Pediatric Keratoconus

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Article initiated by:

Brad H. Feldman, M.D., Olivia F Dutton

All contributors:

Brad H. Feldman, M.D., Vatinee Y. Bunya, MD, MSCE, Colleen Halfpenny, M.D., Zeba A. Syed, MD, S. Grace Prakalapakorn, MD, MPH

Assigned editor:

Angeline Nguyen, MD, Mary Daly, MD

Review:

Assigned status Update Pending

 by Zeba A. Syed, MD on October 3, 2023.

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Contributing Editors:	add

Disease Entity

Disease

Keratoconus is a progressive disease that can create a conical shape of the cornea due to corneal thinning and resulting ectasia. This results in poor visual acuity, progressive myopia, and irregular astigmatism. Pediatric keratoconus has been shown to be more aggressive than keratoconus in adult patients which creates a greater importance on early intervention in pediatric patients.

Etiology

The etiology of pediatric keratoconus is poorly understood, although involves a combination of genetic and environmental variables. It is thought that rubbing of the eyes may further the steepening of the cornea by way of creating microtraumas. Inflammatory markers that react to the microtrauma from rubbing may induce apoptosis of cells in the cornea. Rubbing can be induced by hay fever, allergic conjunctivitis, or vernal keratoconjunctivitis among other reasons.

Risk Factors

Risk factors include environmental factors, family history as well as associated genetic syndromes.

Environmental factors include eye rubbing, atopy, and sun exposure.

Keratoconus is believed to be an autosomal dominant pattern although autosomal recessive inheritance as well as a sporadic inheritance have also been suggested. The positive family history of has been reported to be 20.5% in first degree relatives and contributing to a higher prevalence of keratoconus in monozygotic twins compared to dizygotic twins. There is a clear role of genetic factors in development of keratoconus however it is not clear which specific genes these are.

Additionally environmental and genetic risk factor confound one another making it hard to distinguish the true extent each of these risk factors plays on the development of Keratoconus.

Down syndrome has the highest association with Keratoconus. Marfan Syndrome, Ehlers-Danlos Syndrome, vernal keratoconjunctivitis, retinitis pigmentosa, leber congenital amaurosis, sleep apnea and mitral valve prolapse are all associated with keratoconus.

General Pathology

All layers of the cornea may show pathological findings of keratoconus. Pathological findings include: thinning of the epithelium, fibrillations and breaks in the Bowman’s layer, altered collagen fibrils and loss of lamellae in the stroma, ruptures and folds in Descement’s membrane, and rarely elongation of cells in the endothelium. Eye rubbing can create microtrauma to the epithelium leading to an inflammatory mediator response from the epithelium and stromal layers. Ocular allergies on the other hand may induce an inflammatory response through the release of the allergen into the body. Keratocytes are also reduced in eyes with keratoconus due to apoptosis.

Pathophysiology

The rigidity of the cornea is inversely proportional to age, allowing for the biochemical component of pediatric corneas to be more susceptible to degradation. Upregulation of matrix metalloproteinases (MMP‐14, MMP‐1, MMP‐7, MMP-13and MMP‐2), due to eye rubbing can cause degradation of type I and type II collagen, fibronectin, and glycoprotein in membranes. Additionally inflammatory markers IL‐6, TNF‐α, and MMP‐9 are increased in keratoconus patient’s tears. Ocular allergies react with IgE on mast and basophil cells leading to the release of histamine, proteases, and TNF-alpha. These inflammatory markers are thought to play a role in inducing keratocyte apoptosis which leads to thinning of the extracellular matrix, a reduction in corneal collagen cross-linking stromal volume loss, and ectasia.

Primary prevention

Prevention of keratoconus is limited at this point. However, avoiding allergens and rubbing of the eyes may prove effective at preventing progression of keratoconus. Awareness of genetic risk factors of keratoconus may allow for early intervention and stabilization of keratoconus in children. Halting the steepening of the cornea may help prevent corneal scarring. New genetic testing is becoming more widely available and may be used to determine prevalence of genes that predispose patient to development of keratoconus.

