NORD gratefully acknowledges Nambi Nallasamy, MD, Assistant Professor of Ophthalmology and Visual Science, University of Michigan, for assistance in the preparation of this report.
Keratoconus is an eye (ocular) disorder characterized by progressive thinning and changes in the shape of the cornea. The cornea is the thin, clear outer layer of the eye and is normally dome-shaped. Slowly progressive thinning of the cornea causes a cone-shaped bulge to develop towards the center of the cornea in the areas of greatest thinning. Affected individuals develop blurry or distorted vision, sensitivity to light (photophobia), and additional vision problems. Keratoconus often begins at puberty and most often is seen in teenagers or young adults. The specific underlying cause is not fully understood and most likely the condition results from the interaction of multiple factors including genetic and environmental ones. One factor known to contribute to progression of keratoconus is eye rubbing. In some cases, keratoconus may occur as part of a larger disorder. Keratoconus is treated with glasses or contact lenses early in the condition. A small number of individuals may require surgery.
The corneas in both eyes are usually affected (bilateral), although the progression and severity of the condition in each eye may differ (asymmetric development), which means one eye may be notably worse than the other. Symptoms usually become apparent during adolescence or young adulthood (i.e. late teens through early 20s). Keratoconus may become progressively worse for 10 to 20 years before slowing. Older adults typically do not have worsening of keratoconus. Because of the progressive nature of the disorder, affected individuals may have to change glasses frequently.
The cornea’s primary function is acting as the eye’s most powerful lens, bending incoming light onto the lower-powered internal lens, where the light is then directed to the retina (a membranous layer of light-sensing cells in the back of the eye). The retina converts light to specific nerve signals, which are then transmitted to the brain to form images. The cornea must remain clear (transparent) and the proper shape in order to be able to transmit and focus incoming light.
The abnormal cone-shape that characterizes keratoconus leads to changes in the ability of the cornea to help focus light appropriately on the retina (i.e., refractive abnormalities). Keratoconus may initially cause slight blurring of vision, abnormally increased sensitivity to glare or bright light, and difficulty seeing at night (poor night vision). Some individuals may experience double vision (diplopia) or see a partial, incomplete image around what they are looking at (‘ghost’ images). In some cases, there may be a loss of clarity of vision (visual acuity). With progressive corneal changes, affected individuals experience increased difficulty in seeing far away (nearsightedness or myopia) and further decreased clarity of vision. Overall vision changes can vary from one person to another and the severity can range from mild vision loss to more severe vision loss that causes a decreased ability to see clearly even with corrective lenses. Some affected individuals may develop an irregular astigmatism, in which there is an irregular curvature of the eye.
Rarely, affected individuals may develop a corneal blister that causes swelling of the cornea due to fluid accumulation (acute corneal hydrops) in specific layers of the cornea. This condition can be painful and cause redness of the eye. Scarring of the cornea can occur.
The specific underlying mechanism(s) responsible for keratoconus are not fully understood. Most cases appear to occur randomly for unknown reasons (sporadically). However, a positive family history of keratoconus has been established in some cases. Most researchers believe that multiple, complex factors are required for the development of keratoconus including both genetic and environmental factors.
Researchers believe that some individuals who develop keratoconus have a genetic predisposition to developing the disorder. A person who is genetically predisposed to a disorder carries a gene (or genes) for the disorder, but the condition may not be expressed unless it is triggered or “activated” under certain circumstances such as due to particular environmental factors. Research is underway to identify specific genes associated with keratoconus.
Environmental risk factors that may play a role in the development of keratoconus include contact lens use, repeated eye-rubbing, or atopy, a general term for conditions that involve hypersensitivity reactions such as hay fever (allergic rhinitis), eczema (atopic dermatitis), sleep apnea, or allergic asthma. However, studies have proven an association with any of these potential risk factors and the development of keratoconus.
Traditionally, keratoconus has been considered a non-inflammatory disorder. Inflammation is a normal process that occurs in the body in response to injury or infection. In inflammatory disorders there is an abnormal immune (inflammatory) response, which can lead to symptoms or specific disorders. Although keratoconus has been defined as a non-inflammatory disorder, recent evidence, including abnormally high levels of proteolytic enzymes, an association with free radicals and oxidative stress, or the presence of cytokines, specialized proteins secreted from certain immune system cells that either stimulate or inhibit the function of other immune system cells. More research is necessary to determine the complex, underlying causes of keratoconus.
Keratoconus may also sometimes occur in association with certain underlying disorders, such as Down syndrome, sleep apnea, asthma, Leber congenital amaurosis, and various connective tissue disorders including Ehlers-Danlos syndrome, Marfan syndrome, or brittle cornea syndrome. A direct cause-and-effect relationship between these disorders and keratoconus has not been established. (For additional information on these disorders, please choose the appropriate name as your search term in the Rare Disease Database or see the “Related Disorders” section of this report below.)
Keratoconus affects both men and women and all ethnic groups worldwide. The disorder tends to develop most often among adolescents at or around puberty or during the late teen-age years. Recent studies (2015) show that men, African-Americans, and Latinos have a greater risk of development keratoconus, while women, Asian-Americans, and people with diabetes appear to have a lower risk.
