KEY CONCEPTS
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Pertinent medical (systemic and ocular) and family history must be elicited.
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Many conditions can mimic keratoconus. These can be classified as ectatic and nonectatic disorders.
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Other ectatic disorders include pellucid marginal degeneration, keratoglobus, and postrefractive surgery ectasia.
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Nonectatic conditions to consider include corneal warpage, measurement artifacts, corneal scars, asymmetric and irregular astigmatism, and tear film instability and dry eye.
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Tomographic maps of both eyes must always be analyzed in relation to each other. In suspicious cases, repeat scanning may be done to confirm results.
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Newer imaging with biomechanics can help differentiate tomographic normal cases.
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Patients with equivocal findings must be followed up regularly with repeat corneal imaging.
Introduction
Keratoconus must be differentiated from other forms of keratectasia and other causes of irregular or asymmetric corneal astigmatism, because the management and prognosis are specific for each condition. Identifying underlying ectatic disease is also critical when screening candidates for laser refractive surgery, to avoid inadvertent acceleration of any underlying ectasia. An accurate diagnosis can often be made after consideration of corneal findings on slit lamp biomicroscopy, corneal tomography, and respectively generated keratoconus indices in relation to the ocular history, including details of contact lens wear and any prior corneal ablative or incisional procedure. The presence of other ocular and systemic comorbidities such as vernal keratoconjunctivitis, atopy, and connective tissue disease are also important to establish. Any family history of keratoconus or other corneal and ocular conditions must also be elicited. Newer diagnostics such as epithelial thickness mapping, corneal aberrometry, and corneal biomechanical measurement such as with the Corvis ST (Oculus Optikgeräte GmbH, Wetzlar, Germany) may help detect early ectatic disease. Hence, the differential diagnoses of keratoconus can be classified into other corneal ectatic diseases, and nonectatic conditions mimicking keratoconus.
Ectatic Disorders
The most important conditions to consider are the other ectatic disorders. These include pellucid marginal degeneration (PMD), keratoglobus, and postrefractive surgical ectasia. The latter is easily identifiable once a history of laser vision correction (LVC) is obtained.
PELLUCID MARGINAL DEGENERATION
Like keratoconus, PMD is a degenerative disorder characterized by progressive corneal thinning and ectasia. Both are typically bilateral and asymmetric at presentation, although unilateral PMD has been reported. PMD is often misdiagnosed as keratoconus, because they may closely resemble each other in clinical presentation. Patients with PMD, however, typically present later, between the second to the fifth decades of life, compared with keratoconus, wherein patients present from puberty to the third decade of life. PMD is also less commonly seen than keratoconus, with incidence depending on the geographic location, ranging from 0.0003% in Russia to 2.3% in Central India. , Tummanapalli and colleagues, in a large study of 1133 patients with corneal ectasia, documented keratoconus in 97% of patients and PMD in 3%.
PMD is characterized by a clear, narrow band of peripheral corneal thinning, classically located concentric to the limbus inferiorly from 4 to 8 o’clock and best demonstrated by a full-coverage 12-mm pachymetric map. Superior, nasal, and temporal quadrant involvement have also been reported. , , Between the area of thinning and the limbus often lies 1 to 2 mm of unaffected cornea. There is central or paracentral corneal protrusion, most prominent above the area of thinning, but central corneal thickness (CCT) usually remains unaffected. Keratoconus, on the other hand, usually shows corneal thinning in the paracentral region, with central or inferior steepening and asymmetric bowtie astigmatism on corneal tomography.
The exact etiology and incidence of PMD is still not known. Some authors have suggested that keratoconus, PMD, and keratoglobus may be phenotypic variations of the same underlying corneal disorder. , Another hypothesis is that PMD is a peripheral form of keratoconus. , Reports have also been made of PMD and keratoconus concomitantly occurring in the same eye or in fellow eye. , ,
Patients with PMD tend to present later than those with keratoconus, typically with decreased vision caused by a progressive increase in irregular, against-the-rule astigmatism. , Rarely, patients may experience acute scleral injection, eye pain, or sudden blurring of vision and photophobia from acute hydrops or corneal perforation. , In the largest review of PMD patients to date, Sridhar and colleagues documented hydrops in 7 out of 116 eyes (6.0%), while a more recent study reported hydrops in as much as 11.5% of patients. Most cases of hydrops seen are associated with keratoconus because of its prevalence, but the incidence of hydrops in keratoconus is actually lower than in PMD, with previous clinical estimates at 2.4% to 2.8%. In both conditions, hydrops presents with acute corneal edema and a break in the Descemet membrane secondary to progressive corneal thinning. Corneal vascularization and scarring may be seen after acute hydrops in both keratoconus and PMD. Sridhar and colleagues in their review reported that among seven PMD patients who experienced acute hydrops, the breaks in the Descemet membrane occurred above the area of thinning.
