Continuing Education Activity

Keratoconus is a progressive bilateral corneal ectatic disorder characterized by cone-like steepening of the cornea, irregular stromal thinning, and significant vision loss. Keratoconus is a leading indication for corneal transplantation in Western countries and can be associated with other medical conditions. Although keratoconus was traditionally viewed as a noninflammatory disorder, recent studies suggest the involvement of potential inflammatory components. Patients affected by keratoconus experience decreased visual acuity due to irregular astigmatism and myopia, which results from corneal distortion and scarring.

The initial detection of keratoconus can pose challenges, as patients often experience difficulty achieving adequate visual correction with spectacles and encounter variable reductions in visual acuity, image distortion, and increased sensitivity to glare and light. Microscopic examination reveals thinning of the stromal layer, the presence of iron in the epithelial basement membrane, and ruptures in the Bowman membrane. Although keratoconus may present independently, it can also be associated with other medical conditions such as Down syndrome, Leber congenital amaurosis, and mitral valve prolapse.

Initial treatment options for keratoconus, personalized for each patient, include prescription spectacles, rigid gas-permeable contact lenses, and collagen cross-linking, which, if administered early, may slow or halt disease progression. In advanced cases where contact lenses prove ineffective, keratoplasty may be required as a further intervention. This activity delves into the etiology, epidemiology, pathophysiology, diagnosis, and management of keratoconus, emphasizing early detection of the condition. This activity also provides healthcare professionals with essential knowledge and tools to mitigate morbidity and enhance the overall quality of life for affected patients.

Objectives:

• Identify early signs and symptoms of keratoconus during routine eye examinations.

• Screen at-risk individuals, including those with a family history or predisposing factors, for keratoconus using appropriate diagnostic tests.

• Select appropriate advanced diagnostic techniques and management options based on individual patient factors to accurately diagnose and stage keratoconus.

• Collaborate with multidisciplinary healthcare professionals to coordinate comprehensive care plans and optimize patient care and outcomes.

Introduction

Keratoconus is a progressive bilateral corneal ectatic disorder characterized by cone-like steepening of the cornea. This disorder is one of the leading indications for corneal transplantation in Western countries and can be associated with other medical conditions. Keratoconus typically manifests during puberty or early adulthood, leading to irregular stromal thinning. This results in a cone-like bulge or protrusion and significant vision loss.[1][2] 

Keratoconus is derived from the combination of the Greek words kéras ("cornea") and conus ("cone"). During the early 1700s and 1800s, European eye specialists observed several aspects of keratoconus, such as its appearance, characteristics, and impact on vision. However, it was in 1854 that Dr. John Nottingham, a British physician, offered comprehensive insight into the condition. His work was pivotal in distinguishing keratoconus from other corneal shape abnormalities.[3]

Optical effects of keratoconus include a significant and variable reduction in visual acuity, image distortion, and increased sensitivity to glare and light. The significant asymmetry reduces the ability of spherocylindrical spectacle lenses to correct vision adequately.[4] In modern medicine, keratoconus is recognized as a disorder that affects both eyes, although often with uneven severity, leading to gradual thinning and curvature of the cornea. Patients with keratoconus commonly experience decreased visual acuity due to irregular astigmatism and myopia, which results from corneal distortion and scarring. Keratoconus may remain subclinical and be classified as slightly asymmetric oblique astigmatism. 

Contrary to the traditional notion that keratoconus is unrelated to inflammation, recent research suggests a connection with alterations in inflammatory substances, implying potential inflammatory changes in affected eyes. More prevalent in individuals with a family history of keratoconus, the condition may present independently or alongside other vision or general health conditions.[5] Although keratoconus is a bilateral disease, symptoms may be more pronounced in one eye than the other. The manifestation and progression of the disease exhibit considerable variability. In severe cases, keratoconus may lead to the development of acute corneal hydrops.[6] 

Progression typically ceases by the fourth decade of life. Treatment primarily focuses on vision correction and prevention of disease progression. Early treatment options for progressive keratoconus include corneal collagen cross-linking, which may help slow or halt the disease progression. Many patients manage the disease with the use of rigid gas-permeable contact lenses. In contrast, a minority of patients may eventually require corneal transplantation.

Etiology

The etiology and pathogenesis of keratoconus need to be clearly understood.[7] However, studying keratoconus is challenging due to the absence of acceptable animal models, the rapid degradation of human specimens, and the inadequate numbers of healthy human control groups. Patients with keratoconus typically exhibit lower collagen content in their corneas compared to normal. The progression of keratoconus involves a complex interplay of destructive and regenerative processes.[8] 

Risk Factors

Although the exact etiology and pathophysiology may not be understood, several risk factors are recognized as predisposing individuals to developing keratoconus, as mentioned below.

Systemic conditions: Certain systemic conditions heighten the risk of keratoconus, including Down syndrome, Ehlers-Danlos syndrome, osteogenesis imperfecta, Leber congenital amaurosis, and Noonan syndrome.[1][9] 

Environmental factors: Some studies reveal an association between keratoconus and certain environmental conditions such as atopic disease, asthma, and hay fever.[1][9] 

Eye rubbing: Persistent eye rubbing appears to either cause or exaggerate keratoconus.[10][11] In individuals with a genetic predisposition, persistent eye rubbing and wearing hard contact lenses may induce mechanical trauma, potentially contributing to the progression of keratoconus.[12] This mechanical alteration could be associated with keratocyte changes toward a repair phenotype in response to rubbing-induced trauma.[2][13] Although previous associations between wearing rigid contact lenses and the development of keratoconus exist, it is unlikely that wearing contact lenses alone is the sole cause of keratoconus.  

