some populations rather than being global. There were no studies from the regions of high prevalence.

Diagnostic tools

No surprise when comparing the old with the recent studies in terms of the prevalence of the disease. The significant development and improvement in corneal imaging and mapping technology contribute to the remarkable increase in prevalence because of the improved ability to detect the disease, particularly in the early stages.

Awareness

More awareness ophthalmologists about the disease led to an increase in the diagnosis and prevalence.

Due to the above reasons, the prevalence apparently increased by 100 folds from 0.054% in the population of Rochester County, Minnesota, in 1986,[5] to 4.79% or 1:21 in Saudi Arabia as per the K-map study in 2018.[6]

The prevalence varies between regions. It is considerably higher in the Middle East,[7,8,9,10,11] India,[12] China,[13] and Australia.[14]

Ethnicity is an important factor affecting the prevalence. The Dundee University for Scottish Keratoconus Study found that in Scotland, the keratoconus prevalence was 5% in those of Caucasian origin. In comparison, it was 25% of those with an Asian heritage.[15]

Predisposing Factors

It has been shown that inheritance and environmental factors play a role in the pathogenesis of ectatic corneal diseases. Around 8% resulted from genetic mutations and 92% from environmental factors.[16,17]

The climate was hypothesized to be one of the factors. It was proposed that the corneas of those living in hotter and drier regions are more exposed to keratoconus development. However, there has been no concrete evidence of such to date.

As mentioned above, geographic and ethnic factors were found to be strong predisposing factors.

Keratoconus is usually associated with atopy and eye rubbing. Damien Gatinel described rubbing as a risk factor for keratoconus development and progression.[18,19] This hypothesis was supported by the assumption of Grieve[20] and Rabinowitz[21] that repeated trauma in genetically predisposed individuals is the most likely explanation. However, that hypothesis is still a matter of debate.[18,22,23,24]

Several systemic disorders, such as Down syndrome and connective tissue disorders, have been associated with keratoconus.[25]

Hormonal changes were described as well, such as high estrogen levels during pregnancy,[26,27] selective tissue estrogen regulator (STEAR) therapy,[28,29] and thyroid hormone imbalance.[30]

Although most cases of keratoconus have been deemed sporadic, there is also evidence that Keratoconus is heritable in an autosomal dominant manner.[31]

Moreover, a significant association with consanguinity has been described. In addition, higher concordance was found between monozygotic and dizygotic twins.[30,32]

The prevalence of keratoconus in relatives of people with keratoconus is 15–67 times greater than in the general population.[33,34]

In a systemic review and meta-analysis, the most common risk factors for keratoconus were family history (odds ratio [OR] = 6.42), eye rubbing (OR = 3.09), Eczema (OR = 2.95), and asthma (OR = 1.94).[35]

Diagnosis

Clinical examination

Diagnosis starts with clinical suspicion, including history taking and examination. Keratoconus should be suspected when the patient suffers from higher-order aberration symptoms, such as shadows, glare, and halos, especially at night. Health history may reveal atopy, eye rubbing, and connective tissue-related conditions such as floppy eyelid syndrome, Down syndrome, Ehlers–Danlos syndrome, sleep apnea, or Marfan syndrome.

Eye examination may show nonoptimum best-corrected vision, Munson's sign, oil-droplet in red reflex, steep K readings on autorefraction, unusual astigmatism, anisometropia, and significant changes in astigmatic axes between visits. In the early stage, slit lamp examination may appear normal, but in moderate to advanced cases of the disease, Vogt's striae, a Fleisher ring, and apical scarring may exist.

Using retinoscopy to detect the scissoring reflex was useful, especially in rural areas where advanced technology might not be available.[36] However, the scissoring reflex is not specific to keratoconus; it is found with irregular astigmatism, subtle corneal opacities, and early cataract.

Corneal topography and tomography

The development of topography and tomography went through a long history. In 1619, Christoph Scheiner was the first to measure corneal curvature. In 1847, Henry Goode described the first keratoscope using a square object. Ferdinand Cuignet described the retinoscopy in 1874. Antonio Placido invented the Placido disc in 1880. Allvar Gullstrand invented photo-keratoscopy in 1896 and was the first to analyze the photo-keratoscopic images of the cornea quantitatively. In 1984, Stephen Klyce invented the first computerized video keratoscopes, which was the starting point for all topography devices.

