Continuing Education Activity

Keratoconus (KCN) is a progressive non-inflammatory bilateral corneal ectatic disorder. It manifests with characteristic cone-like steepening of the cornea associated with irregular stromal thinning, resulting in a cone-like protrusion and significant loss of vision. Patients typically experience variable reductions in visual acuity, image distortion, and increased sensitivity to glare and light. Because of significant asymmetry, spherocylindrical spectacle lenses typically are not able to provide adequate vision correction. KCN may remain subclinical and may be classified as slightly asymmetric oblique astigmatism. This activity illustrates the evaluation and treatment of keratoconus and reviews the role of interprofessional team members in managing those with this condition.

Objectives:

• Describe the clinical course of keratoconus.
• Describe the evaluation of keratoconus.
• Review the strategies for managing keratoconus.
• Explain how an interprofessional approach is imperative to the effective management of patients with keratoconus.

Introduction

Keratoconus (KCN) is a progressive bilateral corneal ectatic disorder.  It manifests as characteristic cone-like steepening of the cornea associated with irregular stromal thinning, resulting in a cone-like bulge (protrusion) and significant loss of vision.[1][2]

Optical effects 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 adequately correct vision. 

KCN may remain subclinical (i.e., undetected) and simply be classified as slightly asymmetric oblique astigmatism.

The manifest clinical onset of keratoconus (KCN) may occur at puberty (late teens for male and early twenties for female population) and may progress (continuous stromal thinning and corneal steepening) until the third to fourth decade. Beyond this age, it is very rare that there is any progression. In rare cases, KCN may become manifest at a later age, following alteration in the endocrinologic status such as gestation or pregnancy.

The manifestation and the progression of the disease are highly variable and are most often asymmetric between the two eyes of the same patient. It is widely accepted that there is no unilateral KCN, in the sense of unilateral disease; even when there are no clinical signs of the disease in the fellow eye, it is still considered that is simply not manifest in that eye. Severe KCN may develop in acute hydrops.

Etiology

The etiology and pathogenesis of KCN are not known.  Several associations have been identified, which include rigid gas permeable (RGP) contact lens wear, chronic eye rubbing, Down syndrome, atopic disease, Leber congenital amaurosis,[3] connective tissue disease, tapetoretinal degeneration, and inheritance.[1] Often, KCN presents with no other associated systemic or ocular disease. Some rare associations exist as a result of a chromosomal translocation, abnormal enzyme function, and loss of collagen and/or ground substance.[4],[5].  Significant associations of KCN include Down syndrome, with an incidence ranging from 0.5% to 15%, which 10 to 300 times more common than in the general population,[6] Leber congenital amaurosis (up to 30% of patients older than 15 years), and mitral valve prolapse (58%).[7]  

Persistent eye rubbing appears to either cause or exaggerate KCN.[8], [9] Persistent eye rubbing and hard contact lens wear may induce mechanical trauma that may be associated with keratoconus progression in individuals that are genetically predisposed.[10] The mechanical alteration is possibly associated with some form of keratocyte change to a repair phenotype in response to rubbing-associated trauma.[11][2]

Epidemiology

While environmental factors likely play a role in disease prognosis, KCN is considered hereditary.[12] At least 6% to 8% of reported cases have a positive family history or show evidence of familial transmission.[13]  

A peer-review literature search may reveal that the estimates for KCN incidence estimates may range between 50 and 230 per 100,000 (about 1 per 2,000).[14],[15],[16]  The reported numbers are variable. This may be because of the rarity of the disease, but most importantly, on and the non-standard criteria used to establish the diagnosis. The most common citation for the 1:2,000 number stems from a study which was conducted without the use of corneal topography (diagnosis by scissors movement on retinoscopy). 

More specific and sensitive diagnostic tools may allow subtle KCN forms to be detected in the future. New studies conducted internationally suggest a prevalence as high as 1:375 in some populations. [2]

Pathophysiology

KCN has been traditionally classified as a non-inflammatory disease. With the exception of the significant loss of vision, other classic signs of inflammation (such as heat, redness, swelling, pain) are not usually present.[17]

Clinical findings that are associated with KCN are, by order of importance, the asymmetrical thinning of the corneal stroma and the highly irregular corneal topography, which is often (wrongly) reported as steep astigmatism. Other clinical findings that can be observed biomicroscopically include the Fleischer iron rings, Munson sign, Rizzuti sign, and/or Vogt striae.[18][2]

Histopathology

Advanced KCN often presents with breaks in Bowman’s layer (which are filled by eruptions of underlying stromal collagen) and deposition of iron (ferritin particles) in the corneal epithelium basal layers. The basal epithelium cells may show degeneration and epithelial infiltration into Bowman’s layer.