Family history: Individuals or their family members, especially first-degree relatives, with a history of keratoconus, have a significantly elevated risk of developing the condition. These individuals are estimated to have a 15 to 67 times higher propensity of developing the condition compared to individuals without such a familial history.[14] While most patients with keratoconus present with a sporadic form of the disease, 90% of patients with familial keratoconus display an autosomal dominant inheritance with reduced penetrance. The remainder typically exhibit an autosomal recessive pattern, particularly in families with children of consanguineous parents. Researchers have identified multiple genetic loci associated with the development of familial keratoconus.[15]

Advanced corneal topography enables the identification of asymptomatic individuals, broadening the scope of familial-related cases beyond previous estimations. The development of keratoconus has been linked to 73% or 16 out of 22 human chromosomes. However, only one confirmed keratoconus locus, 5q21.2, has been identified through various linkage studies, suggesting a polygenic nature where multiple affected genes may contribute to its onset.[16] Studies targeting essential candidate genes such as VSX1 and SOD1 have not yielded definitive outcomes, suggesting that specific mutations, coupled with other gene variants known as modifier genes, may be crucial in manifesting keratoconus traits. Keratoconus likely arises from a multifactorial etiology, with both genetic and environmental factors contributing to its development.[15]

Epidemiology

Keratoconus typically manifests during adolescence or early adulthood, progressing into the fourth decade of life.[17] The prevalence of the condition in the general population varies between 50 and 230 per 100,000 individuals.[18][19][20] A recent meta-analysis involving over 7 million lives across 15 countries reports a prevalence of approximately 138 per 100,000 individuals.[21] Specific gender predilection does not exist. Although some studies suggest a higher incidence among individuals of Asian descent from the Indian subcontinent, others do not support this observation. Notably, Black and Latino patients appear to have a 50% higher likelihood of developing keratoconus compared to White patients.[22]

More specific and sensitive diagnostic tools now allow for the detection of subtle cases of keratoconus. New international studies suggest a prevalence as high as 1 in 375 in some populations.[2] Within medical investigations conducted in hospitals and clinics, the occurrence of keratoconus is notably high in the Middle East, particularly in Saudi Arabian adolescents, where it reaches 4790 cases per 100,000 individuals.

A positive family history or familial transmission is evident in at least 6% to 8% of reported cases.[23] Among individuals with Down syndrome, the incidence of keratoconus ranges from 0.5% to 15%.[24] Additionally, keratoconus is prevalent in up to 30% of individuals aged 15 and above with Leber congenital amaurosis and in 58% of patients with mitral valve prolapse.[25]

Pathophysiology

Although keratoconus was traditionally regarded as a noninflammatory disorder, recent studies indicate the potential involvement of inflammatory components. Classic signs of inflammation, such as heat, redness, swelling, and pain, are typically absent except for significant vision loss.[26] However, recent research has uncovered the presence of inflammatory cytokines in keratoconus.

Cellular Aspects of Keratoconus

Keratoconus is associated with altered matrix stiffness, a key regulator of cellular physiology. This change may explain connections between the disease's mechanical and biochemical aspects, affecting cell division, migration, and other processes.[27] 

Various proteins undergo structural and functional modifications,[28] including the wingless-related integration site (WNT) and Hedgehog (HH) proteins, which are known regulators of developmental processes, influencing stem cell differentiation. Dysregulation of the WNT and HH signaling pathways can lead to the development of various diseases. A recent study highlights the crucial role of HH and WNT pathways in maintaining the integrity and structure of corneal endothelial cells. Knocking down WNT7A results in the transformation of corneal epithelial cells into epidermal-like cells, which adversely affects corneal transparency. Furthermore, specific genetic variants in the WNT10A and WNT7B genes have been associated with keratoconus, emphasizing the functional involvement of WNT pathway components in the pathogenesis of the condition.

Proteins and Pathophysiology

A comprehensive study identified a total of 117 proteins and protein groups that have a crucial role in developing keratoconus. These changes manifest through alterations to the corneal structure and composition, including modifications in collagen content and programmed cell death within the stroma.[29] Altered expression of cellular adhesion molecules may potentially contribute to the disturbances in corneal layer structure and integrity observed in keratoconus. Notably, CD34, a cellular adhesion molecule and hematopoietic stem cell marker, is significantly reduced in keratoconus corneal keratocytes. In addition, desmoglein 3 (DSG3), a desmosomal cadherin, exhibits increased expression in samples associated with keratoconus.

Cellular adhesion molecules such as laminin and fibronectin, which are essential for binding basal epithelial cells to the basement membrane, demonstrate overexpression in scarred regions of the anterior keratoconus cornea. This upregulation of cellular adhesion molecules in keratoconus may signify downstream events in the wound healing cascade, suggesting a role for dysregulated wound healing processes in the pathogenesis of keratoconus. Deng et al proposed that keratoconus changes may involve a wound healing–like process, where an unregulated repair mechanism could contribute to disease development.[30]

Oxidative Stress and Antioxidants

Keratoconus is characterized by an imbalance in oxidative stress markers and antioxidants, altering the redox balance in tears, cornea, aqueous humor, and blood. This imbalance leads to elevated levels of oxidative stress markers and reduced antioxidants, thereby contributing to the progression of the disease. Notable aspects of this imbalance include increased reactive oxygen and nitrogen species and a decline in total antioxidant capacity and certain minerals.[31]

A vital detoxifying enzyme potentially associated with keratoconus is aldehyde dehydrogenase 3 (ALDH3), which facilitates the reversible oxidation of alcohols to aldehydes. ALDH3 directly absorbs UV light and eliminates cytotoxic aldehydes from UV-induced lipid peroxidation. Individuals with keratoconus exhibit reduced expression of ALDH3 in their corneal tissue. Oxidoreductases involved in electron transfer within cells are identified as possible sources of superoxide anions. Among these, nicotinamide-adenine dinucleotide phosphate (NADP) dehydrogenase, which is a specific oxidoreductase, catalyzes the generation of reactive oxygen species. Research suggests that acute exposure of keratinocytes to UV radiation can activate NADPH dehydrogenase, leading to rapid production of reactive oxygen species and potentially influencing the progression of keratoconus through UV light exposure. In addition, oxidative stress has adverse effects on mitochondrial DNA.[7]

