73
Noninflammatory Ectatic Disorders
KEY CONCEPTS
• K eratoconus 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.
The noninflammatory ectatic diseases of the cornea discussed in this
chapter are keratoconus, pellucid marginal degeneration (PMD), kera-
toglobus, 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 resem-
bles keratoconus and is presumed to be iatrogenic in nature and will
also be discussed in this chapter.
Corneal thinning is a hallmark of these ectatic diseases. Recogniz-
ing the relationship between the points of maximal thinning and max-
imal 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, partic-
ularly in the case of keratoconus. This has prompted debate on appro-
priate 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 algo-
rithm 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.
Robert S. Feder, Hong-Gam Le
• D eep 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.
When the above treatments fail to achieve adequate visual function,
either deep anterior lamellar keratoplasty (DALK) or penetrating kera-
toplasty (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 convention-
ally thought to be noninflammatory. Cellular infiltration and vascu-
larization 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 100,000.1 Studies in Asia2 and the Middle East3 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,4 cases of unilateral
keratoconus have been reported.5 Asymmetry in keratoconus may be
749
750 PART VII Diseases of the Cornea
$ %
Fig. 73.1 The presence of corneal thinning and the type of contour abnormality can be helpful in recognizing
the type of ectatic disorder. (A) Keratoconus; (B) pellucid marginal degeneration; (C) keratoglobus; and (D)
posterior keratoconus.
related to eye rubbing.6 It has been convincingly shown that contem-
porary diagnostic analysis results in the detection of subclinical kera-
toconus 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 sur-
face, (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.4
Associated Disease
Systemic Disease
Over the past half century, much has been written linking keratoconus
to atopic diseases.7–9
The Dundee University Scottish Keratoconus Study10 (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 Evalu-
ation of Keratoconus (CLEK) study11 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 conjuncti-
val disease can adversely affect contact lens tolerance. As a result, sur-
gical intervention may be required earlier in the course of the disease.
The association with Down syndrome has been strongly estab-
lished12–14 with the prevalence of keratoconus estimated to be 10- to
300-fold higher than the general population.15,16
& '
Keratoconus also occurs with increased frequency among develop-
mentally delayed individuals without Down syndrome, and the inci-
dence of unilateral disease may be substantially higher in this group
compared with the general population.17
Two plausible explanations for this association with keratoconus
are that either genetic abnormalities underlie structural or biochem-
ical changes resulting in the well-recognized phenotype or that eye
rubbing is the root cause. Corneal hydrops occurs with increased fre-
quency in patients with Down syndrome or other forms of intellec-
tual impairment, and this may also result from habitual oculodigital
stimulation.
Keratoconus has long been known to occur in patients with nonin-
flammatory connective tissue disorders.15 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.18 Joint hypermobility in keratoconus
has subsequently been confirmed, especially for the metacarpophalan-
geal and wrist joints.19
An increased prevalence (6%–58%)20–22 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.23
were unable to confirm the association of keratoconus, mitral valve
prolapse, and joint hypermobility in a well-controlled study of 95 ker-
atoconus patients. The association with floppy eyelid syndrome has
been reported with a prevalence of 17%.24 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.25
In two large case-control studies,26,27 the prevalence of diabe-
tes 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.28 found patients with keratoconus and other chronic
eye diseases to be less conforming and more passive-aggressive, para-
noid, and hypomanic than normal control individuals based on per-
sonality testing.
 CHAPTER 73 Noninflammatory Ectatic Disorders 751

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 Greatest in periphery Paracentral posterior exca-
the limbus vation
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

TABLE 73.2 Systemic and Ocular Conditions Associated With Keratoconus

Systemic Syndromes Ocular Syndromes
Alagille syndrome Joint hypermobility Aniridia201
Albers-Schönberg disease Kurz syndrome Essential iris atrophy202
Albinism Marfan syndrome Floppy eyelid syndrome25
Angelman syndrome Mitral valve prolapse Fuchs corneal dystrophy203
Anetoderma204 Mulvihill Smith syndrome Granular corneal dystrophy205
Apert syndrome Nail patella syndrome Iridoschisis206
Autographism Neurocutaneous angiomatosis Lattice corneal dystrophy207
Bardet−Biedl syndrome208 Neurofibromatosis Leber congenital amaurosis33
Brittle cornea syndrome Noonan syndrome Posterior polymorphous dystrophy209
Congenital hip dysplasia Osteogenesis imperfecta Progressive cone dystrophy210
Congenital rubella Oculodentodigital syndrome Retinitis pigmentosa29
Crouzon syndrome Pseudoxanthoma elasticum Retinopathy of prematurity
Down syndrome Rieger syndrome Vernal conjunctivitis29
Ehlers-Danlos syndrome Rothmund syndrome
False chordae tendineae Sleep apnea syndrome25
Focal dermal hypoplasia211 Thalesselis syndrome
Goltz-Gorlin syndrome Tourette syndrome
Hyper-IgE syndrome Turner syndrome
Hyperomithinemia Xeroderma pigmentosa
Ichthyosis
Adapted from Table 1 in Sugar J, Macsai M. What causes keratoconus? Cornea 2012;31(6):716−9.

