Keratoconus is a bilateral, progressive, non-inflammatory ectatic condition in which a conical protrusion appears on the thinned central part of the cornea. Namely, patients face significant vision impairment due to irregular astigmatism and high myopia. The worldwide prevalence of this condition is estimated to be 1.38 per 1,000. Keratoconus affects all ethnicities equally, although prevalence and incidence are higher among South Asians and Middle Easterners compared to those of European descent. This anomaly affects both sexes, but there are also conflicting studies on whether the prevalence differs between the sexes.

Etiology and pathogenesis

Keratoconus is a complex disease with a multifactorial etiology, which includes genetic and environmental factors. Although only 8% to 10% of patients with keratoconus have a family history of the condition, a genetic basis for the condition is supported by autosomal dominant and recessive patterns of inheritance, association with other genetic disorders, and concordance studies in twins.

Mechanical and other risk factors are also involved in the development of keratoconus, such as eye rubbing, trauma from poorly fitted contact lenses, and allergic eye diseases.

The pathophysiology of keratoconus is not fully understood. Biochemical instability leading to central or paracentral stromal thinning is generally attributed to an imbalance between proteolytic enzymes and proteinase inhibitors.

Symptoms

Although keratoconus is bilateral, it usually progresses asymmetrically. Patients often complain of blurring, distortion of vision and frequent changes in the diopter of the glasses. Other symptoms include glare, photophobia, and distorted night vision. In the advanced stage of keratoconus, high myopia, irregular astigmatism as well as stromal scars lead to significant vision impairment.

Emergence and progression 

The onset of keratoconus usually occurs in patients around the second decade of life, and the disease progresses slowly thereafter, and in most patients it stops mostly by the fourth decade of life. In the early stages of the disease, keratoconus is asymptomatic, and many cases remain undiagnosed unless they are evaluated by corneal tomography. 

Complications. 

Acute corneal hydrops and the development of stromal edema after a break in Descemet’s membrane is a potential complication of keratoconus. It manifests itself as a rapid onset of pain and loss of vision. Although corneal hydrops can resolve spontaneously within 40 to 70 days, many patients eventually require keratoplasty treatment due to corneal scarring. 

Diagnosis

There are several important clinical tests used to diagnose keratoconus.

Examination 

Scissoring of the red reflex on retinoscopy is a very reliable and sensitive method for detecting keratoconus in the early stages.

External indicators include Munson’s sign (V-shaped deformity of the lower eyelid caused by a cone when the patient looks down) and Rizzuti’s sign (cone illumination on the nasal sclera when light is directed to the cornea from the temporal side). However, these external signs are usually not noticed in a mild form of keratoconus.

Slit-lamp examination 

Slit-lamp examination of the patient can reveal several key diagnostic features of keratoconus.

A characteristic sign is central and paracentral thinning of the cornea. Fleischer’s ring, a yellow or brown ring surrounding the cone, is caused by hemosiderin deposition, best assessed with a cobalt blue light filter. Vogt striae, often seen in the deep stroma, are bright, parallel lines caused by the stress of stretching the cornea. External pressure on the globe removes these lines during slit-lamp examination. In addition, the corneal nerves can be visualized as fine white lines entering the stroma from the limbus.

Topography and tomography 

Corneal topography and tomography provide valuable information about corneal curvature. Corneal topography enables non-invasive qualitative and quantitative characterization of corneal morphology. Topographic maps will show irregular astigmatism with a steep entry. The following maps are analyzed: anterior, sagittal, and tangential curvature maps, maps of anterior and posterior elevations, and a thickness map.

Corneal tomography provides additional parameters to assess the anterior and posterior surfaces of the cornea. Posterior corneal structural changes are noticeable, including stroma thinning and height changes earlier than those on the anterior surface. This allows reliable detection of keratoconus at an early stage even before the patient becomes symptomatic.

Associated disorders

Keratoconus can be associated with systemic and ocular conditions. Patients with any of the disorders listed below should be carefully examined because there is a possibility of early signs of keratoconus

System associations include 

• Down syndrome
• Ehlers-Danlosov syndrome
• Leber’s congenital amaurosis 
• Marfanov syndrome
• Mitral valve prolapse
• Obstructive sleep apnea
• You
• Turner syndrome

Eye associations include

• Aniridija
• Plave sclera
• Retinitis pigmentosa
• Vernalni keratokonjunktivitisteogenesis imperfecta

Other techniques 

Other auxiliary technologies can make a significant contribution in the final confirmation of the diagnosis of keratoconus. One of them, the Ocular Response Analyzer (Reichert), assesses corneal biomechanics by measuring corneal hysteresis, the difference in applanation pressure when the cornea bends inward in response to an air jet and when it returns to its normal state. Compared to normal corneas, keratoconic corneas usually show lower values ​​of corneal hysteresis.

High-resolution optical coherence tomography (OCT) is a useful and fast diagnostic module of the add-on that enables the analysis and mapping of the thickness of the corneal epithelium. Epithelial mapping shows an increased total thickness of the peripheral epithelium with a thinner central epithelium in cases of patients with keratoconus compared to normal conditions. These changes can occur in the early stages of the disease process and are considered a compensatory mechanism.

