Keratoconus is a disease of the cornea that, if left untreated, can lead to loss of vision, decreased quality of life, and potentially to blindness. Eyecare practitioners (ECPs) are the gatekeepers of keratoconus management. Patients who present with keratoconus can expect to be in the care of ECPs for the continuum of the disease—in other words, for the rest of their lives. Keratoconus requires ECPs to diagnose, assess, and treat; to advise on best patient practices and to prescribe simple-to-advanced refractive tools for best-corrected vision and best quality of life; to monitor for change and progression and to adapt the treatment modality accordingly; and to refer for or perform procedures such as corneal cross-linking (CXL), surgical management of hydrops via pneumatic descemetopexy (anterior chamber air or gas bubble to tamponade Descemet’s membrane) or removal of permanent corneal scarring, and corneal transplants.

HISTORY

In his major 1854 Treatise on the Conical Cornea, Dr. John Nottingham is widely credited as the first author to formally define keratoconus. “Nottingham was the first to fully consolidate and distil the disparate strands into a modern, comprehensive understanding of keratoconus and the first to discuss what we now know as customized contact lenses that are specifically designed as ‘Lenses with posterior surface corresponding to the front of the eye, and anteriorly of regular figure, are amongst the means proposed for correcting the altered refraction; along with these may be mentioned lenses of transparent animal jelly, contained in capsules of glass, to be placed on the front of the eye.’ However, for 150 years prior to this it should be noted that other eye care providers and researchers discussed parts of the disease of keratoconus but not in its entirety.”¹ Nottingham gave credit to his predecessors, and it is noted that understanding of the disease, at least in part, dates back to the late 1600s and early 1700s.

As better understandings of ophthalmic and non-ophthalmic diseases progressed, it was recognized in the research community that understanding the impact of a given disease in the public domain was important to overall awareness, allocation of resources, and individual clinical efforts. The establishment of data regarding prevalence and incidence of a given disease began to take on particular public importance. Prevalence, sometimes referred to as prevalence rate, is the proportion of persons in a population (new and existing) who have a particular disease or attribute at a specified point in time or over a specified period of time. Incidence refers to the occurrence of new cases of disease or injury in a population over a specified period of time.² For example, if a clinician is aware that a particular disease had a prevalence in the population of 1:250, it will be suspected in a differential diagnosis list much more frequently during patient encounters than if the prevalence rate was 1:250,000. This is an important concept to understand as we look at how the prevalence and incidence of keratoconus has increased over the past 30 to 40 years.

EPIDEMIOLOGY OF KERATOCONUS

If you have performed any amount of reading or research on the disease of keratoconus, you will commonly find that the incidence has been reported to be approximately 1 in 2,000 and that the prevalence is estimated to be 54.5 per 100,000.³ At the time of its publication, the data from this 1986 study by Kennedy et al may have been the most accurate that we had, but not today. Let’s investigate this study to gain a detailed understanding of how these numbers came about. Here are some facts about how these estimates were established:³

• The study date range was from 1935 to 1982.
• The sample size was 64 individuals from one county in Minnesota.
• The age range was 12 to 77 years, and only four subjects were over age 40.
• The diagnosis of keratoconus “was based on the examiner’s description of characteristic irregular light reflexes observed during ophthalmoscopy or retinoscopy or irregular mires detected at keratometry.”
• The study infers that all subjects were white, as the incidence rate was adjusted by age and sex to the white population of the United States.

Of particular note is that there was no objective testing, no crossover clinician evaluation, no pachymetry recorded, no evaluation outside of the central 3mm of the cornea, and no evaluation outside of the visual axis. But most importantly, while the Scheimpflug camera/tomographer is the device of choice today for evaluating keratoconic corneas, not even the workhorse of the industry today—the corneal topographer—was utilized at the time of the Kennedy et al study. The corneal topographer was not necessarily commercially available until the early-to-mid 1990s. Therefore, diagnosis of keratoconus for the purposes of prevalence and incidence in this study was not determined by objective computerized evaluation of the cornea. Needless to say, this data is of high bias, low reliability, significant limitation, and of historical value only; yet, many still cite these values today. This needs to change immediately. Clinicians need to be aware of the most accurate prevalence and incidence estimates so as to guide their clinical practice appropriately and to use diagnosis and management strategies that are in the best interests of their patients.

So, what is the most accurate estimate on the prevalence and incidence of keratoconus today? The answer is that it depends. While we know that the numbers are significantly higher than what was previously reported, there is variance in worldwide population studies depending on a variety of factors—one being the variance of testing and reporting. If a study were to ever be developed that can look at a large population within one medical records system and utilize similar testing methods and equipment, a much more accurate estimation could be extrapolated.