Additional associations between keratoconus and systemic diseases
can be found in Table 73.2.
Ocular Disease
Keratoconus may appear in association with other ocular conditions.
A classic example is retinitis pigmentosa.29 Leber congenital amaurosis
is frequently complicated by keratoconus and cataract. In a classic large
study,30 more than one-third of Leber patients over 45 years old also
had keratoconus. Keratoconus occurring in patients with advancing
age has been confirmed.31 Moschos et al.32 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. Elder33 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 kera-
toconus. Nevertheless, the cause of this corneal disorder remains an
enigma.34 The current consensus is that the pathophysiology of kerato-
conus is multifactorial and influenced by environmental, genetic, and
biochemical factors.4 The etiology of keratoconus is considered below
and in the three sections that follow.
Several reports have implicated eye rubbing as an important etio-
logic factor in the development of keratoconus.6,35 In the DUSK study10
752 PART VII Diseases of the Cornea
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 dis-
eases. 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.35 found that while
atopy, eye rubbing, and family history of keratoconus were all associ-
ated 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%36–26.5%37 of cases. A retrospective review37 identified a sub-
group 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.
Biochemistry
Biochemistry has provided an important line of research into the eti-
ology of keratoconus. Since much of the work has been done on host
corneas following PKP, it is important to keep in mind that the results
of many of these studies relate more to advanced keratoconus.
The total amount of protein is decreased in keratoconus.38 Theoret-
ically, an upregulation of degradative enzymes and the downregulation
of proteinase inhibitors could result in a degradation of the extracellu-
lar matrix of the stroma. The level of degradative lysosomal enzymes,
such as acid esterase and acid phosphatase, cathepsins B and G, and
some matrix metalloproteinases, has been shown to be elevated in ker-
atoconus corneas.39,40 These findings are predominately present in the
corneal epithelium.
If an enzymatic imbalance within the epithelium alone caused ker-
atoconus, one might expect a significant recurrence rate following a
corneal graft after replacement with host epithelium. In fact, the recur-
rence rate following PKP is low. One must assume that the pathogen-
esis of keratoconus is more complex than the preceding theory would
suggest.
Keratocytes from keratoconus corneas have been found to have
four times the interleukin-1 binding sites, compared to nonkerato-
conus corneas.41,42 This may result in an increased sensitivity to the
effects of interleukin-1, which has been shown to induce apoptosis of
stromal keratocytes in vitro. Apoptosis has been found in the stroma
of keratoconus corneas, but not in normal controls.43 Wilson et al.44
postulated that the corneal epithelium might release interleukin-1 in
response to microtrauma occurring after eye rubbing or contact lens
wear. This in turn could trigger apoptosis of stromal keratocytes in ker-
atoconus patients with heightened sensitivity to interleukin-1.
Heredity
The most compelling evidence for a genetic origin in some forms of
keratoconus is the degree of concordance between monozygotic twins.
There are reports of at least 18 sets of monozygotic twins45 that identify
one or both siblings in the pair with evidence of keratoconus. Seven
of the 18 pairs evaluated without corneal topography were concordant
for keratoconus. Edwards et al.45 correctly point out that the evidence
of discordance cannot be considered conclusive in the absence of
corneal topography. In addition, evaluations may have been performed
in younger patients, prior to the development of keratoconus. At least
19 concordant pairs have been reported since the advent of corneal
topography.46–49
McMahon et al.50 described two pairs of discordant monozygotic
twins, in which one of each pair had keratoconus and the other had
normal corneal topography in both eyes. It was suggested that an envi-
ronmental trigger might be necessary in addition to a genetic predis-
position or that genetic differences between the individuals may exist,
even in monozygotic twins. A “two-hit” hypothesis, that is, genetic pre-
disposition plus environmental insult, such as eye rubbing, is a leading
theory on the development of keratoconus.34
The frequency of inheritance has been estimated to be 6%.51 Cor-
neal topography has been used to examine family members of kera-
toconus patients.52–54 Corneal contour abnormalities were uncovered
in some clinically unaffected relatives. Whether these patients would
progress to clinically significant disease is unknown. This evidence has
supported a pattern of autosomal dominant inheritance with incom-
plete penetrance. The information gathered using corneal contour
imaging may help create more accurate pedigrees in families with ker-
atoconus, which could be used in future genetic study.
Molecular genetic techniques are being used to study candidate
genes for proteins that may be involved in the development of kera-
toconus, for example, genetic changes in the collagen pathway, the
interleukin-1 system, proteases, and protease inhibitors.54–56 Linkage
analysis has been utilized to map susceptible genetic loci, and many
distinct genomic loci have been mapped to the disease, indicating a
high degree of genetic heterogeneity. Most of these loci were isolated in
large keratoconus pedigrees. Despite efforts to screen numerous can-
didate genes within these loci, identification of causative genes (and
mutations) remains a challenge.
Patients commonly ask if keratoconus is inherited and if their chil-
dren will develop the disorder. Review articles regarding the genetics of
keratoconus focus on the genetic risk factors and possible genetic links
to comorbidities.12,57 Using clinical evaluation and three keratographic
indices, Wang et al.58 found the keratoconus prevalence of first-degree
relatives to be 3.34%, which is up to 68 times that found in the general
population. It seems reasonable to tell parents that the chance that a
first-degree relative would be found to have symptoms of the disease,
while significantly greater than the general population, is still less than
1 in 20. Future studies based on anterior segment optical coherence
tomography (AS-OCT)59 or Scheimpflug tomography60 rather than
Placido-based systems may result in a higher incidence of subclinical
keratoconus.
The phenotypic appearance commonly recognized as keratoconus
may occur in patients having multiple genotypes. Keratoconus study
populations that have associated ocular or systemic diseases in com-
mon or contour characteristics in common may be more likely to share
a common genotype. Identifying such specific study groups is essential
in the genetic study of keratoconus.12,57
Pathology
Every layer and tissue of the cornea can potentially be involved in the
pathologic process of keratoconus. Central epithelial thinning has been
found with variable frequency.61 In contrast, thickening of the epithe-
lium has been demonstrated on clinical imaging with AS-OCT.62 Spec-
ular microscopy of the corneal epithelium has revealed enlargement of
the superficial cells and prominence of elongated cells, specifically over
the apex of the cone. These findings were not seen in long-term hard
contact lens wearers.63 TUNEL-positive epithelial cells were detected
in deeper epithelium, signifying apoptosis and cell death in an atopic
animal model, with findings consistent with keratoconus.64 Early
 CHAPTER 73 Noninflammatory Ectatic Disorders
1 1
$
% Endothelial cell pleomorphism and polymegethism occur in ker-
Fig. 73.2 The Fleischer ring in keratoconus. (A) The Fleischer ring (1)
is a landmark indicating the location of the base of the cone; (2) pupil
margin. (B) The ring results from hemosiderin pigment deposited in the
basal epithelium (Prussian blue stain, ×200).
degeneration of the basal epithelial cells can be followed by disruption
of the epithelial basement membrane. Breaks in the epithelial layer can
be associated with epithelium growing posteriorly into the Bowman
layer (BL) and collagen growing anteriorly into the epithelium, form-
ing Z-shaped interruptions at the level of BL,65 which are typical of
keratoconus.
A hallmark of keratoconus is the Fleischer ring found at the base
of the cone (Fig. 73.2A). The iron ring can be seen histopathologically
(Fig. 73.2B). Light and electron microscopy reveal that ferritin particles
accumulate within and between the epithelial cells, particularly in the
basal epithelium.66
Anterior clear spaces detected clinically within the thinned stroma
of the cone have been correlated with interruptions of BL.67 It has
been postulated that these breaks in BL may later fill with scar tissue
(Fig. 73.3). Consolidation of these fine scars may result in the reticu-
lar branching opacities often seen at this level. Perry et al. found that
breaks in BL occurred with increased frequency in oval, sagging cones
compared with round cones.68
The pathology of collagen fibrils in keratoconus has been well stud-
ied. Pouliquen et al.69 found normal-sized collagen fibers; however, the
number of collagen lamellae was abnormally low. The number found
within the cone was less than half (41%) the number outside of the
cone. Fullwood et al.70 found no significant difference in interfibril-
lar spacing between keratoconus and control corneas. They concluded
that the stromal thinning was not the result of closer packing of the
stromal collagen fibrils.
753
Fig. 73.3 Breaks in the Bowman layer fill in with collagenous scar tis-
sue (1) (hematoxylin and eosin stain, ×400). This process results in the
reticular, subepithelial, and anterior stromal scars typical of keratoconus.
It has been suggested that collagen lamellae are released from their
interlamellar attachments or from their attachments to BL and become
free to slide. This results in thinning without collagenolysis.71 The
interlamellar strength profile in the normal cornea has been found to
be significantly weaker inferiorly and centrally.72 Significant alteration
of the normal orthogonal arrangement of the collagen fibrils found
in keratoconus may be related to this biomechanical instability of the
stromal tissue.73 The most common location for the apex of the cone,
in the central or inferior cornea, may be related to this inherent corneal
weakness. This may also explain the association of eye rubbing with
keratoconus.74
atoconus, but may simply be related to long-term contact lens wear
rather than keratoconus.75 Patterns of endothelial damage vary from
isolated cell membranolysis to denudement of the Descemet mem-
brane. More damage occurs at the base of the cone than at the apex and
correlates with the severity and duration of the disease.76
Diagnosis
The diagnosis of keratoconus depends first on the suspicion of the
condition and then on careful evaluation employing various available
diagnostic and imaging tools as indicated including biomicroscopy,
keratometry, keratoscopy, corneal topography, corneal tomography,
and AS-OCT combined with elevation and thickness analysis. Accord-
ing to the Global Consensus on Keratoconus4 the following findings
are required to diagnose the disease: (1) abnormal posterior elevation,
(2) abnormal corneal thickness distribution, and (3) clinical evidence
of noninflammatory corneal thinning.
Typically, affected patients in their teens or twenties seek consul-
tation for symptoms of progressive visual blurring and/or distortion.
Photophobia, glare, monocular diplopia, and ocular irritation are also
presenting symptoms. Early in the course of the disease, visual acu-
ity may be normal even in symptomatic patients. Contrast sensitivity
measurement may, however, uncover visual dysfunction before Snellen
visual acuity loss can be measured.77 High, irregular myopic astigma-
tism with a scissoring reflex on retinoscopy is common in established
keratoconus. In advanced keratoconus, the corneal protrusion may
cause angulation of the lower lid on downgaze. This nonspecific finding
has been referred to as Munson sign (Fig. 73.4). Usually the diagnosis
of the disease is made long before Munson sign is evident.
Slit lamp examination reveals characteristic findings. An eccentri-
cally located ectatic protrusion of the cornea is noted. While the apex is
usually inferior to an imaginary horizontal line through the pupillary
axis, it can be located in the central cornea. Superior keratoconus also
754 PART VII Diseases of the Cornea