In patients with keratoconus, the weakening and breakdown of collagen fibrils result in fragile and disorganized corneal structures. These alterations gradually cause a shift in the corneal curvature, culminating in cone formation. Furthermore, genetic variations in specific antioxidant enzymes may independently predict the severity of keratoconus, underlining the role of oxidative stress in the disease.[32]

Enzymatic Activity and Corneal Thinning

Individuals with keratoconus have a marked increase in degradative enzymes and a decrease in their inhibitors, leading to corneal thinning. Increased proteinase activity promotes a degradation process within the cornea.[33]

Keratoconus Corneal Damage Gradient

In keratoconus, the central part of the cornea, known as the cone, sustains the most damage compared to the periphery. At the microscopic level, keratocytes penetrate specific layers, and increased enzyme levels contribute to structural damage, providing evidence for this phenomenon.[34]

Histopathology

The cornea is the outermost avascular and transparent part of the eye, consisting of the epithelium, Bowman layer, stroma, Dua layer, Descemet membrane, and endothelium. Histopathological structural changes are observed in all layers except the endothelium. Advanced keratoconus often presents with breaks in the Bowman layer. In addition, degeneration of basal epithelial cells and epithelial infiltration into the Bowman layer may occur.[35]

Stromal histopathology can be affected as well, which is mainly characterized by scarring and opacity, compaction and loss of fibrils arrangement (stromal striae), decrease in collagen lamellae density, presence of normal and degenerating fibroblasts in addition to keratocytes, and fine granular and microfibrillar material associated with the keratocytes.[1][2][36]

Keratoconus includes a wide range of alterations in the cornea. An overview of these changes allows us to categorize them based on specific corneal regions and disease severity.[28]

Changes in the Corneal Layers

General changes:

• Anterior cornea: Particularly affected in early stages of keratoconus.

• Central and peripheral cornea: Central cornea changes are more distinct compared to peripheral regions.

• Endothelium controversy: The relation of the endothelium to keratoconus is debated among researchers. Several studies report no changes to endothelial cells during keratoconus progression.[8]

Histopathological changes:

• Primary affected areas: Corneal epithelium, anterior limiting lamina or the Bowman layer, and stroma.

• Least affected areas: Posterior limiting lamina or the Descemet membrane.[37]

Epithelial changes:

• Thinning: This is a common change observed, although not universally reported.

• Thickening: Associated with breaks in the anterior limiting lamina.

• Apoptosis theory: Epithelial thinning may occur due to cell death from chronic injuries.

• Non-uniformity: Epithelial damage may lead to basal cell degeneration, reduced density, and irregular arrangement.[38] 

Corneal Nerve Visibility

• Changes with severity: Increased visibility is a characteristic sign of keratoconus. Decreased innervation, sensation, and nerve cell density correlate with increased disease severity.

• Abnormal architecture: Distinctive changes in nerve structure, thickness, and layout are observed.[39] The subbasal corneal nerve plexus has a fragmented plexus. 

Anterior Limiting Lamina Breaks

This layer is also known as the Bowman layer and is typically acellular. Patients with keratoconus may present with cellular components within the Bowman layer. Breaks in the anterior limiting lamina, commonly observed in keratoconus, often manifest with characteristic Z-shaped interruptions.[37]

Corneal Stromal Alterations

• Architectural compromise: This affects transparency, reduces lamellae, and includes collagen lamellae changes.

• Rearrangement: In keratoconus, significant changes occur in the collagen lamellae of the anterior stroma compared to a normal cornea. The lamellae in keratoconus are wider and form a smaller angle with the Bowman layer. The affected cornea experiences splitting of stromal lamellae into multiple bundles of collagen fibrils, leading to the loss of anterior lamellae. In addition, downregulation of the ACTB gene, encoding β-actin, is observed in keratoconus, suggesting a potential contribution of reduced stromal keratocytes to the decreased expression of β-actin. Consequently, this decreased expression of β-actin may destabilize the cytoskeleton, contributing to stromal thinning and weakening in keratoconus.

• Ectasia and thinning: These are associated with lamellar splitting and other structural modifications.

• Appearance: Specific examination techniques reveal dark and light bands indicative of stress.[28]

Posterior Limiting Lamina Deformities

• Occurrence: Breaks and deformities are more common in severe cases.

• Corneal hydrops: This involves rupture in the Descemet membrane, allowing aqueous humor to enter the corneal epithelium and stroma. In addition, it represents a severe complication that may necessitate surgical intervention.[36]

Keratoconus involves a complex interplay of changes across different layers of the cornea. Scientific comprehension of these alterations is continuously evolving, with various studies sometimes offering contradictory evidence. The progression of the condition can lead to diverse visual outcomes, necessitating personalized treatment strategies tailored to each patient's distinct manifestations and severity.[40]

History and Physical

Keratoconus typically manifests during puberty or early adulthood and often presents with symptoms such as blurry vision or a sudden decline in visual acuity. An initial indicator may be the inability to correct the patient's visual acuity to 20/20. Symptoms persist and progress until the fourth decade of life. While initial correction with spectacles may be possible, patients may develop irregular astigmatism as the disease advances, necessitating contact lenses for refractive correction.

Although most patients with keratoconus commonly exhibit prevalent clinical signs such as corneal protrusion and a scissors reflex, characterized by 2 bands observed on retinoscopy moving toward and away from each other, the development and association of these signs with the severity of the disease can vary significantly. 

Although keratoconus is frequently associated with substantial myopia, this alone is not a diagnostic criterion. The primary manifestations include irregular corneal astigmatism and localized stromal thinning. Clinicians must focal thinning from overall corneal thinness. Symmetrical significant astigmatism is not indicative of keratoconus; rather, astigmatism associated with keratoconus tends to be highly asymmetrical. Both corneal thinning and asymmetrical astigmatism typically occur in the region of corneal protrusion, often situated in the inferotemporal area.[41][42][43]

Key clinical features indicative of keratoconus include:

• Difficulty with visual correction: Progressive myopia and astigmatism contribute to challenges in spectacle correction and contact lens fitting as the disease advances.