Stroma histopathology can be affected as well, mainly observed as scarring and opacity, compaction and loss of fibrils arrangement (stromal striae), decrease in collagen lamellae density, normal and degenerating fibroblasts in addition to keratocytes, and fine granular and microfibrillar material associated with the keratocytes.[1],[19][2]

History and Physical

KCN has been known since the early days of ophthalmology. The term keratoconus was established later on; originally, there were various names, such as hyperkeratosis or conically formed cornea, all of which described an abnormally deformed and thin cornea, one way or another.[20]

The original description of KCN dates to the early 18th century.  It was first (1854) adequately described and distinguished from other ectatic conditions in the milestone treatise by Nottingham.[21] Possible treatments were also suggested early on. Photinos Pannas (1831- 1902), Professor at the University of Paris, presented a management approach based on glass contact lenses.[2]

Evaluation

While KCN is often accompanied by significant myopia, this is not by itself a criterion. The two most significant presentations are irregular corneal astigmatism and focal stromal thinning. We should distinguish the focal thinning from a generally thin cornea. Also, significant astigmatism, if symmetrical, is not a KCN criterion. It is stressed that the astigmatism noted in KCN is highly asymmetrical. The corneal thinning and the asymmetric astigmatism both occur in the area of the corneal protrusion, which is often infero-temporal. Thus topography, tomography, and pachymetry are the prime diagnostics used in the diagnosis and evaluation of KCN,[22],[23],[24] in addition to biomicroscopic (slit-lamp) evaluation. 

The first use of Placido topography for the diagnosis and classification of KCN was presented by Marc Amsler (1938). Topography can document subtle corneal surface irregularity before other clinical or biomicroscopic signs could be identified. Amsler documented a classification scheme ranging from early changes in cornea shape to clinically detectable keratoconus. Then, he classified KCN into clinically recognizable stages and two latent (subclinical) stages recognizable only by Placido disk corneal topography: forme-fruste[25] and early or mild KCN. 

Today, several ocular imaging modalities, including corneal topography, tomography, and biomechanical evaluation devices have enhanced our ability to detect early KCN in a quantifiable and reproducible manner. Corneal topography is the primary diagnostic tool for KCN detection.[26] The color-coded corneal curvature maps generated by corneal topography may offer a visualization of anterior corneal surface irregularity, mostly noted by a typically infero-temporally located cone area of substantially increased steepening, often as high as 65 D, and a supero-nasally located flat area of decreased steepening, often as low as 35 D. Alternatively, the corneal aberrations map presented by these devices may show substantial amounts of high-order aberrations: a clear presence of coma as the primary aberration, followed by spherical aberration.[27]

Pachymetry data obtained with Scheimpflug-imaging devices, such as the Pentacam (in the past, scanning slit-scan such as the Orbscan), are also used. In addition to the corneal curvature, these devices offer detailed pachymetry maps that present a corneal thinning. The thinnest cornea correlates well with the location of the maximum corneal steepening (cone location).[28] These devices also can be used to produce anterior and posterior corneal surface elevation maps. A characteristic asymmetry in posterior surface elevation is considered a specific and sensitive indicator for the disease.[29] 

Other specific quantitative values produced by Placido topography or Scheimpflug imaging topometry that can be used as progression determinants of the disease are anterior surface irregularity indices, such as the Index of Height Decentration (IHA).[30]

Lately, the use of anterior-segment optical coherence tomography (OCT) has been progressively used in the clinical diagnosis of keratoconus.  The use of OCT can provide meridional cross-section (B-Scan) images of the cornea, revealing the asymmetric corneal thinning and posterior curvature asymmetry.[31]  More recent is the use of spectral-domain OCT as a corneal pachymetry tool, revealing corneal thickness asymmetry associated with KCN.[32]

The investigation of corneal epithelial thickness distribution, facilitated by the most recent Fourier-domain OCT devices, can be a very sensitive and specific indicator for KCN.[33] A key feature of the epithelium is that its thickness is such that it acts as a mask for underlying stromal thickness irregularities. Thus, it can be thinner (even less than 20 micrometers) over the most protruding part of the cornea[34] and thicker (even more than 70 micrometers) over the flatter areas. This epithelial thickness distribution, if not accounted for, results in a false presentation of a slightly more uniform corneal thickness, masking early signs of corneal thickness irregularities measured with other devices so far, such as those based on Scheimpflug imaging, and reducing the degree of corneal curvature irregularity, as measured by Placido topography.  