Due to the limitation of the topography devices to describe the posterior corneal surface and corneal thickness, the technology of tomography was born at the end of the 1990s when the slit scanning tomographer was introduced. However, the Sceimpflug technology was a bit older when Theodor Scheimpflug, an Austrian cartographer navy, invented the technology in 1904. In 1964, Drews RC Introduced Scheimpflug imaging to ophthalmology but was the first implementation as a tomographer in 2002.[37]

In 2015, color light-emitting diode tomography was introduced, and in 2017, the optical coherence tomography (OCT)-based tomographer was implemented for corneal imaging.

Corneal topography is a term used to describe imaging the anterior corneal surface, while corneal tomography describes imaging both corneal surfaces and generating corneal thickness.[38] Many devices in the market combine the two technologies for better accuracy.

Segmental or layered tomography first started with corneal epithelial thickness measurements with very high-frequency ultrasound (VHF-US).[39] The role of the epithelial map in refractive surgery and ectatic corneal disease detection has been highlighted.[40] Reinstein introduced corneal epithelial indices derived from VHF-US and described their use in the classification, the detection of early stages, and monitoring progression.[40,41,42]

The OCT technology was used by Li et al., who developed an extended epithelial thickness map that was used with epithelial indices to detect keratoconus in its early stages.[43,44]

Aberrometry

Because ectatic corneal diseases produce irregular cornea astigmatism and, therefore, corneal higher-order aberration, aberrometry was introduced to detect and classify keratoconus.

The first clinical wavefront sensors were introduced to ophthalmology in the mid-1990s.[45] In 2006, Alio et al. used the aberrometer to grade keratoconus and developed a modified Kurmeich-Amsler classification.[46] Saad and Gatinel used the aberrometer in the detection of forme fruste keratoconus.[47]

Corneal biomechanics

The first in vivo application and measurement of corneal biomechanics was in 2005 by David Luce who introduced the Ocular Response Analyzer (ORA, Reichert Ophthalmic Instruments, Buffalo, NY, USA).[48] Initially, the ORA described the deformity of the cornea by two parameters, corneal hysteresis and a corneal resistance factor. More parameters were developed to increase sensitivity and specificity. However, the ORA was the first to come up with the concept that was modified to develop The Corvis ST Dynamic Scheimpflug analyzer (Oculus, Wetzlar, Germany) in 2011. With the great work of Cynthia Roberts, Paolo Vinciguerra, and Renato Ambrosio. Several parameters derived from this instrument have been introduced, such as the deformation amplitude, the radius of curvature at the highest concavity, the applanation lengths, the corneal velocities, and the corneal biomechanics index.[49]

The integration of Corvis with tomography came up with the tomographic and biomechanical index to enhance ectasia detection.[50]

Tear film biomarkers

The work of identification of tear film biomarkers in keratoconus patients started in 2005 when Lema and Duran found that interleukin-6, tumor necrosis factor-alpha, and matrix metalloproteinase-9 were overexpressed in the tears of patients with keratoconus, indicating that the pathogenesis of keratoconus might involve chronic inflammatory events.[4] Several studies followed to add more evidence and to identify more specific markers.[51,52,53,54,55,56,57,58]

Differential Diagnosis

Different terms are used to describe different entities of ectatic corneal diseases. Differentiation between the entities is important because each entity has specific considerations and treatment planning. The author categorizes the entities into established ectasia, including keratoconus, pellucid-like keratoconus, pellucid marginal degeneration, keratoglobus, and postlaser ectasia; para-ectasia, including forme fruste keratoconus, and keratoconus suspect; and corneas with high potential, including posterior keratoconus, and corneas with unclassified abnormalities. A skillful interpretation of the tomography and correlating the findings with the history-taking and slit-lamp findings is the key to an accurate diagnosis.[59]

Management

The management of Keratoconus and other ectatic corneal disorders aims to halt progression, reduce corneal surface irregularity, and occasionally decrease residual refractive error.

