Noninflammatory Ectatic Disorders

Key Concepts

Keratoconus should be suspected in a young person whose eyes cannot be refracted to 20/20 or requires multiple changes of glasses.
Atopy, Ehlers-Danlos syndrome, Down syndrome, Leber congenital amaurosis, and eye rubbing are associated with keratoconus.
Thinning at the apex of corneal protrusion is the hallmark of keratoconus.
Inferior steepening, superior flattening, skewing of the radial axes, decentered corneal thinning, and islands of anterior and posterior elevation are all corneal topographic and tomographic findings consistent with keratoconus.
Cornea crosslinking to reduce keratoconus progression works best in young patients with mild to moderate disease.
Deep anterior lamellar keratoplasty is appropriate for the keratoconus patient without deep stromal scarring and has the advantage of eliminating the risk of endothelial rejection. Stromal rejection, however, can occasionally be problematic.
The hallmark of pellucid marginal degeneration (PMD) is corneal protrusion central to a peripheral band of corneal thinning, which typically occurs inferiorly. The crab-claw pattern on a power map is often seen in PMD but can also be seen in inferior keratoconus.
In keratoglobus, the cornea is diffusely steep and thin with maximum thinning in the periphery. In contrast to congenital glaucoma and anterior megalophthalmos, the corneal diameter is only slightly enlarged.

The noninflammatory ectatic diseases of the cornea discussed in this chapter are keratoconus, pellucid marginal degeneration (PMD), keratoglobus, and posterior keratoconus. Beside the similarities in name, these conditions, to varying degrees, are similar in clinical presentation ( Table 73.1 ). Corneal ectasia following keratorefractive surgery resembles keratoconus and is presumed to be iatrogenic in nature and will also be discussed in this chapter.

TABLE 73.1

Noninflammatory Ectatic Disorders—Clinical Presentation and Appearance Compared and Contrasted

	Keratoconus	Pellucid Marginal Degeneration	Keratoglobus	Posterior Keratoconus
Frequency	Most common	Less common	Rare	Least common
Laterality	Usually bilateral	Bilateral	Bilateral	Usually unilateral
Age at onset	Puberty	Age 20–40 years	Usually at birth	Birth
Thinning	Inferior paracentral	Inferior band 1−2 mm wide; 1−2 mm from the limbus	Greatest in periphery	Paracentral posterior excavation
Protrusion	Thinnest at apex	Superior to band of thinning	Generalized	Usually none
Iron line	Fleischer ring	Sometimes	None	Sometimes
Scarring	Common	Only after hydrops	Mild	Common
Striae	Common	Uncommon	Sometimes	None

Corneal thinning is a hallmark of these ectatic diseases. Recognizing the relationship between the points of maximal thinning and maximal corneal protrusion is helpful in differentiating these conditions. Distortion of the anterior corneal curvature occurs in keratoconus, PMD, and keratoglobus ( Fig. 73.1 ) and results in varying degrees of reduced visual function.

Corneal topography and corneal tomography have dramatically improved the sensitivity of detection of these ectatic disorders, particularly in the case of keratoconus. This has prompted debate on appropriate terminology for the patient with diagnostic evidence of inferior steepening, islands of elevation, or eccentric thinning, but without overt clinical signs or symptoms of keratoconus. Keratoconus suspect and subclinical keratoconus are commonly used terms. Forme fruste keratoconus refers to disease in which progression appears to have been arrested at an early stage. Topography and tomography have been of great value in refining study populations for genetic studies and are an integral part of the screening examination for keratorefractive surgery.

Keratoconus, PMD, and keratoglobus share a basic treatment algorithm early in the course of disease. Visual correction begins with glasses; when unsatisfactory this is followed by contact lens fitting. Patients with mild to moderate keratoconus may benefit from corneal collagen crosslinking (CXL) to help limit progression. Intrastromal ring insertion may improve contact lens tolerance and visual function. When the above treatments fail to achieve adequate visual function, either deep anterior lamellar keratoplasty (DALK) or penetrating keratoplasty (PKP) has the potential to restore vision.

Posterior keratoconus differs from the other noninflammatory ectatic disorders in many respects. To reduce the confusion caused by the similarity in name, it is included in the discussion that follows.