• Asymmetric visual complaints: Although keratoconus typically affects both eyes, it may present with asymmetric symptoms, with an eye more severely affected. About 41% of patients report unilateral disease at the time of diagnosis. 

• Münson sign: Advanced keratoconus may result in the Münson sign, characterized by a v-shaped lower eyelid indentation during downgaze due to a prominent corneal cone.[2][44]

• Fleisher ring: This brown-colored staining, best visualized with the cobalt blue filter on the slit lamp, is composed of iron from the tear film that flows around the base of the cone. Fleisher rings serve as a subtle early indicator of keratoconus.[2][44][45]

• Vogt striae: These vertical stress lines are formed by compression of the Descemet membrane and are identifiable in the cornea's thinnest area, particularly at the posterior stroma and the Descemet membrane. Gentle pressure applied to the cornea causes these striae to disappear.[2][44][45]

• Rizzuti sign: This sign manifests as a bright reflection from the nasal area of the limbus when light is directed to the temporal limbal area.

• Central and inferior paracentral corneal thinning: Early manifestations of keratoconus include central and inferior paracentral corneal thinning, accompanied by mild cone formation and protrusion.

• Corneal hydrops: This condition occurs in advanced stages and may lead to sudden, painful vision loss and photophobia in patients with keratoconus. Corneal hydrops affect approximately 3% of individuals with keratoconus, with an average onset around age 25, and men potentially experiencing a higher occurrence. Corneal hydrops result from tears in the Descemet membrane and endothelial dysfunction.[2][44][46] Specific risk factors, such as certain allergies and the overall severity of the disease, have been associated with the occurrence of hydrops in keratoconus.[36]

• Corneal scarring: This condition occurs as a result of spontaneous breaks in the anterior limiting lamina as the cornea thins in keratoconus. Nearly 20% of patients with keratoconus have corneal scarring. 

Evaluation

The initial diagnosis of keratoconus in a patient involves careful measurement of the patient's refraction. Clinicians then use additional diagnostic tools such as slit-lamp biomicroscopy, corneal topography, corneal tomography, and pachymetry to evaluate the condition further.[41][42][43] Corneal topography and tomography are particularly sensitive and effective in detecting early signs and evidence of keratoconus. These techniques are conducive even without Vogt striae and Fleischer rings.

Corneal Evaluation and Diagnostic Techniques

Slit-lamp findings: Slit-lamp examination findings in the early stages of keratoconus may initially appear normal. However, as the disease advances, common findings observed include Fleischer rings, Vogt striae, central and inferior paracentral corneal thinning, and corneal scarring.

Corneal topography and tomography: Corneal topography evaluates the anterior curvature of the cornea using Placido disk patterns or mires reflected off the tear film of the anterior cornea, which are then converted to color scales. Meanwhile, corneal tomography includes corneal thickness and posterior curvature, providing a comprehensive assessment of the overall corneal shape. In 1938, Marc Amsler, a professor of ophthalmology, pioneered the use of Placido topography for diagnosing and classifying keratoconus. Topography can detect subtle corneal surface irregularities even before identifying other clinical or biomicroscopic signs. Patients with early keratoconus appear normal on slit-lamp examination. Thus, corneal imaging is crucial in the early detection of suspected keratoconus patients, as well as in monitoring disease progression and guiding treatment decisions.[47] 

Common topographic patterns include:

• An asymmetric bowtie, with or without inferior steepening

• Skewed radial axes

• A superonasal flat area of decreased steepening

• Patients rarely present with central astigmatic changes

• Pellucid marginal degeneration typically shows an inferior lobster claw-like map [48] 

Anterior segment optical coherence tomography (OCT) has become increasingly integral in diagnosing keratoconus. By utilizing OCT, meridional cross-sections or B-scan images of the cornea can be obtained, unveiling both the asymmetric corneal thinning and posterior curvature asymmetry.[49] The recent application of spectral-domain OCT as a corneal pachymetry tool has further revealed corneal thickness asymmetry associated with keratoconus.[50]

The examination of corneal epithelial thickness distribution, facilitated by the latest Fourier-domain OCT devices, proves to be a highly sensitive and specific indicator for keratoconus.[51] A noteworthy characteristic of the epithelium is its variable thickness, acting as a mask for irregularities in underlying stromal thickness. Consequently, it can be thinner, less than 20 µm, over the most protruding part of the cornea, or thicker, greater than 70 µm, over the flatter areas.[52] If not considered, this distribution of epithelial thickness can create a misleading impression of a relatively uniform corneal thickness, concealing early indications of irregularities in corneal thickness detected by other devices such as Scheimpflug imaging. In addition, this effect can also reduce the extent of irregularity in corneal curvature as assessed by Placido topography.

Retinoscopy: Retinoscopy reveals a scissoring reflex attributed to irregular astigmatism—a typical observation in keratoconus.

Keratometry: Keratometry involves projecting a circular mire onto the cornea and analyzing the size and shape of its reflected image. In patients with keratoconus, irregular mires and progressive corneal steepening are commonly observed.