History

Kertatoconus typically begins progression in patients' 20's, with most research finding disease on set after puberty. However, there have been case studies of onset as early as 4 years old. The corneal disease typically presents bilaterally, however rarely symmetrically with the same progression rate in both eyes. The estimated prevalence of keratoconus in the pediatric population is estimated to be 0.16% however many experts believe the prevalence to be higher especially in certain environments. Pediatric keratoconus affects both genders equally. Studies on pediatric keratoconus suggest that at the time of diagnosis, 27.8% are at an advanced stage and 88% progress.

Symptoms

Patients may experience a progressive decrease in visual acuity, distortion of images increasing halos and starbursts around lights. Rapidly changing astigmatism or myopia may also be seen in patients. In more extreme cases patients can experience acute corneal hydrops causing impairment of vision, redness, pain and photophobia.

Examination

Patients suspected of having keratoconus should have a full eye exam including measurements of corneal curvature and thickness. Visual acuities at distance with and without correction should be obtained as well as a refraction to assess progressive astigmatism and myopia. Retinoscopy findings of scissoring can be used to detect early- stage keratoconus.

A slit lamp exam should also be performed for evidence of signs of keratoconus. The slit lamp exam findings may include: central and paracentral thinning, inferior steepening, corneal scars, corneal haze, Fleischer ring and Vogt’s striae. In more sever cases external indicators include the Munson sign and Rizzuti sign. It has been noted that cones appear to form more centrally in pediatric patients compared to adolescent or adult patients.

Diagnosis

Clinical diagnosis

Diagnosis of keratoconus requires a thorough slit lamp examination, supported by pentacam or other topography imaging devices. Topography images allow for early diagnosis of keratoconus as well as tracking the progression of irregular astigmatism and high K values. Ultrasound pachymetry can also be used to determine the central and paracentral thinning of the cornea. Due to the rapid severity of keratoconus in pediatric patients some studies recommend a shorter follow-up time frame such as 1-3 months versus 6-12 months in adult patients.

Anterior and posterior imaging such as Scheimpflug, optical coherence tomography (OCT), and slit-scan tomography are highly effective at measuring anterior and posterior curvature and thus increasing early diagnosis.

Family history and past medical history may be considered in the diagnosis.

Diagnostic procedures

Retinoscopy in patients with keratoconus will demonstrate a scissoring reflex in which the light reflex will split into two separate bands. Keratoconus patients may also demonstrate a Charleaux or "oil droplet" sign upon examination and show a bright reflex at the conical apex surrounded by a dark shadow.

Corneal topography images are more helpful in early diagnosis of keratoconus, especially in pediatric patients when visual acuity may still be corrected using spectacles. When looking at topography images it is especially important to consider the inferior steepening as well. Progression of the K values as measured by the topography imaging may be very quick and differences in K's can be measured in as few as three months.

Scheimpflug Imaging creates a 3 dimensional model of the anterior segment of the cornea. Pentacam and Galilei cameras take over 25,000 elevation points to create the model without any contact to the surface of the cornea. These image representations give information regrading anterior instantaneous curvature, pachymetry, anterior elevation, posterior elevation, pupil indices, to aid in keratoconus detection.

Belin Ambrosio Display (BAD) combines the information from the posterior and anterior elevations and corneal thickness in a single map.

Ultrasound pachymetry using a probe is an effective and efficient way to determine the thickness of a patient's cornea. Pachymetry values can also be found using Scheimpflung imaging, confocal microscopy, scanning slit topography, optical coherence tomography (OCT), partial coherence laser interferometry (PCI), and optical low-coherence reflectometry (OLCR).

Laboratory test

There is currently only one company manufacturing genetic testing for predisposition of keratoconus. The genetic eye test uses next generation sequencing to determine a risk score of developing keratoconus based genes that are highly correlated with the disease.

Differential diagnosis

Congenital Astigmatism can cause blurry or distorted vision in patients due to irregular curvature of the cornea. However, this curvature Astigmastism can be resolved with spectacle correction or refractive laser surgery. Astigmatism has 2 curvatures of the eye whereas keratoconus has more than 2.