A 2016 study⁴ did just that. In this nationwide evaluation from the Netherlands using modern diagnostics, the Dutch database of 4.4 million individuals aged 10 to 40 years was evaluated for keratoconic disease. The shocking results were that values reported for keratoconus incidence and prevalence were five- to 10-fold higher compared to previously reported values in population studies.

ETHNICITY

While gender does not seem to be a factor in keratoconus, ethnicity does play a role. Keratoconus prevalence has been shown to vary among ethnic groups. It has been reported that Asians (Indians, Bangladeshi, and Pakistani) living in the English Midlands had an incidence of the disease that was 4.4 times higher than that of Caucasians.² Therefore, it is important to understand the demographics of keratoconus suspects to assist in the diagnosis and risk opportunity.

GLOBAL CONSENSUS OF CORNEAL ECTASIAS

Today, we have much more advanced equipment for early detection, a global definition of mandatory findings to diagnose the disease, the ability to monitor for progression, advanced medical and ophthalmic devices to improve visual acuity and quality of life, and treatment methods that can halt the progression of the disease. In a landmark paper, representatives from the four major cornea societies around the world convened to establish the definitions, concepts, clinical management, and surgical treatments for corneal ectasia.² The group defined keratoconus as a progressive, bilateral, asymmetric progressive disease of the cornea with environmental and genetic etiologies that is part of a family of diseases named Corneal Ectasias. The four diseases that comprise the corneal ectasias are the following:

• Keratoconus
• Keratoglobus
• Pellucid marginal degeneration (PMD)
• Post-Refractive surgical ectasia

Consensus was achieved regarding the statements “keratoglobus and keratoconus are different clinical entities” and “true unilateral keratoconus does not exist.” In addition, the “thinning location and pattern” are aspects that distinguish keratoconus, PMD, and keratoglobus. Central pachymetry was concluded to be the least reliable indicator (or determinant) for diagnosing keratoconus because keratoconus can be present in a cornea of normal central thickness. These consensus statements regarding the disease itself led to the following determination of the devices required to evaluate the cornea for keratoconus. They concluded that tomography is currently the best and most widely available test to diagnose early keratoconus. Posterior corneal elevation abnormalities must be present to diagnose mild or subclinical keratoconus. Specifically, certain parts of the cornea need to be evaluated for the earliest signs of disease. ECPs need to be aware that tomographic Scheimpflug cameras that can evaluate the elevation of the posterior surface of the cornea for signs of ectasia need to be implemented at this time for earliest identification of disease.

Mandatory Findings to Diagnose Keratoconus The Global Consensus Group also determined the following mandatory findings to diagnose keratoconus:²

• Abnormal posterior ectasia
• Abnormal corneal thickness distribution (e.g., as with abnormal corneal thickness spatial distribution)
• Clinical non-inflammatory corneal thinning

The exact values for any parameter will vary based on the machine being used and, for elevation values, the reference surface. Additionally, the values will vary depending on whether a practitioner is screening (e.g., for refractive surgery), for which sensitivity is the overriding concern, or is treating (e.g., performing CXL), for which specificity assumes greater significance.²

While most eyecare providers diagnose keratoconus using anterior surface topographers, it is important to note that the global consensus group did not include this information as a mandatory finding for diagnosis. This is because anterior surface curvature changes are actually secondary changes that result from the posterior surface pushing forward. The forces associated with normal or elevated intraocular pressure push onto the posterior cornea. In a cornea that has collagen of normal thickness and biomechanical strength, the cornea can maintain its normal anatomical shape. In corneas that have thin and/or biomechanically weak collagen due to keratoconus, the posterior corneal surface takes on a dynamic movement toward the anterior surface. This action can progressively thin the cornea, elevate the posterior surface, and create a resulting curvature change on the anterior surface (Figure 1). To understand this concept better, consider that most keratoconic corneas become steeper and thinner as they progress. There is no way to become steeper and thinner at the same time unless the back surface moves forward at a faster and more significant rate compared to the front surface. This is why particular attention, especially in younger corneas and in early phases of the disease, needs to be paid to the posterior aspect of the cornea.