Fig. 73.4 Angulation of the lower lid in downgaze known as Munson Fig. 73.5 A hallmark of keratoconus is corneal thinning, which occurs
sign, which is a nonspecific sign of advanced keratoconus. at the cone apex, the point of maximal protrusion. Scarring may induce
flattening at the apex of the cone. Corneal flattening is commonly seen
can occur.78–80 Anterior surface power maps demonstrate that inferior superior to the cone.
steepening in keratoconus is associated with superior flattening.81
Corneal thinning is observed at the apex of the protrusion
(Fig. 73.5). Two types of cones have been described.68 The round
or nipple-shaped cone is smaller in diameter, while the larger oval
or sagging cone may extend to the limbus and is more likely to be
associated with contact lens fitting problems.
Keratoconus is in the differential diagnosis of prominent corneal
nerves and when observed it is usually mild and localized.82 Vogt striae
(Fig. 73.6) occur in the posterior stroma just anterior to Descemet
membrane. When the intraocular pressure is transiently raised, by
applying external pressure to the globe, the striae disappear. These fine
parallel posterior striae should be distinguished from the superficial
reticular scars seen at the cone apex, which result from ruptures in BL.
Subtle superficial anterior clear spaces have been identified at the slit
lamp in 38% of 69 consecutive keratoconus cases.67
The CLEK study has found that corneal scarring in keratoconus
is associated with reduced high- and low-contrast visual acuity and
increased symptoms of glare.11 Factors predictive of corneal scarring
include corneal power greater than 52 diopters (D), contact lens wear,
corneal staining, and age less than 20 years.83 Scarring was more than
three times as likely to be found in association with a flat-fitting contact
lens.84 Contact lenses that reduce apical touch may reduce the inci-
dence of corneal scarring. However, patients with steeper corneas are
more likely to scar even without contact lens wear.83
In more advanced cases, deeper opacities can be seen at the apex of
the cone, resulting from ruptures in the Descemet membrane. Acute
keratoconus or corneal hydrops results from stromal imbibition of Fig. 73.6 Vogt striae are fine posterior stromal folds often noted ante-
aqueous through these ruptures (Fig. 73.7A and B). If untreated, the rior to Descemet membrane at the apex of the cone. They tend to dis-
edema may persist for weeks or months, usually diminishing gradually. appear when external pressure is applied to the eye.
Eventually, it is replaced by scar tissue, which in some cases may result
in flattening of the conical contour. blue illumination in the widest possible slit beam can be used in early
Corneal pseudocysts or intrastromal clefts (Fig. 73.7C) have been cases to enhance the visibility of a subtle iron ring.
described in association with hydrops in keratoconus.85,86 Single or The manual keratometer is a helpful tool for measuring anterior
multiple clefts can occur, and bilateral involvement is possible. Clefts corneal curvature. Inability to superimpose the central keratometric
usually close within 6 months, but stromal neovascularization is com- rings suggests irregular corneal astigmatism, a sign of keratoconus.
mon and can affect future graft survival. The presence of large intra- There is no keratometric value beyond which the diagnosis of kerato-
stromal clefts may explain how corneal perforation can occur after conus is definite. There are patients with steep corneas and high astig-
minor trauma in cases of keratoconus with hydrops. matic errors who do not have keratoconus and, conversely, patients
The Fleischer ring (see Fig. 73.2A), a partial or complete annular with keratoconus who have normal or relatively flat central corneal
line, is commonly seen at the base of the corneal protrusion. When contour. Inferior corneal steepening is also an early sign of keratoco-
identified, it provides a landmark for the peripheral edge of the cone. nus. By performing central keratometry, followed by keratometry with
As the ectasia progresses, the ring tends to become more densely pig- the patient in upward gaze, steepening in the inferior cornea can be
mented and narrower, and it may completely encircle the cone. Cobalt identified and documented.
 CHAPTER 73 Noninflammatory Ectatic Disorders
$ most reliable method of detecting early keratoconus. The presence of
% keratoconus, but it is important to detect this condition when keratore-
& One should be mindful that inferior steepening on a power map
Fig. 73.7 Corneal hydrops in keratoconus. (A) Ruptures in the Descemet
membrane permit the stromal imbibition of aqueous and result in the
marked corneal edema seen in this slit lamp photograph. Keratoplasty is
usually necessary if edema persists beyond 3 months or if scarring is exten-
sive or is in the central cornea. (B) Anterior segment optical coherent tomog-
raphy shows a Descemet membrane detachment associated with corneal
hydrops. (Courtesy Asim Farooq, MD.) (C) Intrastromal fluid-filled clefts can
sometimes occur, as seen in this slit view. Clefts can be single or multiple
and usually close, but may be associated with increased neovascularization.
755
Keratoscopy or videokeratography, based on the Placido disk, can
provide qualitative anterior surface contour information. In early ker-
atoconus, a focal area of increased corneal curvature appears as an
isolated area of reduced ring spacing and distortion. As the condition
progresses, the ring spacing decreases overall and becomes increas-
ingly irregular. With the advent of sophisticated corneal contour analy-
sis, keratoscopy and keratography have become less widely used.
Corneal Imaging Overview
Corneal imaging devices have become indispensable for early detec-
tion and for tracking the progression of the disease (Fig. 73.8A and
B).87–89 Systems based on the Placido disk (e.g., TMS-1 [Computed
Anatomy Inc., NY, USA], EyeSys [EyeSys Laboratories, Houston, TX,
USA], Humphrey ATLAS [Zeiss, Oberkochen, Germany]), slit-scan
systems (Orbscan, Bausch & Lomb, Laval, Canada), scanning slit com-
bined with a Placido system (Orbscan II, Bausch & Lomb), and ras-
terstereography (PAR) have all been used for these measurements.90
The term “corneal topography” refers to corneal contour maps based
on Placido disk power maps, while corneal tomography is used when
contour is determined based on elevation or thickness. Tomography
using Scheimpflug photography or AS-OCT is currently deemed the
posterior corneal elevation is most important in diagnosing subclinical
keratoconus.4 Scheimpflug-based devices—Pentacam (OCULUS, Wet-
zlar, Germany), Galilei (Zeimer, Port, Switzerland), TMS-5 (Tomey,
Nagoya, Japan), and Sirius (CSO, Florence, Italy)—can provide accu-
rate mapping of corneal power, elevation, and thickness, and have the
potential to grade the severity of the disease.
Early keratoconus detection has become less dependent on evalua-
tion of an isolated power map and more on a comprehensive analysis
of power, elevation, and pachymetry. It is unclear whether the kerato-
conus suspect patient will ultimately develop clinical manifestations of
fractive surgery is being considered. Of the patients presenting for ker-
atorefractive surgery, 2%–6% were suspected to have keratoconus.91–93
The outcome of refractive surgery in this setting may be unpredict-
able and may lead to progressive keratectasia.94 Although investiga-
tors have reported successful photorefractive surgery in keratoconus
suspects,95,96 caution is recommended until surgery in this setting has
been more thoroughly studied.
Corneal Power
Rabinowitz has suggested four quantitative Placido-based indices as an
aid for screening patients for keratoconus.97 These indices include cen-
tral corneal power value greater than 47.2 D, inferior/superior diop-
tric asymmetry (I-S value) greater than 1.2, Sim-K astigmatism greater
than 1.5 D, and skewed radial axes (SRAX) greater than 21 degrees.
These indices were used to distinguish keratoconus from normal cor-
neas and were most effective when corneal astigmatism was greater
than 1.5 D. Evolution in keratoconus detection has resulted in contin-
ued refinement of the neural network approach by Smolek and Klyce98
and the KISA% index described by Rabinowitz and Rasheed.99 Both
systems purport an ability to detect keratoconus suspects and grade the
severity of keratoconus.
can result from poor patient fixation,100 misalignment of the video-
keratograph,101,102 dry spots on the cornea, inferior eyeball compres-
sion,15 and contact lens–related corneal warping.103 Suspicion should
be raised if the map is grossly inconsistent with other aspects of the
imaging analysis.
756 PART VII Diseases of the Cornea