Pachymetry: Pachymetry involves measuring corneal thickness using a corneal pachymeter. While optical pachymetry, conducted with a device attached to the slit lamp, is commonly used, it is less precise compared to ultrasonic pachymetry, which relies on the speed of sound in the normal cornea. These devices not only measure corneal curvature but also provide detailed pachymetry maps that identify corneal thinning areas. The regions of most significant thinning correlate with the location of maximum corneal steepening.[53] Furthermore, these devices can produce anterior and posterior corneal surface elevation maps. An asymmetry in posterior surface elevation is a specific and sensitive indicator of keratoconus.[6] 

Examination of Corneal Surface Areas

The eye afflicted by keratoconus exhibits a significant difference in the ratio between the anterior and posterior regions of the cornea compared to the unaffected eye. This discernible distinction, determined through OCT or Scheimpflug imaging, likely arises from aberrant alterations on both corneal surfaces. This measurement holds the potential to accurately distinguish mild keratoconus cases from normal eyes, exhibiting a specificity of 96% and sensitivity of 92%.[47]

Analysis of Corneal Structure

Over the last decade, an increasing focus on exploring corneal structures developed for detecting keratoconus. This interest is due to the advent of new instruments such as the Ocular Response Analyzer (Reichert Ophthalmic Instruments, Inc., Buffalo, NY, USA) and CorVis Scheimpflug Technology (OCULUS, Wetzlar, Germany). These instruments evaluate corneal properties based on their response to deformation. As identified through laboratory analyses, these altered properties observed in keratoconus are considered potential markers for early detection of the condition. However, these properties only partially correlate with corneal thickness, and their efficacy in distinguishing normal eyes from early or advanced keratoconus remains uncertain, particularly following corneal surgery.

Current instruments face limitations in capturing data from the central cornea, potentially leading to inaccuracies in representing affected areas in keratoconus. Although these parameters may lack reliability in distinguishing normal eyes from early-stage keratoconus, they could contribute to predicting disease progression with the development of more appropriate metrics. Emerging techniques, such as optical coherence elastography or OCT speckle analysis, hold promise in identifying subtle corneal changes for earlier detection of keratoconus.

Although physical symptoms and examinations are essential, corneal topography remains a primary tool for detecting corneal diseases or structure.[54] Combining different measurements, such as pachymetry and corneal aberration data, along with topography, enhances diagnostic accuracy, especially in early cases. Emerging imaging techniques such as corneal tomography further enhance sensitivity and specificity in detecting corneal changes. In addition, the ongoing development of machine learning algorithms utilizing routine clinical parameters holds promise for identifying the early stages of the disease, thus improving both early detection and ongoing management of keratoconus.[55]

Treatment / Management

The treatment approach for keratoconus is personalized, aiming to correct vision and halt disease progression.[3] The available management options vary based on disease stage and progression. While stabilizing the condition, vision correction takes precedence, yet preventing further advancement remains paramount for all patients.[56]

Nonsurgical Management

Mild keratoconus: Early disease management involves prescribing eyeglasses to patients for mild keratoconus. Spectacles are maintained until they no longer adequately support the patient's visual needs.[57]

Moderate keratoconus: As the disease progresses, visual acuity worsens due to increased astigmatism. At this stage, many patients require contact lenses for effective vision correction. Estimates show that nearly 90% of patients with keratoconus use contact lenses to treat the condition. Typically, rigid gas-permeable corneal lenses are commonly the preferred choice for patients with keratoconus, as the rigid structure and surface of these lenses eliminate corneal irregularities and promote tear formation behind the lens. However, patients with irregular or elevated scarring may find them intolerable.

Rigid gas-permeable lenses can pose challenges in keratoconus, and patients may experience intolerance and allergic reactions such as giant papillary conjunctivitis, corneal abrasions, and neovascularization.[58] Alternative options include hybrid lenses with a rigid center and soft periphery, scleral lenses, or piggyback lenses, where patients prefer combining a rigid lens over a soft lens.[59][60] Scleral lenses, filled with saline before insertion, rest on the sclera without contacting the cornea, offering improved comfort and reduced scarring. 

Specific contact lens fitting techniques

• Apical clearance: The lens vaults the corneal apex, bearing on the paracentral cornea.[61]

• Apical touch: Provides good vision but may increase scarring.

• Three-point touch: This design provides support at 3 points, has a higher success rate, and may be associated with corneal flattening. Different designs and aspherical models, such as multi-curve, are available with limited success in reverse geometry designs.

Another alternative option is the Prosthetic Replacement of the Ocular Surface Ecosystem or PROSE (BostonSight, Massachusetts, United States). This system utilizes computer- and software-designed custom prosthetic devices. A study demonstrates superior and faster visual acuity improvement compared to patients undergoing corneal transplantation.[62] 

Severe keratoconus: Scleral lenses may be necessary for patients with severe keratoconus or those who cannot tolerate conventional lenses. When contact lenses prove ineffective, corneal surgical interventions may be necessary.[63][64]

Surgical Management

Strengthening the cornea through collagen cross-linking: Corneal collagen cross-linking with riboflavin technique helps halt the progression of keratoconus by increasing the mechanical strength and stability of the cornea. The procedure involves removing a 6- to 7-mm central portion of the corneal epithelium and applying a riboflavin solution, followed by UV-A light exposure at a specific wavelength. This process activates riboflavin, fostering bond formation in the corneal stroma. Due to potential toxic effects, this procedure is unsuitable for corneas <400 µm, patients with active or a history of herpes simplex virus keratitis, or corneal hydrops. Early implementation is necessary.

Patients must avoid rubbing their eyes to help control the disease. Common adverse effects are transient corneal haze, keratitis, corneal edema, pain, and blurred vision, typically resolving within 6 months. Although corneal collagen cross-linking may not directly enhance vision quality, early intervention can significantly impact keratoconus management success. Biomechanical stabilization provided by corneal collagen cross-linking can mitigate future vision loss by addressing corneal irregularity and thinning, especially with early intervention.