To achieve this target, several adjuvant therapies in combination with corneal collagen cross-linking (CXL) treatment have been proposed, and the term “CXL plus” emerged in 2011 to describe several combined management modalities studied to enhance the results of CXL.[60]

Combined management modalities range from noninterventional measures, such as spectacles and contact lenses,[61] to interventional measures, including photorefractive keratectomy,[62,63,64,65,66,67,68,69,70,71,72,73,74] transepithelial phototherapeutic keratectomy,[75,76,77,78] intrastromal corneal ring segments implantation,[79,80,81,82,83,84,85,86,87,88,89,90] phakic intraocular lens (PIOL) implantation,[91,92,93,94,95] and multiple techniques combined with CXL.[96,97,98,99,100,101,102,103]

Parameters of treatment

The choice of management modality depends on several parameters such as the patient's age, gender, environment, and geographic location; the stage of the disease; corneal transparency; the presence of Vogt's striae; contact lens tolerance; progression; corneal thickness; uncorrected distance visual acuity (UDVA); corrected distance visual acuity (CDVA); potential visual acuity (PVA) and refractive error.

Age

Previously, it was thought that keratoconus usually starts at puberty and shows the most aggressive progression in the second and third decades of life.[2,104] In contrast, PMD usually begins in the second to fifth decades of life.[6] In recent studies, it has been shown that keratoconus can begin in early childhood regardless of being syndromatic or not. In some areas in the world, the prevalence of keratoconus in the pediatric population was reported to be 1:20.[105]

Therefore, CXL should be considered as a primary treatment choice in the younger population with Keratoconus, and even in older age group with PMD.

Gender

Changes in estrogen, cortisol, and thyroxin levels during pregnancy may alter corneal biomechanics and trigger Keratoconus progression and late onset of keratectasia after LASIK.[3,106,107,108,109] Additionally, pregnancy was reported as a factor of exacerbation of iatrogenic ectasia despite CXL.[106]

Environment

Keratoconus is a multifactorial disease combining genetic, biochemical, biomechanical, and environmental factors.[110,111,112,113] Environmental factors, that have been recognized, are eye rubbing and atopy, although the relative contribution of these factors is currently unknown.[114] An association between eye rubbing and Keratoconus has long been described and accepted as a risk factor.[115,116,117,118,119,120,121] A positive association between atopy and Keratoconus has been reported.[122,123,124,125] In addition, allergy, induced by pollen, dust, antibiotics, or animal fur is often associated with Keratoconus compared to controls or the general population.[15,24,32,117,122,123,124,125,126,127,128] This issue should be considered because allergic conjunctivitis and eye rubbing are risk factors for Keratoconus progression after CXL.[129] At the same time, eye rubbing is a risk factor for postoperative complications.

Topical multiple-action anti-allergic medications (i.e., antihistamines, mast cell stabilizer, anti-inflammatory) are advised in patients with Keratoconus with atopy or a history of eye rubbing.[110]

Although there is no direct relationship between Keratoconus and dry eye, keratoconus patients suffer from dry eye, probably due to the inhomogeneity of the tear film over the irregular cornea.[110]

Corneal transparency and Vogt's Striae

Corneal scarring indicates corneal grafting, which might be lamellar or penetrating, depending on the scar location, size, and depth. On the other hand, Vogt's striae are an indicator of advanced disease[64,104] where the following are usually found: K-max >60D, high refractive error (S. E. >6D), and corneal thickness <350 µ. In such cases, lamellar keratoplasty is usually indicated. However, other factors, such as visual acuity, may further affect the decision.

Contact lenses

In cases where contact lenses can be tolerated, they represent the treatment of choice for most keratoconus patients,[130] although they do not halt the progression of the disease.[110]

Progression of the disease

When progression has been documented, CXL is internationally recognized as a measure to halt or delay the progression unless contraindicated.

Corneal thickness

The minimum corneal thickness criterion for the standard CXL treatment is 400 μm without the epithelium. However, some techniques were developed to treat thinner corneas as will be mentioned below.

Treatment Modalities

Glasses

They are the best choice as long as the patient can achieve satisfactory visual function.

Contact lenses

Previously, rigid contact lenses were the only type of contact lenses. They were associated with a high percentage of intolerance. New designs of contact lenses were developed to achieve a wider coverage of cases and better tolerance.