Fig. 73.8 Corneal topography and tomography are useful in detecting keratoconus at various stages of progression. Representative stages of
disease are demonstrated. (A) Subclinical keratoconus. Orbscan II (Bausch & Lomb) anterior elevation map (upper left) shows an eccentric area of
elevation, posterior float (upper right) shows prominent elevation coincident with the anterior elevation, power map (lower left) shows asymmetric
dumbbell with mild skewing of radial axes and superior flattening, pachymetry map (lower right) shows point of maximal thinning eccentric and coin-
cident with elevation on anterior and posterior float maps. Even the thinnest part of this cornea (518 μm) is within the range of normal. (B) Moderately
advanced keratoconus. Pentacam (OCULUS, Wetzlar, Germany) power map, upper left, shows moderate inferior steepening, superior flattening,
and corneal astigmatism measuring 8.1 D and steepest power, Kmax, 62.7 D; prominent islands of elevation are noted anteriorly, upper right, and
posteriorly, lower right; eccentric and abnormal corneal thinning is noted in the pachymetry map, lower left, with the thinnest cornea measuring 368
microns. Maximum thinning, protrusion, and steepening are coincident in this cornea.
 CHAPTER 73 Noninflammatory Ectatic Disorders
Corneal Elevation and Thickness
The scanning-slit topography device (Orbscan II, Bausch & Lomb)
provides a power map, a pachymetry map, and maps based on eleva-
tion relative to a best-fit sphere. These consist of an anterior elevation
map (anterior float) and a mathematically derived posterior elevation
map (posterior float) (see Fig. 73.8A). The elevation difference front to
back should not exceed 40 μm if laser in situ keratomileusis (LASIK) is
being considered. Values greater than 50 μm are suggestive of kerato-
conus. The posterior float is the least reliable of the four maps.104 The
pachymetry map gives a relative overview of corneal thickness, but the
values should not be considered equivalent to pachymetric readings
measured by ultrasound or Scheimpflug photography.
Scheimpflug-based tomography is a more accurate means of mea-
suring corneal elevation and thickness (see Fig. 73.8B). A virgin cornea
with an isolated island of anterior elevation measured with the Pen-
tacam, which exceeds the best-fit sphere by more than 11 μm, and/or
posterior elevation greater than 20 μm is suspicious for an ectatic cor-
neal contour. Posterior elevation may be the first indication of ectatic
disease. The Pentacam software can enhance the detection of early ker-
atoconus by analyzing elevation data, excluding the area around the
thinnest part of the cornea from best-fit sphere calculations, increas-
ing the sensitivity of detection of islands of elevation (Fig. 73.9A). In
addition, the change in corneal thickness starting from the thinnest
position on the cornea and moving outward toward the periphery can
be used to determine the rate of thickness change in comparison to
normative data (see Fig. 73.9B). The Scheimpflug-based Keratoco-
nus Assistant (KA), a program developed for automatic detection of
keratoconus by using 25 Pentacam-derived parameters, was recently
validated with an accuracy of 98.9% and sensitivity of 99.1% in differ-
entiating keratoconus eyes from normal eyes.105
AS-OCT was first applied by Li et al.106 to obtain precise pachymet-
ric maps in keratoconus (Fig. 73.10A and B). The authors established
five OCT parameters felt to be consistent with keratoconus. Kanel-
lopoulos et al.62 found using AS-OCT that there is increased overall
thickness and increased variation. It is possible that this increased
epithelial thickness may compensate for underlying irregular stromal
distribution, thus masking early stage keratoconus on other imaging
devices. Li et al. reports that pattern analysis of the corneal and epi-
thelial thickness maps derived by Fourier-domain OCT could detect
early keratoconus.59 In a study comparing asymmetric keratoconus
(AKC) from a normal control population, Hwang et al.107 found that
combining anterior curvature and asymmetry indices from Scheimp-
flug photography with regional total thickness and epithelial thickness
variability metrics from spectral domain OCT effectively distinguished
the 2 populations. This highlights the improved detection of kerato-
conus obtained by combining data derived from various imaging
technologies.
An important consensus of the Delphi panel on keratoconus and
ectatic disease4 concluded there was no appropriate classification sys-
tem for keratoconus and no effective way to assess progression. Histor-
ical classification systems such as the Amsler-Krumeich system or the
CLEK11 system do not consider diagnostic information provided by
current technology. Classification of keratoconus is important not only
to characterize the current status, but also to track progression. The
ABCD keratoconus grading system108 (Table 73.3) relies on corneal
tomography. It is based on an evaluation of a 3 mm area around the site
of thinnest pachymetry, specifically anterior radius of curvature (A),
posterior radius of curvature (B), thinnest pachymetry reading (C),
and distance visual acuity (D) to stage the disease. The cornea is staged
grade 0 to grade IV. It can also be used to identify progression over time
within the various parameters. Progression is defined as a worsening of
1 parameter to a 95% CI or 2 parameters to an 80% CI. Tracking the
757
keratoconus patient in this way over time and detecting progression
earlier may help preserve vision by permitting intervention at an earlier
stage.
Biomechanical Measurement
The Ocular Response Analyzer (Reichert Technologies, Buffalo, NY)
is capable of directly measuring biomechanical properties of the cor-
nea in response to an air puff. Both corneal hysteresis, which indicates
the viscoelasticity of the cornea, and the cornea resistance factor are
depressed in patients with corneal ectasia. These indicators can be
used in addition to corneal tomography to evaluate patients at risk for
corneal ectasia. The Corvis ST (Oculus Optikgeräte GmbH, Wetzlar,
Germany), not currently available in the United States, employs a non-
contact tonometer to monitor the response of the cornea to an air pres-
sure pulse captured with ultra-high speed Scheimpflug photography.109
The Corvis Biomechanical Index (CBI) based on corneal thickness
profile and deformation parameters was shown to be highly sensitive
and specific in separating healthy from keratoconic eyes.110
Treatment
The management of keratoconus is focused on two important goals:
arresting progression and providing visual rehabilitation. Patients with
keratoconus should be reminded to avoid eye rubbing and any asso-
ciated atopic disease should be optimally managed. Patients can often
tolerate higher degrees of astigmatism and anisometropia than normal
patients; however, when glasses fail to provide adequate visual function,
contact lens fitting is indicated. Surgery is considered when patients
cannot tolerate or are not fully satisfied with nonsurgical treatments.
CXL, recently approved in the United States, has the potential to arrest
progression of keratoconus, particularly in mild to moderate disease.
Contact Lens
Contact lens wear improves visual function by creating a new anterior
refractive surface (Fig. 73.11). Contact lenses do not prevent progres-
sion of corneal ectasia. While they appear to be associated with the
development of keratoconus in some cases, this important mode of
therapy should not be withheld for fear of causing progressive disease.
Contact lens fitting must be tailored to the individual’s visual needs
and comfort tolerance. Given ample time and motivation, fitting exper-
tise, and access to all available contact lens modalities, many keratoconus
patients can achieve good visual function with a stable, well-tolerated lens.
Soft contact lenses may be effective for patients with mild disease.
As the ectasia progresses, various gas-permeable hard lens options and
specialty lenses are available. Relatively flat-fitting, rigid gas-permeable
(RGP) hard contact lenses with light apical corneal touch, the so-called
three-point touch technique, remains the mainstay of contact lens treat-
ment for keratoconus.111,112 Apical touch has been associated apical
scarring.83 An apical clearance fitting technique is also commonly used.
Other options include soft toric lenses, standard bicurved hard lenses,
custom back-toric lenses, scleral lenses, and mini-scleral lenses.113
Hybrid lenses,114 such as the SoftPerm lens (CIBA Vision Corp., Duluth,
GA, USA) and SynergEyes KC lens (SynergEyes, Inc., Carlsbad, CA,
USA), and piggyback systems may be more comfortable for patients
who cannot tolerate an RGP alone.
The Rose K system (Menicon America, Inc., Waltham, MA, USA) is
an additional option for keratoconus patients unable to wear conven-
tional RGP lenses.115 The trial set contains lenses with posterior curves
that more closely fit the abnormal conical contour.
Scleral and mini-scleral lenses have become increasingly popular in
the management of corneal ectasia. These lenses rest on sclera but do
not touch cornea or limbus, providing a tear fluid reservoir, correct-
ing astigmatism, and improving comfort and stability.116 Mini-scleral
758 PART VII Diseases of the Cornea
%
Fig. 73.9 Accurate measurements of elevation and pachymetry using
Scheimpflug technology can be used for enhanced keratoconus detec-
tion. (A) The Pentacam (OCULUS) subtracts an area encompassing the
thinnest part of the cornea from the calculation of the best-fit sphere
anteriorly and posteriorly (middle right and left), which highlights an
island of elevation (middle right) and generates a difference map (lower
right and left). (B) Accurate measurements of corneal thickness using
Scheimpflug technology and the Pentacam software produce analyses
of thickness progression from thinnest part of the cornea to the periph-
ery. Patient curves that extend below the normative curves are sugges-
tive of ectatic disease. The indices below indicate significant deviation
from the mean of each parameter consistent with corneal ectasia.
lenses (15.0–18.0 mm) such as MSD (Blanchard Contact Lens, Inc.,
Manchester, NH, USA) and Maxim (Acculens, Denver, CO, USA)
have scleral bearing and minimal corneal clearance. Full scleral lenses
(18.1–24.0 mm) such as Jupiter (Medlens Innovations, Front Royal, VA
or Essilor Contact Lens, Inc., Dallas, TX, USA) and Tru-Scleral lens
(Tru-Form Optics, Bedford, TX, USA) have scleral bearing and max-
imum corneal clearance.117 They are advantageous for patients with
more irregular corneas and delay the need for keratoplasty in eyes with
advanced keratoconus.
PROSE treatment, which utilizes a custom lathed scleral lens devel-
oped by the Boston Foundation for Sight, is now available at multiple
%
Fig. 73.10 Anterior segment optical coherent tomography (OCT) can
be used to generate cross-sectional images of the cornea. These can
be used to create anterior and posterior corneal power, elevation, and
pachymetry maps. The image above (A) based on spectral domain OCT
technology demonstrates apical thinning as well as anterior stromal scar-
ring near the apex of the cone. Below (B) is the associated pachymetric
map. (Optovue, Freemont, CA.) (Courtesy Robert Weisenthal, MD.)
sites around the country and can improve visual function with a com-
fortable and stable-fitting lens.118,119 This system has the advantage of
eliminating apical touch.
One form of contact lens intolerance may result from epithelial
breakdown overlying a subepithelial fibrotic scar occurring at the apex
of the cone. Using a self-retaining wire speculum and topical anesthe-
sia, this fibrotic nodule is easily debrided at the slit lamp. After the cor-
nea has healed, the patient may resume contact lens wear, obviating the
need for more invasive surgery. Phototherapeutic keratectomy (PTK)
has also been used in this setting.120 While it may be helpful in some
cases, PTK may cause keratolysis,121 increased scarring, and ectasia,
thereby hastening the need for PKP.
Intrastromal Ring Segments
Contact lens-intolerant keratoconus patients without central scarring,
who have mild or moderate disease, may be candidates for intrastromal
ring segment insertion (Fig. 73.12A). The ideal candidates also have low
spherical equivalents and average keratometry readings of less than 53
D. The procedure improves visual acuity by flattening the central cor-
nea, reducing astigmatism, and centering the cone.122–125 The goal of the
procedure is to improve contact lens fit and comfort. It may also improve
best spectacle-corrected visual acuity (BSCVA). It is important to set
proper patient expectations prior to surgery and inform the patient that
glasses and/or contact lenses will still be needed after surgery.
 CHAPTER 73 Noninflammatory Ectatic Disorders 759