Standard corneal collagen cross-linking treatment, known as epi-off corneal collagen cross-linking, has shown efficacy in improving vision and halting disease progression in many long-term studies. Corneal collagen cross-linking is effective in both children and adults with progressive keratoconus, although individual outcomes vary. Despite surgery, most patients still require contact lens correction. While epi-on corneal collagen cross-linking methods are less painful and may reduce some complications, they may be less effective in certain aspects. Furthermore, corneal collagen cross-linking has been successfully combined with other surgical approaches.[34]

Refractive surgery: Refractive surgical techniques also manage keratoconus after stabilization. Refractive surgeries include 3 main types, as listed below.[65]

• Corneal refractive surgeries: Photorefractive keratectomy uses a laser to reshape the front central portion of the cornea, offering some success in managing keratoconus. This surgery often accompanies corneal collagen cross-linking. Intracorneal ring segments are another option for patients with mild-to-moderate keratoconus. Thin, semicircular plastic inserts are implanted into the mid-corneal layers to flatten the cornea, reduce astigmatism, improve visual acuity, and potentially decrease the necessity for corneal transplantation.[66] Previously used techniques such as radial keratotomy and thermal therapy are now less common due to their limited success.[67]

• Intraocular lenses: Intraocular lenses, including phakic and pseudophakic ones, are implanted to improve vision in keratoconus patients, often in combination with other methods. Toric intraocular lenses are considered by surgeons in stable, mild-to-moderate cases with low irregular astigmatism.[68] 

• Combination techniques: Combining several surgical approaches, including double and triple procedures, yield varying degrees of success.

Corneal transplants: A corneal transplant or keratoplasty is the treatment of choice when contact lenses are no longer effective and fail to provide adequate vision correction. About 10% to 15% of individuals with keratoconus eventually require this procedure.

• Full-thickness corneal transplant: Penetrating keratoplasty or full-thickness keratoplasty involves removing the entire host cornea and replacing it with donor tissue.[69] This procedure boasts a success rate exceeding 90%, with many patients achieving 20/40 or better visual acuity. Approximately 15% of patients do not require visual correction afterward, while 40% need spectacles and 26% rely on contact lenses. A severe adverse effect, graft rejection, occurs in 20% to 35% of cases within the first year and is treatable with corticosteroids. Astigmatism is a common issue post-surgery, which is addressable through various methods, such as contact lens correction, refractive surgery, relaxing incisions, wedge resection, and compressive sutures.

• Deep anterior lamellar keratoplasty: Deep anterior lamellar keratoplasty is a surgical method that involves replacing the front layers of the diseased cornea with donor tissue while preserving the patient's back corneal layers. Advantages include faster recovery, quicker vision restoration, and fewer postoperative complications. While patients receiving full-thickness transplants tend to achieve clearer vision, they face higher risks, such as loss of cells from the inner cornea layer and transplant rejection, compared to those undergoing deep anterior lamellar keratoplasty.[70] This procedure is less commonly used in the United States.

• Anterior limiting lamina transplantation: This technique involves placing a layer from the front part of the donor cornea either within or onto the patient's cornea. The procedure may stabilize progressive ectatic corneal changes in eyes with keratoconus, which are too steep or thin for UV corneal cross-linking or intracorneal ring segments. By doing so, patients avoid or postpone penetrating keratoplasty or deep anterior lamellar keratoplasty. Early results indicate that this technique can halt progression and maintain vision with contact lenses for up to 5 to 7 years.[71]

Intrastromal stem cell transplantation: Researchers are exploring various ways to rejuvenate or replace the corneal layers in patients with keratoconus. Experimental methods involve injecting stem cells directly into the cornea or embedding them with supportive structures to rejuvenate or replace corneal layers in keratoconus patients. Experimental methods also include combining stem cells with corneal tissue. Further studies are necessary to validate these techniques.[72]

Differential Diagnosis

The potential differential diagnoses for keratoconus include various conditions, including contact lens complications, contact lens—induced corneal warpage, corneal ectasia, ectasia due to refractive surgery, diplopia, interstitial keratitis, keratoglobus, pellucid marginal degeneration, posterior keratoconus, Terrien marginal degeneration, and corneal scarring. Congenital disorders such as congenital hereditary endothelial dystrophy, other corneal dystrophies such as Fuchs endothelial dystrophy, and infectious or non-infectious keratitis are also included in the potential differential diagnoses for keratoconus.[73]

Pertinent Studies and Ongoing Trials

Assessment of Corneal Light Distribution

Recent innovations have enabled modeling the distribution of corneal light intensity using Scheimpflug imaging. This technique analyzes the microscopic properties of the cornea after wearing contact lenses, distinguishing between keratoconic and non-keratoconic corneas under mechanical strain. Statistical analysis of these parameters reveals promising sensitivity ranging from 76% to 96% and specificity from 76% to 88% for detecting keratoconus. These percentages improve when combined with central corneal thickness measurements. Although this imaging method can identify the base of the cone, further research is necessary to determine its efficacy in early keratoconus detection and disease monitoring.[74]

Role of Artificial Intelligence

Over the last decade, artificial intelligence, incorporating machine learning and deep learning algorithms, has emerged as a valuable tool for automating the detection and categorization of keratoconus. When applied to corneal topography or tomography and OCT data, these artificial intelligence–driven algorithms have demonstrated high precision, often achieving sensitivity and specificity ratings surpassing 95%. Furthermore, specific techniques have effectively differentiated between different stages and types of keratoconus. Future applications may involve leveraging longitudinal corneal information to predict disease progression and identify cases that benefit from regular monitoring or early treatment.[75]

Staging

Identifying and classifying the symptoms and indicators of keratoconus poses significant challenges due to the diverse presentation of the disease. Despite the development of various categorization approaches, primarily focusing on factors such as corneal thinning, the curvature of the front and back of the cornea, and the location and shape of the cone, a universally accepted system for classifying keratoconus does not exist. Assessment methods evaluate optical and visual capabilities, including higher-order aberrations and visual acuity, alongside features such as scarring and Fleischer rings.

This section explores existing methods for assessing the severity of keratoconus, focusing on the following:

• The physical appearance of the cornea and the progression of the disease.

• Functions relating to optics and vision.

• Properties describing the corneal shape, such as index-based systems.[3]

Classification Based on Corneal Structure and Disease Progression

Morphological or Buxton classification: The Buxton classification, or morphological classification, categorizes keratoconus based on the form and location of the cone into oval, nipple, and globe keratoconus.

• Oval keratoconus impacts 1 or 2 areas of the cornea, typically the lower quadrant.

• Nipple keratoconus refers to a cone with a diameter of 5 mm or less in the central or near-central cornea.