Moderate cases of PMD may be easily identified on biomicroscopic examination because of the classic location of inferior thinning with protrusion above the thinnest area, in contrast to keratoconus in which the thinnest area coincides with the most ectatic region. , A “beer-belly” contour of the central and inferior cornea may be observed when the eye is viewed from the side, compared to a conical profile in keratoconus. , Early cases, however, may look unremarkable, and severe cases may resemble keratoconus if the corneal thinning extensively involves the inferior cornea. A Fleischer ring, apical corneal scarring or vascularization, lipid deposition, Rizutti’s phenomenon, and Munson’s sign do not develop in PMD. , Descemet folds may be seen concentric with the inferior limbus. These folds disappear when pressure is applied to the cornea. , ,
Corneal Tomography
Corneal tomography is the gold standard for distinguishing between the two conditions. , Early PMD may show a topographic pattern of mild to moderate against-the-rule astigmatism, normal keratometric values, and normal CCT ( Fig. 9.1 ). A “crab-claw” pattern, also known as “butterfly,” “lobster,” or “kissing doves” sign, on the sagittal anterior curvature map, signifying steepening of the inferior corneal periphery and flattening along the vertical meridian, has been commonly cited as the classic finding in patients with advanced PMD ( Fig. 9.2 ). , , However, previous studies have shown that this pattern can also be present in inferior keratoconus, in which the cone is located away from the center of the cornea ( Fig. 9.3 ). , , , In a study by Koc and colleagues of 47 eyes with crab-claw pattern on corneal topography, a higher probability of a patient having inferior keratoconus than PMD was found. The pachymetric map, however, will reveal an absence of inferior crescentic thinning in eyes with keratoconus. In another study, Tummanapalli and colleagues evaluated corneal elevation and thickness indices in PMD and keratoconus. Among the indices, asphericity had the highest area under the receiver operating characteristic (AROC) curve in distinguishing the two disorders, followed by the ratio of average power values of the nasal and temporal quadrants to that of the inferior and superior quadrants. A generated PMD index by the authors had 90% sensitivity and 93.7% specificity in distinguishing PMD from keratoconus.
Corneal Biomechanical Response
Several studies have investigated corneal hysteresis (CH) and corneal resistance factor (CRF) in patients with PMD. These showed that CH and CRF were also significantly decreased in PMD eyes, as in keratoconus, compared to healthy eyes.
Higher Order Aberrations
Higher order aberrations (HOAs) secondary to keratoconus and PMD are different, probably because of the difference in the relative position of the corneal apex to the pupil. Trefoil has been shown in some studies to be the most relevant HOA in PMD; this finding is very uncommon in keratoconus. , Less primary coma and a trend to larger magnitude and less negative spherical aberration values have also been reported in PMD, compared with keratoconus. , However, no compelling evidence is available to support HOAs as a tool to distinguish between the two conditions. Fig. 9.4 shows Pentacam tomography images of a 27-year-old male with superior PMD who had bilateral asymmetric bowtie astigmatism with superior steepening and associated corneal thinning. No angling of the hemi-meridians of the bowtie patterns was seen and posterior elevation maps were normal. Although the corneal biomechanical indices (CBIs) were only suspicious in the right eye and normal in the left eye, the Belin-Ambrósio enhanced ectasia display total deviation (BAD-D) values were markedly abnormal, leading to high tomographic and biomechanical indices (TBIs) in both eyes. Zernike analysis revealed increased coma and trefoil aberrations in both eyes. Spherical aberration was +0.733 μm on the right eye and −0.203 μm on the left eye. The case in Fig. 9.2 similarly showed increased coma, trefoil, and spherical aberrations (+0.753 μm).