TABLE 73.3 ABCD Keratoconus Grading System

ABCD Staging Criteria A B C D
Anterior Radius of Curvature* Posterior Radius of Curva- Thinnest Pachymetry (μm) Best Corrected Distance Acuity
(ARC) ture*(PRC)
Stage 0 >7.25 mm (<46.5 D) >5.90 mm >490 μm ≥20/20 (≥1.0)
Stage I >7.05 mm (<48.0 D) >5.70 mm >450 μm <20/20 (<1.0)
Stage II >6.35 mm (<53.0 D) >5.15 mm >400 μm <20/40 (<0.5)
Stage III >6.15 mm (<55.0 D) >4.95 mm >300 μm <20/100 (<0.2)
Stage IV <6.15 mm (>55.0 D) <4.95 mm ≤300 μm <20/400 (<0.05)
*ARC and PRC are based on a 3 mm zone around the thinnest pachymetric reading.
From Belin MW, Duncan JK. Keratoconus: the ABCD grading system. Klin Monbl Augenheilkd 2016;233(6):701–7.

 

 

Fig. 73.11 The effect of hard contact lens wear on the anterior refractive surface in a case of advanced kera-
toconus. (1) Without the contact lens a scarred, markedly flat cone apex is seen. (2) This correlates with the
variably spaced rings in this irregular keratograph. (3) With a hard contact lens on the same cornea the power
map has an appearance approaching normal. (4) This is verified in the keratograph on the lower left in which
the edge of the contact lens can be seen.