Definition of Ectasia Progression The Global Consensus Group also defined “ectasia progression” by a consistent change in, at minimum, the following three parameters in which the magnitude of the change is above the normal noise of the testing system:²

• Steepening of the anterior corneal surface
• Steepening of the posterior corneal surface
• Thinning and/or an increase in the rate of corneal thickness change from the periphery to the thinnest point

GENERAL CONCERNS REGARDING CONTACT LENSES FOR KERATOCONUS

The visual challenges of keratoconus can primarily be addressed by masking the anterior corneal surface irregularity and creating a smoother, more regular anterior optical surface.⁵ There are typically three key elements to success in all areas of contact lens treatment: 1) providing appropriate vision correction; 2) providing acceptable comfort during lens wear; and 3) providing an appropriate ocular physiological response to lens wear. With regard to keratoconus, it is always imperative to avoid mechanical pressure on the apex of the cornea, to avoid hypoxia-induced stress to the cornea, to provide maximum comfort through contact lens fitting design, and to optimize vision through contact lens optical design. This would include not only visual distortion from keratoconus but also residual astigmatism, presbyopia, and other influences on visual performance.

Following are types of contact lenses for keratoconus:

• Soft Spherical and Soft Toric If possible, an attempt to improve visual acuity in the keratoconic eye should always be made with soft spherical or toric contact lenses. While visual acuity may be improved with an advanced medical contact lens (e.g., hybrid, scleral, fully customized impression-based or topography-designed scleral), comfort and wearing time should be considered, as individuals who have keratoconus are highly dependent on the vision provided by their contact lenses. This increases typical wearing time as compared to contact lens wearers who do not have keratoconus.
• Corneal GP Once the gold standard of keratoconus vision improvement, corneal GPs still represent a valuable option due to the quality of vision that a GP lens provides on an irregular cornea. It is important to utilize a diagnostic set and to work closely with your laboratory. A mild feather touch (i.e., “three-point touch”) or a mild apical clearance fitting relationship is recommended.
• Hybrid—GP Center/Soft Skirt Hybrid contact lenses play a role in the continuum of care for keratoconus, as they offer the consistent optics of a rigid lens while the periphery provides the comfort and easy adaptation of a soft lens, especially for newly diagnosed keratoconus patients. The latest generation of hybrid lenses available in the United States helps to maintain the corneal integrity by clearing the apex without over-vaulting through the use of reverse geometry curves while providing maximum oxygen transmission through the use of a hyper-Dk GP center surrounded by a silicone hydrogel skirt. For oblate corneas or peripheral ectasias, another design that allows for flatter base curves with reverse geometry helps to ensure clearance and tear fluidity.
• Piggyback Lens System This is a combination of soft and GP contact lenses, in which the soft contact lens is placed directly on the cornea for initial comfort purposes, and a GP lens is placed on top of the soft lens to improve the quality of vision.
• Scleral Scleral contact lenses are one of the most successful modalities for the contact lens correction of keratoconus. The peripheral aspect of the scleral lens “lands” or rests on the sclera (actually, on the conjunctiva overlying the sclera and episclera) and vaults over the irregular cornea. This avoids contact with the anterior surface of the cornea, which in turn decreases contact lens-related complications and provides high-quality vision in a large population of patients who wear them.
• Impression-Based or Topography-Customized Scleral Impression-based scleral devices and new scleral lenses that are customized through topography measurements are designed to match the exact contours of each individual eye, providing the best vision and comfort possible.
  In very mild cases of keratoconus, spectacles may provide ample refractive correction. Regardless of the type of contact lens that a patient is wearing, it is important to make the patient aware that the contact lens will not slow down the progression or worsening of the disease.
  With any diagnosis of keratoconus, patients need to be made aware that rubbing of the eyes can both worsen the condition and make it progress at a faster rate.⁶ Patients (and close family and friends) need to be made aware that patients are not to rub their eyes. Additionally, ocular allergy/atopy has also been associated with worsening of disease.⁷ Instruct patients who have keratoconus and allergy/atopy to use anti-allergy eye drops.

CORNEAL CROSS-LINKING

While contact lenses are a very important component of the continuum of care for keratoconus patients, if a patient exhibits progression of the disease, CXL treatment may be a necessary intervention to halt its progression. In April 2016, a U.S. medical device company was granted U.S. FDA approval for its CXL system and riboflavin solution specifically indicated for progressive keratoconus and for post-refractive surgery ectasia.