Other ocular clinical diagnostics that can be used as facilitators in the diagnosis of keratoconus include the tear fluid as a biomarker for KCN[35] and corneal biomechanics.[36]  [2] 

Treatment / Management

The available options for the management of KCN are highly dependent on the stage of the disease and its progression. If the disease is stabilized (no progression), the emphasis is given in correcting the vision. If the disease is progressing, the emphasis is to slow (arrest) the procession.[37]

Since the effects of KCN in cornea shape distortion and stromal thinning are highly asymmetric, vision correction with spectacles and with spherical/toric soft contact lenses is suboptimal and only applicable to the early stages of KCN.  Custom-designed soft contact lenses which incorporate aberration-controlled designs may provide some control of the primary aberrations associated with KCN such as coma and spherical aberration.[38]

Rigid gas permeable (RGP) contact lenses and scleral lenses are the mainstays of vision treatment for modest-to-advanced KCN. Their main advantage is the creation of the tear pool between the lens and the cornea, which naturally neutralizes the ocular aberrations associated with the keratoconic ectasia, thus possibly providing nearly excellent corrected vision.[39] A disadvantage relating to the use of RGP lenses is that they may not be tolerated. RGP lens wear in KCN is often complicated. Primary complains include intolerance, allergic reactions (such as giant papillary conjunctivitis), corneal abrasions,[40] and neovascularization. Alternatives include hydrogel contact lenses, piggyback contact lenses or scleral contact lenses. The latter provide excellent vision and improved comfort.[41]

Corneal collagen cross-linking (CXL) is a minimally invasive outpatient procedure that has been shown to be effective in the arrest of the progression of KCN.[42] It leads to an increase of stromal rigidity, thus slowing and eventually stabilizing the progression of the keratectasia. This has been demonstrated in ex vivo studies through mechanical (tensile test) and biological testing (enzymatic digestion).[43] CXL application, when successful, leads to far less need for penetrating keratoplasty.[44]

When activated with UVA light (365 nm), riboflavin 5‘-phosphate functions as a photo enhancer and generates singlet oxygen and reactive species which are responsible for cross-linking. The classical, or Dresden protocol,[45]  involves epithelial debridement (to facilitate penetration of riboflavin and a high level of UVA absorption in the stroma), soaking the exposed stroma with riboflavin for about 30 minutes (to allow sufficient saturation in the stroma), and irradiation by 3 mW/cm2 of UVA for 30 minutes. Total energy dissipated is 5.4 J/cm2. A drug and device combination product was approved for cross-linking for the treatment of progressive keratoconus by the US Food and Drug Administration (FDA) in April 2016.

Other CXL protocols have been suggested and are in use outside the United States, which involve the use of increased irradiation and shorter exposure time. CXL has also been combined with topography-guided laser-ablation corneal surface normalization (Athens protocol)[46] in an effort to combine the effects of ectasia arrest (CXL) with improved visual function.[47]

While CXL does not necessarily improve the quality of vision, it is important to stress that early diagnosis may make a significant difference in the success of keratoconus management.  If the disease is diagnosed at an early stage, then both the corneal irregularity and thinning may be only minimally affected. In those cases, the effect of biomechanical stabilization provided by CXL will prevent future vision loss.

Other treatment modalities include intra-corneal ring segments (INTACS). This is a small curved PMMA ring or set of rings that is implanted in the cornea to help flatten corneal curvature in an effort to improve vision.[48]   

Corneal transplant is considered the last resort when the cornea is too thin to receive CXL and the symptoms are severe. The cornea is replaced fully (penetrating keratoplasty) or in part (lamellar keratoplasty) with healthy donor cornea tissue. [2]

Differential Diagnosis

• Contact lens complications

• Contact lens-induced corneal warpage

• Corneal ectasia

• Corneal ectasia due to refractive surgery

• Diplopia

• Interstitial keratitis

• Keratoglobus

• Pellucid marginal degeneration

Enhancing Healthcare Team Outcomes

When primary providers, such as physicians, physician assistants, and nurse practitioners encounter patients with vision problems, referral to an optician, ophthalmic nurse, and ophthalmologist is highly recommended. Keratoconus is primarily managed by eye surgeons. Today, several treatments are available including corneal transplant. So far no treatment is ideal and patient selection is important. [49][50] an interprofessional team is best for followup involving both the specialists and primary care providers. [Level V]