To achieve the desired effect, the ring segments must be inserted at
approximately two-thirds depth; therefore the cornea should be at least
450 μm thick (see Fig. 73.12B). Ring segments are available in various
thicknesses, and enhanced effect is generally achieved with the thicker
segments. Stromal channels of the appropriate width and depth can be
prepared with a specially designed keratome or femtosecond laser.126
While wide channels make insertion easy, the desired effect can only be
obtained with a snug fit. Colin and Malet124 reported that contact lens
wear was restored in over 80% of cases.
While the ring segments are removable, the procedure should not be
considered completely reversible. The ring segments do not prevent pro-
gression of the underlying disease. If keratoplasty later becomes necessary,
the surgery should occur at least 1 month following ring segment removal.
Corneal Crosslinking
CXL may slow or halt the progression of keratoconus by using a
photo-oxidative treatment to increase the rigidity of the corneal
stroma.127–129 While widely used outside the United States for many
years, CXL has more recently become FDA approved for use in the
United States.
The procedure in its classic form, the Dresden protocol, begins with
the removal of the central epithelium to enhance stromal saturation
with the topically applied riboflavin (vitamin B2). The cornea is then
irradiated with ultraviolet A (UVA) light at 370 nm for 30 minutes (Fig.
73.13A). The irradiation of the riboflavin results in chemical reactions
that create covalent bonds, which bridge amino groups of the stromal
collagen fibrils.130
The principal effects of crosslinking are localized to the anterior
300 μm of the stroma.131 The biomechanical effect in human corneas
is a 328.9% increase in corneal rigidity.132 Increased resistance to enzy-
matic degradation shown in porcine eyes following crosslinking may
also contribute to biomechanical stability.133
The improvement in visual acuity after CXL is the result of
decreasing both corneal curvature and astigmatism. Raiskup-Wolf
et al. reported a 2.68 D reduction in corneal power at 1 year postop-
eratively.127 Three years after the treatment, the BCVA improved one
line in 58% of 33 eyes and remained stable in 29% of eyes (P < .01).
The astigmatism had diminished by a mean of 1.45 D in 54% of eyes.
The induced topographic changes have the potential to improve con-
tact lens fit. CXL appears to be most beneficial for patients with mild
760 PART VII Diseases of the Cornea
$ up to 1 year. Further investigation is needed to compare outcomes
% undersizing the donor to further flatten the postoperative corneal con-
Fig. 73.12 Intracorneal ring segments. (A) Diffuse illumination reveals
two ring segments in a keratoconus cornea. (B) Slit view demonstrates
the appropriate depth for ring segment placement.
progressive keratoconus. It is less effective in patients with advanced
keratoconus. CXL has been shown to halt progression of ectasia fol-
lowing LASIK and PRK, but the effect is less pronounced than in
keratoconus.134
CXL poses a risk of dose-dependent keratocyte apoptosis affecting
the anterior 300 μm of the cornea (see Fig. 73.13B). UVA irradiance
of 0.36 mW/cm2 has been found to be cytotoxic to the rabbit cor-
neal endothelium, which corresponded to a human corneal stromal
thickness of less than 400 μm.129,135 Therefore pachymetry should be
performed preoperatively to confirm that the corneal stroma thick-
ness is greater than 400 μm. Preliminary studies have shown that the
lens and retina are not adversely affected.136 Other risks include cor-
neal infection, stromal haze, and stromal infiltrates, which seem to
occur more often in older patients. An alternative treatment proto-
col in which the epithelium is left in place may reduce postoperative
discomfort and the risk of complications. However, adequate stromal
concentration of riboflavin may not be achieved, and the long-term
efficacy of CXL using the “epi-on” technique may be less than with the
traditional approach.137–139 A recently published meta-analysis of 455
eyes in five randomized control trials and three nonrandomized com-
parative trials compared standard CXL versus transepithelial CXL.140
At 1 year after surgery, epi-on CXL has a more significant reduction
of mean K than does epi-off CXL (P = .03). However, there were no
statistically significant differences in Kmax, visual acuity measure-
ments, pachymetry, or endothelial cell count density. The results sug-
gest that epi-on and epi-off techniques have similar efficacy, at least
beyond 1 year.
CXL can also be performed in combination with photorefractive
keratectomy (PRK), LASIK, thermal keratoplasty, intrastromal ring
segments, and orthokeratology.141 McQuaid et al. reported more than
2.0 D of corneal flattening and improvement in visual acuity in 70% of
cases in which PRK was performed in conjunction with CXL.142
CXL used in combination with ring segments were thought to
increase its flattening effect, reducing irregular astigmatism and
improving visual acuity.143 This approach has been recommended for
patients with moderate to severe disease with a minimal corneal thick-
ness of 450 μm.144 Ring segments should be placed before CXL is per-
formed. Further studies are needed to study the long-term effects of
these combined procedures.
Keratoplasty
When a stable, comfortable contact lens fit cannot be obtained or fails
to provide adequate vision or when significant corneal scarring is pres-
ent, the cornea is very thin (<200), or when corneal hydrops fails to
resolve, a more invasive surgery such as keratoplasty is recommended.
The type of keratoplasty depends on the individual patient’s needs and
the surgeon’s preference. While PKP has traditionally been the surgery
of choice, lamellar surgery has definite advantages for patients with
mild to moderate disease. Recurrent keratoconus in the donor follow-
ing cornea transplant has been reported;145,146 however, recurrent ker-
atoconus is far more likely to be related to incomplete excision of the
cone. The iron ring, found at the base of the cone, should be used as a
reference when planning graft size.
Post-keratoplasty myopia can be reduced by using the same-sized
donor and host corneal buttons.147–150 Some have even suggested
tour.151 In order to prevent postoperative hyperopia, same-size donor
and host corneal buttons should be avoided when the anterior lens-
to-retina length is less than 20.19 mm, the mean length for normal
emmetropic individuals.152
DALK is an alternative to PKP. It is not recommended, however,
in cases of deep stromal scarring or after corneal hydrops. Since
the host endothelium is preserved, the risk of endothelial rejection
is eliminated. Stromal rejection is still possible and occasionally
problematic. The risk of endophthalmitis is theoretically less in this
largely extraocular procedure. In the event of trauma, intact host
Descemet membrane occurring after DALK affords greater wound
 CHAPTER 73 Noninflammatory Ectatic Disorders 761

A B

Fig. 73.13 (A) Cornea crosslinking treatment on a patient using riboflavin/ultraviolet A (UVA). Appearance of
the red cross-hairs ensures that the UVA source is a proper distance from the cornea. A 9 mm epithelial defect
has been created and the stroma saturated with topical riboflavin according to the Dresden protocol. The
stroma must be at least 400 μm to control the risk of endothelial cytotoxicity. (B) Light microscopy 24 hours
after crosslinking in human cornea showing depletion of keratocytes down to 250 μm. Note the absence of
inflammatory cells in the treated anterior cornea due to apoptosis. (Hematoxylin and eosin stain, magnifica-
tion ×200.) (Image courtesy of Gregor Wollensak, MD and Eberhard Spoerl, PhD.)