Corneal Densitometry
Eyes with keratoconus show an increase in corneal densitometry values at the central (0–2 mm) and paracentral (2–6 mm) regions of the cornea. This is because of backscattering of light from disruption of the epithelial and stromal layers. Only one study to date has investigated corneal densitometry in PMD. Koc and colleagues evaluated densitometric, topographic, and tomographic properties of eyes with PMD and inferior keratoconus who had crab-claw patterns on sagittal topography and compared them with control eyes. Densitometry values were shown to be significantly higher in PMD compared with normal eyes in all corneal zones and layers. These were also significantly higher in PMD than in inferior keratoconus at the 6- to 10-mm and 10- to 12-mm zones. More studies are needed to determine if these values can be used to help distinguish PMD from keratoconus.
KERATOGLOBUS
Keratoglobus is a rare form of corneal ectasia in which globular protrusion results from diffuse corneal thinning ( Figs. 9.5 and 9.6 ). , , It may be confused with cases of advanced keratoconus, in which the cornea may also appear globular and thin. However, a small area of the superior cornea in advanced keratoconus may still be of relatively normal thickness as opposed to the diffuse thinning seen in keratoglobus.
Keratoglobus is typically bilateral and present at birth; inheritance has been assumed to be autosomal recessive as previously described by Pouliquen and colleagues. , Rathi and colleagues in their series documented a history of consanguinity in 3 out of 21 pediatric patients, 2 of whom had blue sclera syndrome. Keratoglobus may be associated with certain connective tissue disorders such as Ehlers-Danlos syndrome, Marfan syndrome, and Rubinstein-Taybi syndrome. Similar clinical features have been reported in association with vernal keratoconjunctivitis, chronic marginal blepharitis, idiopathic orbital inflammation, and thyroid eye disease. , As mentioned earlier, keratoconus, PMD, and keratoglobus are believed by some to represent a spectrum of the same underlying ectatic disorder. Keratoconus and keratoglobus have been found among different members of the same family. Reports of keratoglobus occurring in eyes with keratoconus and in eyes with PMD have also been made. , , , Some authors hypothesize that “acquired” keratoglobus represents a severe, advanced form of keratoconus, , whereas others believe it may be a result of circumferential extension of the peripheral gutter in PMD. Corneal thinning in keratoconus is localized centrally or paracentrally, whereas the thinning in keratoglobus extends from limbus to limbus and is maximal at the periphery (see Fig. 9.6 ). , , Associated scleral thinning in keratoglobus has also been reported. Central and paracentral elevation and steepening are demonstrated on corneal tomography. Although disease progression is absent to minimal, patients have poor vision owing to high myopia and irregular astigmatism. ,
Keratoglobus corneas are typically clear at presentation unless they develop hydrops and subsequent scarring. Unlike in keratoconus, Vogt striae and Fleischer rings are not seen. The incidence of acute hydrops in keratoglobus and PMD is higher than in keratoconus. In the largest series to date, Rathi and colleagues documented 13.2% of 53 eyes with keratoglobus to have presented with acute hydrops and another 13.2% showed scars consistent with healed hydrops. Other series have reported the incidence of hydrops in keratoglobus to range from 11.0% to as high as 90.48%. Compared to those with keratoconus, patients with keratoglobus are more prone to experiencing corneal perforation, either occurring spontaneously or after mild eye trauma, as the thinning can progress to as much as to 20% of normal corneal thickness. , , Hard contact lenses are thus contraindicated and protective eyewear encouraged in these patients.
CORNEAL ECTASIA AFTER REFRACTIVE SURGERY
Corneal ectasia should be suspected in patients who have had any prior ablative or incisional refractive procedure, especially myopic laser in-situ keratomileusis (LASIK). Ectasia in this population can develop because of postsurgical biomechanical instability of the cornea with or without unrecognized preexisting keratoconus, subclinical keratoconus, or PMD, or by chance secondary to other intrinsic factors such as eye rubbing and subclinical atopy. Similar to keratoconus, post-LASIK ectasia manifests as progressive central or inferior corneal steepening and thinning ( Figs. 9.7 and 9.8 ) leading to increased myopia, irregular astigmatism, decreased uncorrected and best corrected visual acuity, and optical phenomena including glare and halos. , The epithelium is also significantly thinner over the corneal apex in both keratoconus and postoperative corneal ectasia when compared with normal eyes. Corneal tomography in post-LASIK ectasia may show signs of posterior corneal elevation alone without an increase in the maximum keratometry (K max) or a decrease in uncorrected visual acuity.