• Globe keratoconus describes a condition where the cone involves more than 75% of the frontal cornea.[61]

Keratometric classification: This method categorizes keratoconus into 4 stages based on the intensity of central corneal power.

• Mild: <45 D.

• Moderate: Between 46 D and 52 D.

• Advanced: Between 53 D and 59 D.

• Severe: >59 D.[76]

Hom's classification: This approach categorizes keratoconus into 4 levels based on observable symptoms.

• Preclinical: No observable signs.

• Mild: Characterized by slight corneal thinning and a scissors reflex.

• Moderate: Marked by inferior visual quality and corneal thinning without scarring.

• Severe: Marked by the existence of scars, inconsistent refraction, and significant corneal thinning.[77]

Amsler-Krumeich classification: This classification is widely used in clinical settings and integrates several physical and clinical attributes related to keratoconus. However, this somewhat dated system must consider modern clinical data and technological developments. Some researchers characterize keratoconus as advancing if, within 1 year, one or multiple of the following changes occur.

• An increase in astigmatism of 1.0 D or more.

• Considerable adjustments in the direction of refractive axes.

• An increase of 1.0 D or more in the optical strength of the steepest corneal meridian.

• A reduction of 25 µm or more in the corneal thickness.[78]

Optical and Visual Function-Based Systems

The modifications associated with the progression of keratoconus extend beyond the anatomical and shape changes in the cornea. The disorder may also lead to a significant reduction in optical quality, characterized by increased eye distortions and, in some instances, a loss of corneal clarity, which impacts the quality of life in a patient.[3]

Alio-Shabayek system: Relying on the Amsler–Krumeich classification, this approach not only assesses corneal thinning and keratometry readings but also considers corneal scars and front corneal deviations to measure the severity of keratoconus.[78]

Keratoconus severity score: This scoring system grades the severity of keratoconus on a scale ranging from 0 (suspected) to 5 (severe). The score utilizes 2 corneal topographic indices along with the keratoconus topographical pattern and slit-lamp clinical indicators.[79]

RETICS classification: This framework incorporates corneal biomechanical parameters, including hysteresis and resistance factors, into the variables of optical and visual function, along with clinical symptoms.[80]

Belin ABCD grading system: This grading system rates the severity of keratoconus based on the following 4 factors.

• A: The front and rear corneal radius.
• B: The curve of the thinnest corneal location's 3.0 mm central zone.
• C: Slimmest corneal pachymetry.
• D: Best corrected distance visual acuity.[81]

Index-Based Systems Analysis

Researchers incorporate index-based approaches into multiple tools designed for evaluating corneal shape and identifying keratoconus. These approaches typically involve the combination of one or more variables for keratoconus detection, often using specific threshold values to distinguish between normal corneas, suspected cases of keratoconus, and clinically confirmed keratoconus.[82]

Prognosis

Keratoconus is a progressive eye condition characterized by the progressive thinning and forward protrusion of the cornea, which can result in vision impairment.[3] Prognosis varies among patients, with factors such as younger age and steeper keratometry measurements at diagnosis associated with a higher likelihood of progression. Progression is also associated with corneal scarring and a decline in visual acuity. Approximately 10% to 20% of patients may eventually require corneal transplantation, but early interventions, such as corneal collagen cross-linking, can slow or halt progression.[83] Early diagnosis and proper management are crucial, including regular monitoring and corrective lenses.[34] Data suggest that although progressive, the disease stabilizes over time in most patients.

Complications

Potential complications resulting from keratoconus include a range of ocular issues, including progressive myopia and astigmatism, corneal scarring, thinning, and hydrops. In addition, acute corneal swelling, increased sensitivity to light, intolerance to contact lenses, and decreased vision despite corrective measures may occur. Other complications include Vogt striae or stress lines in the deep corneal layers, corneal transplantation, glare and halos at night, apical scarring, and peripheral corneal neovascularization. In some cases, corneal transplantation may be necessary, and associated risks such as graft rejection and corneal haze are present. Furthermore, keratitis, corneal edema, pain, and blurred vision can develop after corneal collagen cross-linking.

Postoperative and Rehabilitation Care

A general overview of postoperative and rehabilitative care for patients with keratoconus undergoing surgical interventions is mentioned below. 

Corneal Collagen Cross-Linking

Postoperative care:

• Eye protection: Patients are often advised to use a bandage contact lens to protect their cornea.

• Medication: Patients are prescribed antibiotics and anti-inflammatory eye drops.

• Avoid rubbing: Patients should avoid rubbing their eyes to prevent further irritation or damage.

• Follow-up visits: Patients are strongly advised to schedule regular visits with an ophthalmologist to monitor the healing process and promptly detect any complications. 

Rehabilitation:

• Visual rehabilitation: Patients may require eyeglasses or special contact lenses to correct refractive errors as the cornea heals.

• Ongoing monitoring: Regular eye examinations must be conducted to monitor the progression of the condition and evaluate the effectiveness of treatment.[84] 

Corneal Transplant

Postoperative care:

• Eye care: Patients should wear an eye patch or shield and apply medicated eye drops to protect their eyes, prevent infection, and control inflammation.

• Regular monitoring: Patients should regularly schedule visits with an ophthalmologist, which is crucial for assessing the healing process and adjusting medications as needed.

• Activity restrictions: Patients should avoid heavy lifting and strenuous activities to prevent strain on the eye.

Rehabilitation:

• Gradual vision improvement: Patients should understand that vision improvement may take several months as the eye heals from the procedure.

• Visual rehabilitation: Prescription glasses or contact lenses may be necessary to aid in vision correction as the eye adjusts after the surgery.

• Long-term monitoring: Lifelong visits to an ophthalmologist and regular check-ups are crucial to detect and manage potential complications, such as graft rejection, ensuring ongoing eye health and optimal visual outcomes.[85]

Intacs

Intacs are small plastic ring-shaped semi-circular inserts placed in the cornea for reshaping.