stability than occurs following PKP. High postoperative astigmatism
can still occur after DALK, just as in full-thickness surgery. Visual
outcomes are comparable to PKP153,154 provided the residual stro-
mal bed thickness is minimized. Late reduction of endothelial cell
density postoperatively is less than PKP.155 DALK is technically
more challenging and time-consuming, which may explain its lim-
ited popularity. There are various DALK techniques such as the big
bubble technique,156 manual layer-by-layer pre-Descemetic DALK
(pdDALK), pdDALK with viscodissection, pdDALK with the light
reflex guided Melles technique,157 and femtosecond laser-assisted
dissection.
The treatment of keratoconus is rarely an emergency. The exception
is corneal hydrops, resulting from a rupture in the Descemet mem-
brane (see Fig. 73.7B). The break in the Descemet membrane can be
identified using AS-OCT or ultrasound biomicroscopy (UBM). A dra-
matic reduction in vision occurs due to marked stromal edema. This
may be accompanied by redness, discomfort, and photophobia. Proper
management includes patching or bandage contact lens, topical cyclo-
plegia, hypertonic sodium chloride ointment and/or drops, and reas-
surance. Topical steroids are rarely needed.
Intracameral air has been used in the management of corneal
hydrops. The air acts as a mechanical barrier, reducing aqueous flow
into the stroma through the rupture. Because the air is absorbed over
a few days, the longer lasting intracameral gasses sulfur hexafluoride
(SF6) and perfluoropropane (C3F8), in isoexpansile concentrations, are
advantageous. C3F8 in 14% concentration may persist in the anterior
chamber up to 6 weeks. A concentration of 20% SF6 gas is nontoxic
to the endothelium and can last up to 2 weeks. The pupil should be
dilated and laser peripheral iridotomy should be considered to prevent
pupillary block. Panda et al. reported the safety and efficacy of SF6 in
expediting resolution of corneal edema.158 Hydrops that does not clear
by 3–4 months is best treated by PKP.
Bowman Layer Transplantation
BL transplantation is a novel surgical technique introduced by Dijk
et al.159 The goal of BL transplantation is to implant donor BL to the host
mid-stroma through a scleral tunnel. Twenty-two eyes of 19 patients
followed for 3 years demonstrated improvement in BCVA, reduction of
mean keratometry by approximately 8 D, and a 28 μm increase in cor-
neal thickness. Advantages are preservation of the host endothelium,
reduction in graft rejection, and reduction in steroid use.160
Post-Keratorefractive Surgery Corneal Ectasia
Post-keratorefractive ectasia resembles keratoconus, with the typical
clinical and tomographic findings of progressive thinning and pro-
trusion and resultant loss of visual function. Ectasia can present years
after laser refractive surgery and can occur in some patients even in the
absence of any apparent risk factors.161,162
An understanding of cornea stromal ultrastructure and biome-
chanics can help explain how ectasia can develop in some cases.
Dawson et al.163 have shown that the anterior and peripheral stroma
are more rigid and have greater cohesive tensile strength than the
posterior two-thirds of the stroma. They concluded that this is per-
haps related to observed differences in the direction of collagen fibrils
between the anterior and posterior stroma and/or the degree of col-
lagen lamellar interweaving in BL. Stromal ablation into the poste-
rior stroma could potentially create a postsurgical cornea with less
rigidity and cohesive tensile strength. This situation would arise if the
degree of myopia is high, the cornea is thin, or the flap is uninten-
tionally thick.
Patients with an abortive form of ectasia, the so-called forme fruste
disease, might remain in the subclinical state if left untouched. A
young patient may develop manifest disease in the absence of surgery
if followed over time. Brenner et al.164 found preoperative forme fruste
keratoconus in 58 of 77 patients with post–LASIK ectasia. In another
762 PART VII Diseases of the Cornea
$
Fig. 73.14 Pellucid marginal degeneration appearance. (A) The profile of a cornea with pellucid marginal
degeneration shows protrusion and sagging of the inferior cornea. (B) This slit lamp photograph demonstrates
corneal protrusion superior to the point of maximal thinning.
study165 forme fruste disease was a risk factor in 21.4% of postoperative
ectasia patients. It is imperative to successfully identify these patients
and counsel them against LASIK surgery.
With the advent of newer technologies, for example, Scheimpflug
photography and AS-OCT, more accurate elevation maps have become
useful tools for detecting subclinical disease (see Fig. 73.9A). Isolated
islands of elevation, significant differences in thickness between the two
eyes, or areas of eccentric thinning are all helpful indicators. The rate
of corneal thickening moving from the thinnest point to the periphery
can also be suggestive of ectasia (see Fig. 73.9B). Proper preoperative
evaluation requires the refractive surgeon to use multiple maps and
analyses before concluding that the risk of ectasia following keratore-
fractive surgery is minimal.
Randleman et al.166 studied patients with post-LASIK ectasia and
identified five main risk factors for this complication. These included
young age at the time of surgery, abnormal preoperative topography,
reduced residual stromal bed thickness, decreased preoperative cornea
thickness, and high myopia. These variables were incorporated into a
scoring algorithm to quantitatively assess the risk of ectasia. Binder and
Trattler conducted a large retrospective review to evaluate Randleman’s
ectasia risk scores. They found that in patients with normal preopera-
tive topographies, the scoring system may not predict an increased risk
of postoperative LASIK ectasia.162 Tatar et al.165 found deep ablation
(>75 µ) to be the most significant risk factor, but 21.4% (9/42) had no
preoperative ectasia risk factor.
PELLUCID MARGINAL DEGENERATION
PMD is a bilateral, peripheral corneal ectatic disorder characterized
by a band of thinning 1–2 mm in width, typically in the inferior cor-
nea, extending from the 4 to 8 o’clock position. The area of thinning
%
is usually found 1–2 mm central to the inferior limbus. Atypical
cases of PMD with thinning extending beyond the inferior 4 o’clock
hour occur,167 as do cases in which the thinning is confined to a
superior location.168,169 At least 6 cases of unilateral PMD have been
reported.170
In contrast to keratoconus, maximal corneal protrusion typi-
cally occurs just superior to, rather than within, the area of thinning
(Fig. 73.14). The result is a corneal contour reminiscent of a “beer
belly.” The protruding cornea is of normal thickness. The abnormal
corneal contour induces a shift in the axis of astigmatism from against-
the-rule, superiorly, to with-the-rule, near the point of maximal pro-
trusion. PMD and keratoconus can occur in the same eye.171 The two
diseases can also be seen in the same family.29
Patients with this condition usually present for treatment between
the second and fifth decades of life complaining of blurred vision due
to irregular astigmatism. There is no racial or gender predisposition.
Maguire et al.172 have described the corneal contour in PMD
using power maps. The typical crab-claw (Fig. 73.15) illustrates the
shift in astigmatism from the superior to the inferior cornea. The
crab-claw appearance on a power map can also occur in patients with
inferior keratoconus and tomography is helpful to differentiate the
two conditions.
Patients with PMD are poor candidates for refractive surgery
because of the risk of progressive ectasia. Review of corneal topogra-
phy as well as tomography can help identify the patient with contour
abnormalities even when the best corrected acuity is 20/20.
The corneas in PMD are generally clear and avascular. The typical
findings of keratoconus, protrusion within the area of corneal thin-
ning, striae, and iron ring, are not seen in PMD. Stromal scars have
been described at the level of the Descemet membrane extending into
the mid-stroma, located at the superior aspect of the thinned area.
 CHAPTER 73 Noninflammatory Ectatic Disorders 763

Fig. 73.15 Pellucid marginal degeneration—or is it? The power map upper left shows the classic crab-claw
configuration often seen in pellucid marginal degeneration; however, the pachymetry map, lower left, fails to
show a band of thinning inferior to the protrusion noted on the elevation maps, upper right and lower right.
This is actually an inferior cone and illustrates the need to look beyond Placido-based topography to make the
correct diagnosis.