The treatment, currently approved in an epithelium-off fashion, is the only U.S. FDA-approved commercially available method to halt or slow progression of these visually devastating disorders. The company says that epithelium-off CXL requires the removal of approximately 8mm to 9mm of central corneal epithelium for application and corneal absorption of the riboflavin solution. Once the riboflavin solution has been absorbed throughout the full thickness of the cornea, the UV-A light source can be applied. The company says that a reaction between the UV-A light and the riboflavin solution generates a singlet oxygen that is responsible for the cross-linking. After treatment, the eye is irrigated, and a bandage contact lens is placed over the open epithelial wound. The cornea is managed postoperatively with ophthalmic antibiotics, steroids, and artificial tears. Short-term postoperative care includes monitoring the cornea for epithelial closure, potential ulcerative keratitis, dry eye, light sensitivity, reticular haze formation, and refractive recovery. Long-term management of the post-CXL cornea involves monitoring for continued progression. ECPs need to particularly watch for signs and/or symptoms of progression that include:

• Worsening myopia or myopic astigmatic changes
• Patient complaints of increasing visual blur
• Corneal thinning
• Corneal steepening
• Posterior or anterior elevation increases on tomography

If these signs or symptoms are identified, a retreatment of CXL may be indicated. Long-term studies show that progression of keratoconus after cross-linking may occur in about 8% of cases.²

While epithelium-off CXL is the current FDA-approved method of treatment, the company has recently completed enrollment of a pivotal U.S. Phase 3 epithelium-on CXL clinical trial for progressive keratoconus. If this procedure gains FDA approval, this would make treatment and recovery much less painful, with lower rates of infection, inflammation, and corneal haze for individuals receiving treatment. In addition, the visual recovery would be quicker. There are epithelium-on treatments currently being performed in the United States; however, they are not FDA-approved and, as such, represent “off-label” treatments.

CORNEAL TRANSPLANTS

Through population studies and eye bank information, we know that the implementation of CXL as a treatment option for progressive keratoconus has reduced the number of corneal transplants. According to the Dutch National Organ Transplant Registry, approximately 25% fewer corneal transplants were performed in the three‐year period following the introduction of CXL compared to the three‐year period prior to the introduction of CXL.⁴

However, if a corneal transplant does need to be performed, it can either be full- or partial- thickness in nature. The amount of diseased tissue, overall corneal thickness, and ocular health will dictate the preferred treatment. The post-transplant eye must be monitored frequently for signs of infection, inflammation, ocular disease, refractive error, and transplant rejection.

MANAGING PEDIATRIC KERATOCONUS

For any clinician, patient age at keratoconus onset is the most important consideration. It has been widely recognized with near unanimous consensus that younger patients should be examined for change at shorter time intervals, as ectatic change and disease progression can advance rapidly in this group.² That is to say that if an individual younger than 18 years of age presents with a primary diagnosis of keratoconus, I recommend that patients return for follow up at least once every three months until either progression stability is absolutely established or a referral for CXL has been made. This clinical reasoning is based on the fact that 88% of children diagnosed with keratoconus have progressed within 12 months.⁸

CONCLUSION

Keratoconus is a disease of the cornea that can produce a significant decrease in quality of vision, reduced quality of life, and potentially blindness. We now know that the prevalence and incidence of the disease is much higher than what is typically reported in the literature. Keratoconus is not a rare disease. We know this in part because of access to new technology that can evaluate the posterior surface of the cornea for early and subtle elevation changes. This information allows ECPs to be on high alert for early evidence of disease. Preservation of best vision will occur only with early detection and proper management. As with all cases of keratoconus, visual improvement with refractive devices such as standard and advanced medical contact lenses is critical to patient quality of life. ECPs should routinely educate keratoconus patients to not rub their eyes and to manage their systemic/ocular allergy and atopy as aggressively as possible, as both can worsen the disease.

As increasingly less invasive methods of CXL begin to receive FDA and CE marks of approval, ECPs should be on the forefront of the treatment and management of progressively worsening keratoconic corneas. Early detection is the key to saving vision. The most important consideration in the prevention of keratoconus-related vision loss is to monitor pediatric keratoconus as early as possible and to have patients on a frequent follow-up schedule. CLS

Acknowledgements: Many thanks for continued discussion, input, and assistance to my fellow International Keratoconus Academy of Eye Care Professionals Executive Board members and Medical Advisory Board members Drs. Barry Eiden, Clark Chang, Bill Tullo, Loretta Szczotka-Flynn, Joe Barr, John Gelles, Steven Sorkin, and Christine Sindt.

REFERENCES

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3. Kennedy RH, Bourne WM, Dyer JA. A 48-year clinical and epidemiologic study of keratoconus. Am J Ophthalmol. 1986 Mar 15;101:267-273.
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