Keratoconus

Definition

Keratoconus is a condition in which the cornea assumes a conical shape because of thinning and protrusion. The process is conventionally thought to be noninflammatory. Cellular infiltration and vascularization do not occur. It is usually bilateral, although it may present with marked asymmetry. The disease typically involves the central two-thirds of the cornea with the apex of the cone usually centered just below the visual axis. This condition may result in mild to marked visual impairment.

Prevalence, Distribution, and Course

Keratoconus occurs in people of all races with no significant gender predominance.

Reported prevalence of keratoconus varies widely depending on diagnostic criteria and geographic location, ranging from 0.3 to 2300 per 100,000. Studies in Asia and the Middle East suggest higher rates of keratoconus in these regions compared with reported rates in Caucasians.

Keratoconus usually occurs bilaterally. While some experts believe that true unilateral keratoconus does not exist, cases of unilateral keratoconus have been reported. Asymmetry in keratoconus may be related to eye rubbing. It has been convincingly shown that contemporary diagnostic analysis results in the detection of subclinical keratoconus in the fellow eye. With this in mind, the incidence of unilateral involvement is probably in the range of 2%–4%.

The onset of keratoconus occurs at about the age of puberty. The cornea begins to thin and protrude, resulting in irregular astigmatism with what is usually a steep curvature. The rate of progression is more rapid in the teens and 20s, slows in the 30s, and typically stops in the early 40s. For this reason, younger patients should be examined more frequently. If a faint broad iron ring is present early on in the course, it becomes a thinner, more discrete ring over time.

Progression has been defined as a consistent change in at least 3 of the following parameters: (1) steepening of the anterior corneal surface, (2) steepening of the posterior corneal surface, or (3) thinning and/or an increase in the rate of corneal thickness change from the periphery to the thinnest point.

Associated Disease

Systemic Disease

Over the past half century, much has been written linking keratoconus to atopic diseases.

The Dundee University Scottish Keratoconus Study (DUSK) reviewed 200 keratoconus subjects and found the incidence of hay fever to be 30%, asthma 23%, eczema 14%; comparative survey results of 100 control patients showed that incidence of these disorders was 16%, 6%, and 16%, respectively. The Collaborative Longitudinal Evaluation of Keratoconus (CLEK) study of over 1200 keratoconus patients found a 53% incidence of atopic disease. The diagnosis of keratoconus in this study was made prior to the advent of tomography.

A thorough evaluation of the keratoconus patient should include a complete history of atopic disease. Appropriate referrals can be made if significant atopic disease is newly revealed. Allergic lid and conjunctival disease can adversely affect contact lens tolerance. As a result, surgical intervention may be required earlier in the course of the disease.

The association with Down syndrome has been strongly established with the prevalence of keratoconus estimated to be 10- to 300-fold higher than the general population. ^,

Keratoconus also occurs with increased frequency among developmentally delayed individuals without Down syndrome, and the incidence of unilateral disease may be substantially higher in this group compared with the general population.

Two plausible explanations for this association with keratoconus are that either genetic abnormalities underlie structural or biochemical changes resulting in the well-recognized phenotype or that eye rubbing is the root cause. Corneal hydrops occurs with increased frequency in patients with Down syndrome or other forms of intellectual impairment, and this may also result from habitual oculodigital stimulation.

Keratoconus has long been known to occur in patients with noninflammatory connective tissue disorders. Most notable among these are Ehlers−Danlos syndrome and osteogenesis imperfecta. Robertson found the prevalence of hypermobility of the joints to be 50% in 44 consecutive keratoconus patients. Joint hypermobility in keratoconus has subsequently been confirmed, especially for the metacarpophalangeal and wrist joints.

An increased prevalence (6%–58%) of mitral valve prolapse has been found in keratoconus patients. The prevalence appears to increase with severity of the corneal disease. In contrast, Street et al. were unable to confirm the association of keratoconus, mitral valve prolapse, and joint hypermobility in a well-controlled study of 95 keratoconus patients. The association with floppy eyelid syndrome has been reported with a prevalence of 17%. Given the well-established association between floppy eyelid syndrome and sleep apnea, it is not surprising that a higher proportion of keratoconus patients was found to either suffer from or were at risk of sleep apnea in a study based on the Berlin Questionnaire.

In two large case-control studies, ^, the prevalence of diabetes was significantly lower in keratoconus patients versus a control group. Statistical analysis demonstrated a strong protective effect of diabetes against keratoconus. This effect was only seen in type 2 diabetes.