While the cornea can become quite thin, rupture rarely occurs.173,174
Hydrops can occur, resulting in edema, scarring, and vascularization
of the inferior cornea.
Spectacles usually fail to adequately correct the high irregular
astigmatism associated with PMD. Large-diameter, RGP contact
lenses can be tried. However, a stable long-term fit can be difficult
to achieve. The hybrid lenses and scleral lenses have been used suc-
cessfully in PMD.175 These patients are also candidates for PROSE
treatment.118
A surgical approach may be required for visual rehabilitation.
Large-diameter or eccentric PKP is usually required to encompass the
area of peripheral thinning. Placing the graft wound in proximity to the
limbal vasculature increases the risk of endothelial rejection. Success
with large-diameter PKP in the absence of corneal neovascularization
has been reported.176 Varley et al.177 reported a rejection rate of 64%,
but none of the 12 large, eccentric grafts failed because of rejection over
a mean follow-up period of 3 years.
Newer surgical techniques are being used in the treatment of
PMD.178,179 DALK has the advantage of eliminating the risk of endo-
thelial rejection completely; stromal rejection is still problematic,
however. CXL180 and ring segments181 have been described but have
not been well studied in this setting. Alternative surgical procedures
include crescentic lamellar keratoplasty182 and crescentic wedge exci-
sion.183 Long-term astigmatism drift may be a problem following
resection procedures.
KERATOGLOBUS
Keratoglobus is a bilateral ectatic disorder that is usually nonprogres-
sive or minimally progressive. The typical globular protrusion of the
cornea results from generalized thinning, most marked in the periph-
ery (Fig. 73.16). Associated scleral thinning has also been described.184
While minimal corneal scarring may be seen, an iron ring is not
observed. The cornea is of normal or slightly increased diameter.
Acute hydrops occurs less frequently than in keratoconus;185 however,
the opposite is true about corneal perforation and rupture. Corneal
rupture can occur after minimal trauma.
The corneal topography and tomography in patients with kerato-
globus have not been well described. The central and paracentral eleva-
tion and steepening with generalized thinning one might expect to see
is demonstrated in Fig. 73.17. Keratoglobus can occur in the fellow eye
of a patient with PMD.
764 PART VII Diseases of the Cornea
$ Prominent folds can result from compression of the markedly ectatic
1 POSTERIOR KERATOCONUS
% excavation associated with variable amounts of stromal scarring (Fig.
Fig. 73.16 Keratoglobus appearance. (A) The typical globular contour of
the keratoglobus can be seen in this cornea photographed in profile. (B)
Generalized thinning is common (1), with the greatest thinning found in
the periphery.
Unlike keratoconus, keratoglobus is not associated with atopy,
tapetoretinal degeneration, or hard contact lens wear. Acquired kera-
toglobus has, however, been described in association with vernal kera-
toconjunctivitis186 and hyperthyroidism.187
While there is no association with Down syndrome, keratoglobus
has been reported in association with Rubinstein-Taybi syndrome, in
which intellectual impairment occurs.188 As in keratoconus, there is
evidence to suggest an association with abnormalities of connective
tissue. Keratoglobus and blue sclera have been linked to other findings,
such as hyperextensible joints, abnormalities in teeth and hearing, a
high incidence of fractures, and consanguinity.187
Keratoglobus associated with other disorders of connective tis-
sue bears some resemblance to the ocular form of Ehlers-Dan-
los syndrome, but keratoglobus patients do not demonstrate skin
hyperelasticity, marked joint laxity, microcornea, or reduced skin col-
lagen hydroxylysine.184
No definitive inheritance pattern has been demonstrated in kerato-
globus. There may, however, be a genetic relationship between kerato-
globus and keratoconus. Keratoglobus and keratoconus can be found
in different members of the same family.
Spectacle correction is the first step in the management of
keratoglobus. Functional vision can sometimes be obtained with
glasses. Spectacles also afford the patient some protection from
corneal rupture associated with trauma. A stable contact lens fit is
difficult to achieve due to the abnormal corneal contour; however,
PROSE treatment (prosthetic replacement of the ocular surface
ecosystem) may be successful.189 One must weigh the advantages of
contact lens wear and a nonsurgical approach against the increased
the risk of trauma associated with manipulation during insertion
and removal.
Surgical intervention should be considered when functional vision
cannot otherwise be obtained. A lamellar graft has the advantage of
being an extraocular procedure with no risk of endothelial rejection.
cornea. The use of partial-thickness corneoscleroplasty to preserve the
anterior chamber angle, followed at a later time by a smaller-diameter
PKP has also been recommended.190,191 Kanellopoulos and Pe describe
an alternative, nonpenetrating procedure of suturing a corneoscleral
ring graft around the cornea.192
As in PMD, a large-diameter PKP would be required to encom-
pass the markedly thin peripheral pathology. Grafts of this size are at
greater risk of endothelial rejection. There is also a greater propensity
to develop glaucoma caused by outflow channel compromise. If possi-
ble, surgical intervention should be delayed.
In posterior keratoconus, thinning results from an increase in the cur-
vature of the posterior cornea. Corneal involvement can be diffuse
or localized. In keratoconus posticus generalis, the entire posterior
corneal surface has an increased curvature and the cornea typically
remains clear. In keratoconus posticus circumscriptus, there may be
one, or occasionally more, central or paracentral areas of posterior
73.18). Corneal guttae are often seen within the area of involvement,
and pigment is sometimes found at the peripheral edge of this poste-
rior lesion.
While corneal astigmatism can occur, it is generally not the high
irregular astigmatism seen in keratoconus.193 This relative lack of
involvement of the anterior refractive surface explains why posterior
keratoconus results in only mild to moderate reduction in visual func-
tion. Vision decrease, when it occurs, is usually caused by stromal scar-
ring, associated ocular disease, or amblyopia. Corneal topography has
demonstrated central steepening in the area of posterior excavation as
well as surrounding flattening.
Posterior keratoconus is developmental, usually nonprogres-
sive, noninflammatory, and usually unilateral.29 Bilateral involve-
ment, however, is not uncommon.194 Acquired cases occur and are
usually associated with trauma.195 The histopathologic findings in
posterior keratoconus have been described.196,197 Irregular epithe-
lium with focal disruption of the epithelial basement membrane is
seen, and BL is replaced with fibroblastic proliferation. The stroma
is thin with lamellar disorganization. The central portion of the
Descemet membrane is not thin but may show marked disorga-
nization. A ring of thickened Descemet membrane at the edge of
 CHAPTER 73 Noninflammatory Ectatic Disorders 765

1 2

Fig. 73.17 Keratoglobus topography. (1) Orbscan II (Bausch and Lomb) power map reveals diffuse steepen-
ing with the flattest Sim K reading 51.9 diopters; (2) pachymetric map shows diffuse thinning, with the inferior
part of the cornea being thinnest.

2 2
1

$ %

Fig. 73.18 Posterior keratoconus. (A) In the localized form an area of relative lucency (1), which corresponds
to the site of posterior excavation, is surrounded by stromal scarring (2). (B) This slit view demonstrates
thinning (1), which results from steepening in the posterior corneal contour. The anterior corneal contour is
relatively unaffected.
766 PART VII Diseases of the Cornea
the posterior cone may be associated with pigmented excrescences.
Electron microscopy of Descemet membrane reveals an abnormal
anterior banded layer. This finding suggests that the developmental
changes, which result in posterior keratoconus, occur before the
formation of the anterior banded layer, between 6 and 8 months of
gestation.198
Clinically, there are similarities between posterior keratoconus
and Peters anomaly. However, a difference is observed histopatho-
logically. In Peters anomaly, the corneal endothelium and Descemet
membrane are either absent or markedly thinned,199 unlike posterior
keratoconus.
Many ocular abnormalities have been found in association with
posterior keratoconus. Changes consistent with mesodermal dysgen-
esis as well as associated aniridia, ectropion uvea, iris atrophy, glau-
coma, anterior lenticonus, ectopia lentis, and anterior lens opacities
have been described.200 Abnormalities other than in the eye have
also been reported.196 These include hypertelorism, a flattened nasal
bridge, lateral canthal displacement, cleft lip and palate, webbed neck,
brachydactyly, genitourinary anomalies, short stature, and abnormal
gait.
Posterior keratoconus usually requires no treatment, particularly
when the abnormality is outside of the visual axis. Visual rehabilita-
tion with a contact lens seems reasonable if a focal area of paracentral
anterior steepening or irregular astigmatism is demonstrated. Glasses
and contact lenses do little to correct vision loss caused by mid- and
posterior stromal scarring. PKP can be considered in patients with
poor vision, although amblyopia may compromise the final visual
result.
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