Postoperative care:

• Eye protection: Patients should use an eye shield at night to protect the eye while sleeping.

• Medication: Patients must use antibiotics and steroid eye drops as prescribed by their doctor.

• Avoid water exposure: Patients should avoid exposing their eyes to water to prevent infection.

Rehabilitation:

• Visual rehabilitation: Patients may still require eyeglasses or contacts for vision correction.

• Regular monitoring: Patients should schedule regular visits to an ophthalmologist to ensure proper healing and alignment of intacs.

Postoperative care and rehabilitation for patients with keratoconus vary depending on the type of surgical intervention. A personalized approach that includes close monitoring, medication management, eye protection, and visual rehabilitation is critical for successful recovery and long-term visual improvement. Collaboration between the patient and the eye care team, including an ophthalmologist, optometrist, and other rehabilitation specialists, is essential for optimal outcomes.[86]

Consultations

When a patient presents with a history and clinical findings indicative of keratoconus, they must undergo a comprehensive examination by an ophthalmologist, preferably including a cornea specialist, to assess their condition accurately and plan appropriate treatment. The stage of keratoconus guides the decision-making process between opting for conservative management or considering surgical intervention.[87] 

Deterrence and Patient Education

Deterrence Strategies

• Regular monitoring: Regular eye examinations are crucial in detecting keratoconus in its early stages, allowing for prompt intervention.

• Lifestyle modifications: Patients are advised to avoid eye rubbing and adopt protective measures such as wearing sunglasses outdoors, which can reduce the risk of disease progression.

• Family screening: Family members of affected individuals should receive screening to identify potential cases early on. 

• Avoiding contributing factors: Identifying and avoiding potential contributing factors, such as prolonged eye strain or improperly fitting contact lenses, may deter the progression of the disease.[87]

Patient Education

• Understanding the condition: Providing comprehensive information about keratoconus, its symptoms, and the importance of regular monitoring empowers them to take an active role in their care.

• Treatment options: Ensuring patients are well-informed about available treatment options, including corrective lenses, collagen cross-linking, and surgical interventions, enables them to make informed decisions tailored to their needs.

• Self-care techniques: Educating patients on proper eye care practices, such as avoiding eye rubbing and correctly handling contact lenses, is vital in minimizing risk factors.

• Emotional support: Providing psychological support and connecting patients with support groups can be highly beneficial, as keratoconus can affect a person's quality of life.

• Compliance with treatment: Encouraging patients to adhere to their prescribed treatment plans, attend follow-up appointments, and follow medical recommendations diligently is essential for optimal management of keratoconus.

Deterrence and patient education are pivotal in managing this progressive eye disorder. Through regular monitoring, lifestyle modifications, and comprehensive patient education, the progression of the disease can be slowed or halted, contributing to a higher quality of life. Collaborative care involving eye care specialists, primary care physicians, and patients forms the cornerstone of effective keratoconus management.[3]

Pearls and Other Issues

Pearls

• Early detection: Detecting the condition in its early stages using topography and tomography can help manage and slow disease progression.

• Treatment spectrum: Treatment options may range from corrective lenses to surgical interventions, including corneal cross-linking or transplantation.

• Consideration of coexisting conditions: Given that keratoconus may coexist with other eye issues, such as vernal keratoconjunctivitis, it is crucial to conduct a comprehensive eye examination to address all aspects of the patient's ocular health.

• Monitoring: Consistent eye examinations are crucial for monitoring disease progression.

• Individualized treatment: Treatment plans for keratoconus should be customized by clinicians to meet each patient's unique needs and account for the specific stage of the disease.

• Long-term oversight: Lifelong follow-up may be necessary to ensure ongoing management and optimal outcomes, particularly following surgical interventions such as corneal transplantation.[88]

Pitfalls

• Diagnostic delays: Keratoconus may be misidentified as routine astigmatism, leading to delays in diagnosis and appropriate treatment.

• Contact lens challenges: Proper contact lens fit may require specialized expertise, and improper fitting can lead to discomfort and complications.

• Potential for rapid progression: Although keratoconus usually progresses slowly, in some instances, it may advance rapidly, necessitating urgent intervention.

• Preventive measures: Educating patients about the importance of avoiding eye rubbing and protecting their eyes from excessive UV rays can provide significant benefits.

• Early intervention: Initiating treatments such as collagen cross-linking during the early stages can prevent or slow the progression of keratoconus.

• Genetic factors: A familial background and specific systemic conditions, such as Down syndrome, can increase the risk of keratoconus.

• Lifestyle considerations: Healthcare professionals should educate patients on avoiding eye rubbing and utilizing appropriate eye protection to minimize risks.

• Psychological impact: Given the progressive nature of the disease, it can significantly impact an individual's lifestyle and emotional health. Thus, offering psychological support can be invaluable.

In summary, keratoconus is a complex and potentially life-altering condition that requires early identification, vigilant monitoring, personalized treatment, and comprehensive patient education. A thorough understanding and effective management can significantly contribute to maintaining visual function and quality of life.[83]

Enhancing Healthcare Team Outcomes

Keratoconus is a progressive eye disease that can result in significant visual impairment. Early detection and intervention are crucial to potentially slow its progression. Patients with keratoconus or those predisposed to it benefit from a collaborative healthcare approach, ensuring patient-centered care and minimizing overall morbidity. Primary care providers, ophthalmologists, optometrists, and other healthcare professionals involved in patient care must possess the necessary clinical expertise to diagnose and manage keratoconus effectively. This includes identifying individuals at risk of developing the condition and understanding the array of diagnostic methods available.

A strategic approach is essential to ensure early screening for patients at risk of keratoconus and regular monitoring for those diagnosed with the condition to prevent disease progression. Seamless interprofessional communication enables efficient information exchange and collaborative decision-making among team members. This coordination minimizes delays, enhances patient safety, and ultimately improves outcomes. Patient-centered care prioritizes the overall well-being of individuals affected by keratoconus, emphasizing their needs and preferences throughout the treatment journey.