Mannis et al. found patients with keratoconus and other chronic eye diseases to be less conforming and more passive-aggressive, paranoid, and hypomanic than normal control individuals based on personality testing.

Additional associations between keratoconus and systemic diseases can be found in Table 73.2 .

TABLE 73.2

Systemic and Ocular Conditions Associated With Keratoconus

Adapted from Table 1 in Sugar J, Macsai M. What causes keratoconus? Cornea 2012; 31 (6):716−9.

Systemic Syndromes		Ocular Syndromes
Alagille syndrome	Joint hypermobility	Aniridia
Albers-Schönberg disease	Kurz syndrome	Essential iris atrophy
Albinism	Marfan syndrome	Floppy eyelid syndrome
Angelman syndrome	Mitral valve prolapse	Fuchs corneal dystrophy
Anetoderma	Mulvihill Smith syndrome	Granular corneal dystrophy
Apert syndrome	Nail patella syndrome	Iridoschisis
Autographism	Neurocutaneous angiomatosis	Lattice corneal dystrophy
Bardet−Biedl syndrome	Neurofibromatosis	Leber congenital amaurosis
Brittle cornea syndrome	Noonan syndrome	Posterior polymorphous dystrophy
Congenital hip dysplasia	Osteogenesis imperfecta	Progressive cone dystrophy
Congenital rubella	Oculodentodigital syndrome	Retinitis pigmentosa
Crouzon syndrome	Pseudoxanthoma elasticum	Retinopathy of prematurity
Down syndrome	Rieger syndrome	Vernal conjunctivitis
Ehlers-Danlos syndrome	Rothmund syndrome
False chordae tendineae	Sleep apnea syndrome
Focal dermal hypoplasia	Thalesselis syndrome
Goltz-Gorlin syndrome	Tourette syndrome
Hyper-IgE syndrome	Turner syndrome
Hyperomithinemia	Xeroderma pigmentosa
Ichthyosis

Ocular Disease

Keratoconus may appear in association with other ocular conditions. A classic example is retinitis pigmentosa. Leber congenital amaurosis is frequently complicated by keratoconus and cataract. In a classic large study, more than one-third of Leber patients over 45 years old also had keratoconus. Keratoconus occurring in patients with advancing age has been confirmed. Moschos et al. studied 233 keratoconus patients and found 2.6% with electroretinogram abnormalities and 3.9% with abnormal visual evoked response, confirming the presence of diffuse or central tapetoretinal degeneration. Elder found a much higher incidence of keratoconus among children with Leber congenital amaurosis compared with a group of children blind from other causes. As a result of this study, a genetic basis, rather than an environmental cause such as eye rubbing, was suspected.

Additional associations between keratoconus and ocular diseases appear in Table 73.2 .

Etiology

The various associations with systemic and ocular diseases have led to the development of many theories regarding the etiology of keratoconus. Nevertheless, the cause of this corneal disorder remains an enigma. The current consensus is that the pathophysiology of keratoconus is multifactorial and influenced by environmental, genetic, and biochemical factors. The etiology of keratoconus is considered below and in the three sections that follow.

Several reports have implicated eye rubbing as an important etiologic factor in the development of keratoconus. ^, In the DUSK study of 200 keratoconus patients, 48% reported frequent eye rubbing, while only 11% reported never rubbing their eyes.

The microtrauma associated with eye rubbing may be the etiologic link between conical cornea and associated systemic and ocular diseases. Itching, ocular irritation, and eye rubbing are common features of vernal keratoconjunctivitis and atopic disease. Vigorous eye rubbing has frequently been observed in patients with Down syndrome and may explain the high incidence of associated corneal hydrops. Finally, eye rubbing is commonly seen in poorly sighted patients with Leber congenital amaurosis and retinopathy of prematurity, both of which are associated with keratoconus. Bawazeer et al. found that while atopy, eye rubbing, and family history of keratoconus were all associated with the development of keratoconus, only eye rubbing reached statistical significance on multivariate analysis.

Contact lens wear is another form of corneal microtrauma that is associated with keratoconus. Retrospective studies have found a history of contact lens wear before the diagnosis of keratoconus in 17.5% –26.5% of cases. A retrospective review identified a subgroup of keratoconus patients who were not thought to have had the condition before beginning contact lens wear. These long-term contact lens wearers were older and tended to have central cones and flatter corneal curvature than keratoconus patients with no history of contact lens wear before diagnosis.

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