Although less common, ectasia has also been documented after radial and hexagonal keratotomy ( Fig. 9.9 ), , photorefractive keratectomy (PRK), and more recently, small-incision lenticule extraction (SMILE). , Some patients may not recall having had LVC, so a careful search for a LASIK flap or a SMILE incision, which may not be obvious on cursory examination with broad beam illumination, must be undertaken to avoid a misdiagnosis of keratoconus. Post-PRK patients do not have corneal flaps or incisions; thus evaluation of curvature and pachymetry maps of both eyes must be analyzed in relation to each other. An ablation pattern seen on sagittal and pachymetric maps in the uninvolved eye will reveal prior LVC. Recurrence of ectasia has also been described following penetrating keratoplasty , and deep anterior lamellar keratoplasty for keratoconus. , Some controversy still exists as to whether keratoconus pathology reemerges by migration of the disease from host to donor cornea, or from incomplete excision of the cone. Latency for recurrence following penetrating keratoplasty is long (mean 19 years; range 3–40 years).
Non-ectatic Disorders
Corneas without frank ectasia may be misdiagnosed as keratoconus when an abnormal topographic pattern is detected. A wide variety of pseudokeratoconus conditions exist that may also demonstrate focal corneal steepening, high astigmatism and posterior corneal elevation, significant negative corneal asphericity, and increased anterior and posterior corneal aberrations. Stein and Salim reviewed 1000 consecutive patients who were referred for corneal cross-linking, topography-guided PRK, and intrastromal corneal rings for presumed keratoconus, PMD, or ectasia after LVC. They found 26 eyes without ectasia in 20 patients. Among these were, in order of decreasing frequency, epithelial basement membrane dystrophy, superficial punctate keratitis, amblyopia secondary to high astigmatism, whorl-like keratopathy, corneal warpage secondary to contact lenses, measurement error with topography, and corneal scars. An integrated analysis of corneal biomicroscopic findings, tomographic and epithelial maps, and biomechanical properties is needed to differentiate ectatic from nonectatic disease, thus avoiding unnecessary or contraindicated treatments such as PRK and LASIK in the former and cross-linking and intrastromal corneal ring segment implantation in the latter.
CONTACT LENS–INDUCED CORNEAL WARPAGE
Chronic wear of contact lenses, especially rigid gas-permeable and soft toric lenses, may lead to reversible alterations in the anterior corneal topographic pattern. , This warpage may be due either to a direct mechanical effect or to a combination of mechanical and metabolic changes related to the corneal epithelium. As many LVC candidates wear contact lenses, differentiation between warpage and keratoconus is crucial for the proper selection of patients for refractive surgery and for the identification of patients with ectasia who could benefit from collagen cross-linking. , Clinical signs of corneal warpage include changes in refractive error, a reduction in corrected visual acuity, and absence of progressive corneal thinning. Patients suspected of having corneal warpage may be instructed to discontinue hard lenses for at least 1 month or soft lenses for at least 1 week. Regular follow-ups with serial corneal topography are then used to monitor for partial or complete reversal of findings typically seen with corneal warpage, to arrive at a definite diagnosis. , The time required for significant stabilization varies among individuals and contact lens type. A long waiting period that may reach several months may not be acceptable to patients who lead a spectacle-free lifestyle and have planned for LVC at a specific time.
Corneal warpage can also result in focal topographic steepening. It may mimic the topography seen in ectasia, especially when the steepening is located inferiorly or inferotemporally, but is not progressive. Fig. 9.10A shows superior corneal steepening without associated thinning or increased corneal elevation on Orbscan imaging of a patient who was a chronic soft contact lens user. Repeat imaging showed the same pattern. After 2 months of discontinuation of soft contact lens use, resolution of the corneal warpage was seen with restoration of normal symmetric bowtie astigmatism (see Fig. 9.10B ). Fig. 9.11 shows Pentacam images of a patient who was using orthokeratology lenses in both eyes. Corneal warpage was indicated by unusual evenness across the entire corneas on curvature maps. Small central islands of depression secondary to orthokeratology lens wear were also seen on anterior elevation maps, whereas posterior elevation maps were unremarkable.