The incidence and prevalence rates reported in the medical literature for keratoconus tend to vary widely. One long-term study in the United States indicated a prevalence of 54.5 diagnosed individuals per 100,000 individuals in the general population, or approximately 1 in 2,000 individuals. However, some estimates suggest that the incidence may be as high as 1 in 400 individuals. Individuals with a family history of keratoconus are at a greater risk of developing the condition than people the general population.
Keratoconus may be diagnosed based upon a complete patient and family history and thorough eye examination. Such an examination may include evaluation of the external appearance of the eyes, visual acuity, eye movements, and visual fields; the use of a special, illuminated microscope that allows physicians to view the eye through high magnification (slit-lamp examination); and/or additional tests or procedures.
A specific imaging test known as corneal topography is used to aid in a diagnosis of keratoconus, in part by detecting very early keratoconus where the corneal changes are not visible by a doctor looking at the eye (subclinical). This is sometimes referred to as “forme fruste” keratoconus. Corneal topography is an imaging study that typically uses an instrument to project a series of light rings onto the surface of the cornea. These rings of light are reflected back to the instrument and recorded. These recording can show changes in the shape and integrity of the cornea. Corneal topography is useful for determining the severity of keratoconus and monitoring the progression of the disorder.
The treatment of keratoconus is based upon the severity of the condition in the individual and the rate of progression of the disorder. In some individuals with mild symptoms, vision may be improved with the use of appropriate eyeglasses or soft contact lenses. However, progressive changes in vision often necessitate frequent prescription changes.
In many individuals, rigid gas permeable contact lenses (a modern version of ‘hard’ contact lenses) may be required. These lenses can reshape the corneal surface to hide or mask the underlying cone-shaped defect of the cornea. In some individuals, these contact lenses may become uncomfortable and are not tolerated well. In such cases, individuals can use ‘piggyback’ contacts lenses in which hard contact lenses are placed over soft lenses. The underlying soft lenses provide comfort and support, while the hard lenses improve vision. Other types of contact lenses that may be used include hybrid lenses, which have a rigid center and soft ring on the outside, or scleral lenses, which are larger traditional contact lenses and which rest atop the sclera (the whites of the eyes) and mount above the cornea.
However, some severely affected individuals may not be able to wear contact lenses due to progressively severe corneal thinning, corneal scarring, and/or contact intolerance. In cases of severe visual deterioration in which contact lenses cannot sufficiently correct vision or are not tolerated, surgery may be required such as intracorneal ring segments or a corneal transplant (keratoplasty).
In 2004, the U.S. Food and Drug Administration approved intracorneal ring segments for the treatment of individuals with keratoconus. During this procedure, two, tiny crescent-shaped plastic pieces are inserted into the cornea. These inserts can help to flatten, strengthen, and support the cornea and improve vision. Typically, eyeglasses or contact lenses are still required for proper vision.
In 2016, the U.S. Food and Drug Administration granted the first approval of a collagen cross-linking device to treat progressive keratoconus. This device, the Avedro KXL, uses UV light and riboflavin formulations to strengthen the cornea.
A corneal transplant is a surgical procedure in which abnormal corneal tissue is removed and replaced with healthy donor corneal tissue. This surgery is generally reserved for individuals with severe disease (e.g. the cornea is extremely thin and/or vision is significantly compromised) or who cannot tolerate or did not respond to more conservative treatments. A corneal transplant may also be indicated after an episode of corneal swelling (corneal hydrops) that does not respond to other treatment options. There are several different corneal transplant procedures that may be used. Corneal transplants are generally effective for treating individuals with keratoconus, but do carry a small risk of complications, including rejection of the donated tissue by the body (graft rejection). Of note, individuals who have a corneal transplant typically still need hard contact lenses after the transplant because the cornea, while flatter, still does not have a perfect shape.
A procedure known as corneal collagen cross-linking (CXL) has been used to successfully treat individuals with keratoconus. This procedure uses ultraviolet A (UVA) light and riboflavin, a type of B vitamin, to slow or halt the progression of keratoconus. During the procedure, riboflavin is placed on the cornea via eye drops. Riboflavin acts as a photosensitizer, which allows corneal tissue to absorb the ultraviolet light. Basically, this procedure creates new bonds in the collagen of the cornea, strengthening the cornea and halting progression. In some cases, the cornea obtains a flatter shape after CXL, but it does not return to ‘normal’ entirely.
A procedure known as topography-guided photorefractive keratectomy has been combined with collagen cross-linking to treat some individuals with mild to moderate keratoconus. Photorefractive keratectomy is a type of laser eye surgery that is most often used to treat individuals with mild or moderate nearsightedness, farsightedness or astigmatism. Generally, laser surgery is not recommended (contraindicated) for individuals with keratoconus. During this procedure a laser is used to reshape the affected cornea(s). More research is necessary to determine the long-term safety and effectiveness of this potential procedure for specific individuals with keratoconus.
Researchers are also studying the effectiveness of combining investigational therapies such as collagen crosslinking combined with intracorneal ring inserts.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
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Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/
For information about clinical trials sponsored by private sources, contact: www.centerwatch.com
For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
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For more support, visit the Keratoconus Group
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