Axial Myopia in children may progress through the first and second decade of life. Combined with astigmatism, these patients should be moniored closely for keratoconus due to the rapid nature of pediatric keratoconus. Patients with high myopia have been shown to have a greater risk of developing keratoconus, one study sites almost double the risk in high myopic patients compared to control patients .

Pellucid Marginal Corneal Degeneration (PMD) is often confused with keratoconous. PMD causes abnormal thinning of the periphery of the cornea and severe inferior steepening on anterior corneal maps. Keratoconus usually presents with topographical signs decades before PMD patients.

Keratoglobus is the bilateral thinning of the cornea and an abnormal globe-shaped (globular) or spherical form to the cornea. Unlike keratoconus fleischer rings, Vogt striae, and anterior stromal scarring are not typical, but Descemet membrane thickening and folds are common in keratoglobus.

Management + Treatment

Management of keratoconus includes avoidance of recurrent ocular microtrauma by making sure to prevent eye rubbing and nocturnal pressure on eyes as much as possible. Ocular allergies should be controlled adequately prior to surgical interventions due to the increased likelihood of infection. Additionally, if the disease has not stabilized corneal collagen cross linking is the recommended surgical option to halt progression of the steepening of the cornea and worsening visual acuity. Management of keratoconus, once stabilized, includes follow ups with topography and pachymetry testing as well as management through spectacle or contact lens usage.

Corneal Collagen Crosslinking (KXL) has quickly become the most popular treatment options for adults with progressive keratoconus and standard epithelium-off KXL treatment has been reviewed for pediatric patients as well. The goal of the treatment is to increase the biomechanical rigidity of the cornea through the use of riboflavin and UV light. Riboflavin increases the absorption of UV‐A by the corneal stroma. The riboflavin generates reactive oxygen when exposed to UV-A light. The reactive oxygen then reacts with available groups to create chemical bonds between amino acid residues thus increasing "cross‐linking between proteoglycans and collagen with the resultant photopolymerization of collagen fibrils improving biomechanical properties". Epi-off has proven to stabilize the corneas in both pediatric and adult patients however pediatric patients do have a higher rate of progression after KXL . This standard for KXL has reported stability up to five years in pediatric patients with studies reporting 80% of pediatric patients had improved visual acuity and Kmax values reducing over the span of four years after KXL.

Epi-on KXL has also been used in pediatric patients because it reduces pain postoperatively and has a reduced risk of infection. This is important for pediatric patients as compliance may not be as high as with adult patients. However, the stabilization rates after the procedure have shown variable results, often with progression of K values after a 12 month period.

Keratoplasty options for treatment of advanced keratoconus include Deep anterior lamellar keratoplasty (DALK) and Penetrating keratoplasty (PK). However, keratoplasty in pediatric patients has a poorer prognosis than in adult patients. DALK is increasingly more common than PK due to the reduction in graft rejection and better stability. In both cases there still remains an uncertainty of whether or not a patient may need a second graft in their lifetime, especially in pediatric patients.

Contact lenses often offer keratoconus patients the best visual acuity. Spectacles and soft toric lenses can be used to correct astigmatism in mild and stable cases of keratoconus. However, in moderate to severe cases of keratoconus, rigid gas permeable contact lenses are needed as these offer improvement in visual acuity by neutralizing the irregular astigmatism. These contact lenses may be uncomfortable to keratoconus patients and cause dryness, pain, and itching. To alleviate such symptoms, specialty contact lenses that are customized to each patient such as RoseK, or other options such as semi-scleral contact lenses, piggyback lens use (hard lens over soft lens), scleral lenses, hybrid lenses, and PROSE (prosthetic replacement of the ocular surface ecosystem) may also be a better fit for irregular and steep corneas found in keratoconus.

Prognosis

Most patients, given proper treatment and early intervention, have good visual acuity with correction. Progression of the disease has been noted in studies in about 20% of patients and thus patients should be followed regularly. Patients with steeper corneas prior to KXL seem to show similar rates of stability after the procedure, thus emphasizing that severity of disease will not impact the effectiveness of KXL's ability to stabilize the cornea at the point it is at.