Corneal cross-linking

The aim of corneal cross-linking is to halt the progression of the disease and reduce the need for further sophisticated treatment, especially keratoplasty. The first introduction of corneal cross-linking to corneal tissue was in 1997 by Spoerl et al.[131] Dresden protocol was established in 2003 by Wollensak et al.[132] The minimum corneal thickness required to apply the protocol was 400 µm without the epithelium. To treat thin corneas, some modifications were introduced, starting with the hypo-osmolar protocol in 2009 by Hafezi et al.,[133] epithelial-on (trans-epithelial) techniques in 2009 by Wollensak et al.,[92,134,135] intrastromal pockets in 2011 by Vinciguerra et al.,[136] epithelial disruption in 2013 by Alio et al.,[137] Iontophoresis in 2014 by Richichi et al.,[138] contact lens assisted in 2014 by Jacob et al.,[139] lenticule assisted in 2015 by Sachdev,[140] and recently, the sub400 protocol in 2020 by Hafezi et al.[141]

Dresden protocol consisted of the removal of the epithelium, application of riboflavin for 30 min, and application of UVA 3 mW/cm² for 30 min.[131] To shorten the duration times of the procedure, reduce patient discomfort, and minimize postoperative complications, the accelerated protocols came with modification of the formulations and the delivery methods of riboflavin as well as altered UV exposures. In 2011, Wernli et al. proved that the accelerated 10 mW/cm² for 9 min showed an equivalent effect to the Dresden protocol.[131] Attempts to increase the power and decrease the time of exposure followed. In 2013, Wernil showed that there was a sudden decrease in effect after the power of 45 mW/cm².[142] On the other hand, in 2014, Hammer et al. published a study showing that the biomechanical stiffness efficacy of 9 mW/cm² for 10 min is comparable to the Dresden protocol, while the 18 mW/cm² was ineffective.[143] Contrary to that, Mita[144] and Tomita[145] published two studies showing that the results of the 30 mW/cm² for 3 min were comparable to the Dresden protocol.

The role of oxygen in corneal cross-linking was established in 2013 when Richoz et al. could explain the failure of the initial attempts of trans-epithelial CXL Their study helped fine-tune the high-pulse CXL.[146]

Customization of the pattern of the UVA application was also performed by Seiler et al. They customized the energy into zones related to the cone location.[147]

The combination of CXL with surface ablation to treat keratoconus was first described by Kanellopolous and Binder.[148] Since that time, several studies have been published showing different outcomes. However, whether CXL should be performed simultaneously[149] or sequentially[150] is still controversial.

Intracorneal rings

The first introduction of intracorneal rings was in 1999 when the FDA approved INTACS implantation for myopic treatment.[151]

Very quickly, INTACS were used to treat mild to moderate keratoconus by Ertan and Colin.[152,153]

The aim was to modify the corneal shape without removing tissue or manipulating the central cornea to improve the spectacle-corrected visual acuity.[154]

Since that time, different types and sizes of rings and different nomograms have been developed.[79,80,81,82,83,84,85,86,87,88,89,90,155]

All types aim at reducing the steepness and irregularity of the cornea, and they give good outcomes when properly indicated.

Some studies were published to compare different types, and they showed comparative outcomes.[156,157,158]

Allografts

Re-implantation of the allografts started in 2012 when Angunawela et al. re-implanted SMILE lenticule in rabits’ eyes.[159] In 2018, Jacob et al. invented the C.A.I.R.S, which stands for corneal allogenic intrastromal ring segments, as an alternative to the PMMA segments. They combined it with corneal cross-linking for the treatment of keratoconus.[160] A number of studies were published and showed the efficacy and safety of this procedure.[161,162,163,164] Moreover, customization of the implants and the tunnels has been developed by Prof. Awwad.

Other allografts were suggested, such as intrastromal Bowman layer transplantation to support the keratoconic stroma.[165,166]

Phakic intraocular lens implantation

They can be used to treat refractive error and astigmatism in keratoconus.

In 2005, Budo et al. used the Atisan in keratoconus patients,[167] and in 2010, Alfonso et al. used the STAAR ICL for the same purpose.[168]

That was followed by a number of studies supporting the safety and efficacy of the PIOLs in the treatment of this disease.[91,92,93,94,95]

Customized laser vision correction

The first application of customized laser ablation to treat refractive error and higher-order aberrations was in 1998 when Schwiegerling and Snyder introduced the corneal asphericity adjustment.[169,170] Two years later, Knoz applied the topographically guided laser to treat corneal irregularities.[171] In 2002, the wavefront-guided ablation profile was introduced and applied by Mrochen et al. to treat irregular corneas due to decentred ablation zones.[171] In 2006, the corneal asphericity adjustment was further developed and applied for myopia treatment by Koller et al.[172] However, the first introduction of topography-guided ablation to treat keratoconus was in 2007 by Kanellopolous et al.,[64] who developed the Athens protocol in 2011.[69]

Over the last decade, a significant improvement in laser profiles has occurred to improve the predictability and accuracy of customized treatment.