Classification

Morphologically, keratoconus is distinguished in three types of so-called “cones” that increase in size: 1) small, isolated, round cones with a steep curvature; 2) ellipsoid oval cones; and 3) large globular cones covering most of the cornea. 

gradeing 

The oldest and most common grading system, the Amsler-Krumeich scale, is based on corneal thickness, anterior keratometric measurements, and refractive error.

A recently developed classification known as the ABCD grading system includes the average anterior radius of curvature (A) and the average posterior radius of curvature (B), both measured in a 3 mm zone centered on the thinnest point of the cornea, along with the thinnest pachymetry measurement (C) and best visual acuity at distance corrected by glasses (D). This system integrates tomographic values ​​and visual acuity to better characterize the anatomical and functional aspects of the keratoconic cornea.

Differential diagnosis

Several ectatic corneal disorders require careful differentiation. Forme fruste keratoconus (subclinical KC) is an early, asymptomatic form of the disease without obvious clinical signs; it can only be diagnosed by analyzing the corneal morphology.

Pellucid marginal degeneration (PMD) is a bilateral, non-inflammatory ectatic disorder similar to keratoconus. Clinically, patients with PMD are usually asymptomatic, except for a mild, progressive decrease in visual acuity resistant to spectacle correction. PMD is characterized by inferior thinning of the cornea, typically in the area of ​​a strip band concentric to the limbus on slit-lamp examination and the appearance of a “crab-claw” on topography.

Keratoglobus is a corneal thinning disorder characterized by global thinning and bulging. Unlike keratoconus, it is usually non-progressive and is present from birth. Although the thinning in keratoconus is focal, keratoglobus shows bulging and thinning of the entire cornea and is much more prominent in the peripheral parts compared to keratoconus.

Management

Over time, a variety of approaches have been developed to improve the quality of vision in patients with keratoconus and, in some cases, to slow or stop the progression of the disease. The choice of therapy depends on the severity of the disease and the patient’s age. Patients with keratoconus who are in their third decade of life should be monitored every six months.

Patients with higher risk factors, including pregnancy or younger patients (under 20 years of age), should be evaluated every three months. Patients with a severe form of keratoconus often require combined therapy.

Glasses and contact lenses

Glasses can be used to correct astigmatism at an early stage, in cases of stable keratoconus. When astigmatism can no longer be managed with glasses, contact lenses are the next step. Soft contact lenses may be sufficient for mild forms of keratoconus, and hard contact lenses become necessary mainly for forms of the disease that are in an advanced stage. However, although there are many different designs on the market, conventional contact lenses can be uncomfortable on the keratoconic eye, and patients can experience dryness, itching and pain.

Scleral lenses

Compared to conventional contact lenses that rest directly on the cornea, scleral lenses have a larger diameter and rest on the sclera, being worn over the cornea. With these lenses, there is a liquid layer between the lens and the cornea. The PROSE (Prosthetic Ocular Surface Ecosystem Replacement; BostonSight) treatment includes a scleral lens customized for each patient. Although scleral lenses have a higher price and a more challenging fitting process, they offer greater stability, improved visual results and better comfort compared to standard contact lenses. 

Collagen cross-linking 

The collagen cross-linking technique (Crosslinking – CXL) with ultraviolet A and riboflavin stabilizes the corneal tissue, stopping the progression of the disease. In addition, CXL was found to improve BCVA by 1 to 2 lines and decrease the maximum keratometry (Kmax) by 1 to 2 D. 

Crosslinking – CXL is recommended for patients with progressive keratoconus who have a clear cornea and a minimum corneal thickness of 400 µm. The introduction of this modality reduced the need for keratoplasty procedures. Side effects that may occur include infectious keratitis, edema, and haze.

Implantation of intracorneal rings 

Intracorneal ring segments (ICRS) are made of polymethyl methacrylate and can be implanted into the deep corneal stroma. Through the arc shortening effect, rings (ICRS) flatten the surface of the cornea, reducing refractive error. The amount of refraction correction depends on the diameter and thickness of the rings. Shorter and thinner arcs are used to correct astigmatism, while longer and thicker arcs correct myopia. Complications that may occur with ICRS treatment include fluctuating visual outcomes, infection, dysphotopsia, and corneal melting.

Keratoplasty 

When less invasive procedures are not effective and do not give a satisfactory result, patients may need a corneal transplant. Penetrating keratoplasty (PK) for keratoconus is an effective procedure with good visual outcomes. Recovery takes several weeks to several months, and visual functions stabilize up to a year after the operation. Reported complications include allograft rejection, iatrogenic astigmatism, and keratoconus recurrence. 

To preserve intact native endothelial cells, surgeons may perform deep anterior lamellar keratoplasty (DALK) if Descemet’s membrane has not previously ruptured, as in hydrops. Although visual outcomes are comparable to keratoplasty, DALK eliminates the risk of endothelial rejection and steroid-induced secondary glaucoma.

Over the past two decades, technological advances have greatly improved the early diagnosis and management of keratoconus. The diagnostic workup includes a detailed medical history, a thorough slit-lamp examination, and analysis techniques such as tomography and OCT. Treatment plans remain patient-specific and should be based on a shared discussion that appropriately addresses the individual’s expectations of visual outcome.