Classifications

Since the definition of the disease, some classifications were presented to describe the stage of the disease. The first keratoconus classification based on disease evolution was proposed by Amsler.[174,175] After that, Krumeich et al.[173] made some modifications to Amsler's classification and came up with the Amsler-Krumiech grading system for Keratoconus. However, this over-20-year-old analysis is limited[176] because it does not reflect many of the more diagnostic measurements, such as posterior corneal surface and corneal thickness.[177] Alio and Shabayek added another modification to the Amsler-Krumeich grading system, which is corneal higher-order aberrations, especially coma-like aberrations.[177] Ishii et al.[178] described a new classification based on the Amsler-Krumeich grading system. In their classification, they integrated visual acuity, the minimum radius of curvature of the anterior corneal surface, and six indices, namely: ISV, index of surface variance, which describes corneal surface irregularity; IVA, index of vertical asymmetry, which describes curvature symmetry; KI, keratoconus index, which also describes curvature symmetry; CKI, center keratoconus index, which describes the severity of central Keratoconus; IHA, index of height asymmetry, which is similar to IVA but based on corneal elevation and is thus more sensitive; and IHD, index of height decentration, which describes the decentration in elevation data in the vertical direction.

However, none of the classifications were based on treatment modalities until Alfonso et al. established the morphological classification of keratoconus for intracorneal ring implantation.[179]

The Functional Classification

Several algorithms were developed to make decision-making simple and based on the findings. However, different algorithms depend on different parameters, such as corneal transparency, the presence of Vogt's striae, disease status, corneal thickness, maximum K-readings (K-max), refraction, amount of astigmatism, higher-order aberrations, and visual acuity.

In this section, the author will present his functional approach that classifies the disease into three grades based on the symptoms (shadows, glare, starbursts), uncorrected (UDVA), best-corrected (CDVA), and potential distance visual acuity (PVA) measured by the best-fit contact lens.

Grade 1

Mild symptoms, CDVA >0.6 decimal, CDVA-UDVA >2 lines, the RMS corneal coma at 6 mm <2.0 µm.

Grade 2

Moderate symptoms, CDVA ≤0.6 decimal, PVA >0.6 decimal, PVA-CDVA >2 lines, the RMS corneal coma at 6 mm 2.0–4.0 µm.

Grade 3

Severe symptoms, CDVA ≤0.6 decimal, PVA ≤0.6 decimal, PVA-CDVA ≤2 lines, the RMS corneal coma at 6 mm >4.0 µm.

In this classification, treatment options are categorized into three categories, aiding measures (contact lenses, glasses, and PIOL), corneal remodeling measures (customized laser ablation and ICR implantation), and corneal transplantation.

In grade 1, the aiding measures are suitable. The selection of the best option depends on the magnitude of refractive error and the patient's tolerance to contact lenses. However, corneal remodeling can be applied to reduce the irregularities and improve the quality of vision before applying the aiding measures.

In grade 2, contact lenses are the best option if the patient is tolerant; otherwise, corneal remodeling is the first step before applying the aiding measures.

In grade 3, corneal transplantation is the first step. After full recovery, visual rehabilitation can be by aiding measures or by customized laser ablation before.

Corneal cross-linking is applied in grades 1 and 2 when indicated.

Progression

Not every case of keratoconus is progressive. Progression is related to some factors, such as young age and eye rubbing. Confirmation of progression has been an area of research and debate. The very early studies depended on a single or a few parameters to describe progressions, such as the change in K-max, refraction, or corneal thickness. However, there was no agreement on the cut-off values in those studies. Many attempts followed to standardize the parameters, create indices, and build new softwares to diagnose progression efficiently and accurately.

The softwares differ in terms of the number of used indices, correlating notable abnormal points, comparison with the fellow eye (inter-eye asymmetry), comparison with the normative data, and implementing artificial intelligence (AI).

In 2015, the consensus defined progression as “a consistent change in at least two of the following parameters where the magnitude of the change is above the “normal noise” of the testing system: (1) progressive steepening of the anterior corneal surface, (2) progressive steepening of the posterior corneal surface, and (3) progressive thinning and/or an increase in the rate of corneal thickness change from the periphery to the thinnest point.[3] However, this consensus failed to define the cut-off values!

The most commonly used softwares that proved to be of high sensitivity and specificity are “Belin ABCD Keratoconus Staging,”[180] the SCORE software “Radar Map,”[43] the epithelial map scoring system[181] and the biomechanical comparison display in Corvis.

When to start monitoring after corneal cross-linking?

The cornea shows changes after corneal cross-linking. The K readings usually increase during the first 3 months in comparison to the preoperative baseline, decrease back to the baseline during the second 3 months and keep decreasing slowly for at least 1 year.[182,183,184,185,186,187] In addition, the cornea thins by 30–50 µm during the first 3 months and increase back to the baseline during the following year.[188,189,190,191,192,193,194,195,196]

Due to the above changes, it is not recommended to check the progression of the disease or failure of the procedure 6 months after the operation.

Challenges in Keratoconus

Despite the advancements in diagnostics and management modalities, there are still challenges and areas of hard work to be done.

Pediatric keratoconus

The disease has been reported in the pediatric population as early as age 4, with aggressive progression.[197] Moreover, children were shown to have a more advanced stage at diagnosis, with 27.8% being stage 4 versus 7.8% of adults.[198] That is because keratoconus in children usually progresses more rapidly than in adults, with subsequent deterioration of vision, worsening of myopia and irregular astigmatism, and inefficient vision with glasses and/or contact lenses.[38]

Diagnosis of pediatric keratoconus is challenging, especially at young ages when using diagnostic devices might be difficult due to the child's uncooperation. Therefore, other simple tools can lead to early diagnoses, such as using the retinoscopy to detect the scissoring reflex,[199] changes in the glasses’ prescription in comparable periods, unusual astigmatism, anisometropia, suboptimal and best-corrected visual acuity. Asymmetric astigmatism is a common finding in keratoconus.[200]

Even when the patient cooperates with diagnostic devices, a reasonable, skillful interpretation of the tomography is essential to rule out false findings due to active allergic conjunctivitis, vernal keratoconjunctivitis, dry eye, and eye rubbing habits. Such pathologies must be adequately treated before putting the child on the device.

Another challenge in the pediatric population is corneal cross-linking. The epi-off protocols are still the gold standard. However, they may bear the risk of infection besides the pain, especially in uncooperative children. The epi-on protocols were proposed as alternatives despite their shallow and transient effect.

Determination of refraction

It is challenging, and the more advanced the disease, the more complex the refraction. Several reasons are behind that, irregular astigmatism, the method of refraction, inter-observer, and intra-observer variation, association with dry eye and punctate erosion, corneal transparency, and diurnal fluctuation of corneal shape.

A good refraction can be obtained by careful examination, sufficient time, and using different tools, such as the cross-cylinder lens, slit lens, and fan chart.

Biometry

Biometry is challenging in ectatic corneal diseases. Despite the significant advancement in biometry formulas, there is still a debate in the answers to three questions: What is the best formula? Which K-reading to consider? And what is the best suitable type of IOL? That is because corneal measurements are unreliable, there is usually a hyperopic outcome, pre- and post-operative refraction is not exact to judge, and sometimes the progression of the disease.

The economic burden

Keratoconus disease has always been an economic burden on the personal and societal levels for the following reasons. First, in some regions, the disease incidence is relatively high. The affected age is the young population. The availability of treatment is challenging in some areas. The affordability of medicines is a big issue when there are no government supporting programs, the patient has no insurance, or the insurance does not cover some types of treatment: the rehabilitation period and sick leave.

The personal burden

No question that the disease affects the quality of life.[201] It has been found that there is a proportional relationship between daily living activities and emotional well-being and the increasing severity of keratoconus.[202] It is well documented that keratoconus is associated with depression and anxiety due to the low quality of life, deterioration of vision day-by-day, and the concerns over disease progression and the potential need for penetrating keratoplasty.[203]

What do We Still Need from the Future?

Despite the massive advancement in diagnostic tools and management modalities, many questions remain to be answered and gaps to be filled. We still need the following:

1. The actual incidence of the disease

2. National programs for early detection

3. More investigations about specific genes

4. Simple and quick diagnostic tools for children

5. Standardized protocols for diagnosis and treatment

6. Make the treatment available and affordable

7. Psychological support to patients.

The Future of Keratoconus and Ectatic Diseases

In the coming 50 years, our expectation includes:

1. Genetic therapy to prevent the presentation of the disease

2. Implementation of AI in the diagnosis and planning of treatment

3. Medical cross-linking rather than UV based

4. New treatment modalities to modulate the cornea back to normal by noninvasive methods.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.