AMO Resident Most Challenging Contact Lens CaseCatherine Pannebaker, O.D.
INTRODUCTION
Keratoconus is an asymmetric condition of corneal ectasia and thinning with onset usually in early teens to early twenties, with an incidence of about 1/2000 [1]. Patients can be markedly visually impaired with high amounts of irregular astigmatism and myopia.
Classic objective signs seen by biomicroscopy include stromal thinning, central scarring, vertical lines in the posterior cornea (Vogt’s striae), and prominent corneal nerves; quite often a brownish or olive green colored ring of iron deposition (Fleischer’s ring) is seen at the base of the “cone” or apex of the protrusion. Additional signs include a bowing outward of the inferior lid in downgaze (Munson’s sign) and steepened keratometry or topography readings.
In some advanced cases of keratoconus, breaks in the posterior cornea can occur. This causes an influx of aqueous humor, and leads to an acute and painful onset of corneal edema. These episodes of corneal hydrops usually result in scarring. Fibrotic scarring near the visual axis and apex of cone are also evident in many patients even in the absence of hydrops.
Although improved with pinhole, the best corrected visual acuity in keratoconus patients is often reduced with spectacle correction; therefore, most patients are managed with rigid gas permeable contact lenses in a wide range of specifications. Some patients may require penetrating keratoplasty if contact lenses are no longer a management option.
Keratoconus is historically defined as a non-inflammatory condition. The exact etiology is unknown, however, recent literature suggests that inflammation molecules and abnormal levels of enzymes are present in patients with keratoconus [2,3]. Other research indicates that keratoconus may also have genetic components [4]. Frequent associations include history of allergies, atopy (asthma, hay fever, eczema), eye rubbing, eye injuries, rigid contact lens wear, and family history of keratoconus [5]. Curiously, the condition seems to cease progression with increasing age [6,7].
The sections to follow will summarize literature regarding studies on related proteins in corneal tissues and tears, as well as possible genetic and inflammatory aspects involved in the etiology and progression of keratoconus.
Tear Proteins
Extensive tear protein work performed by Souza et al has resulted in the identification of 491 proteins, both extracellular and intracellular, the latter of which may result from cell death in the epithelium of the cornea [8]. Many proteins are contained in the aqueous layer of the tears and are secreted by the lacrimal and accessory glands. The majority of these proteins in the normal tear film consist of lysozyme, lactoferrin, secretory immunoglobulin A, serum albumin, lipocalin, and lipophilin [9]. In addition, these proteins are in a relatively high concentration (8 ųg/ųL), and easily accessed in tear collection methods, making the tear film very promising for extensive protein analysis via such methods as enzyme-linked immunosorbent assay (ELISA), mass spectrometry and others [8]. The study of proteins, or proteomics, is valuable in identification of molecular markers involved in such processes as wound healing, the immune response, inflammation, and oxidative stress, or damage to tissues resulting from the inability to process reactive oxygen species.
Tissue and Ocular Surface Disorder
Teng used electron microscopy in the 1960’s to investigate the pathologic changes in the corneal tissue of keratoconus patients [10]. He confirmed the decomposition of the basement and Bowman’s membranes, and stated that the result of enzyme activities could affect collagen and nerve fibers along with Descemet’s membrane.
Additional studies by Jongebloed and Sawaguchi revealed not only a lack of replacement of epithelial cells leading to holes exposing Bowman’s membrane in some areas, but also an “accelerated aging process” in the epithelium [11-14].
Murat Dogru et al studied changes in the ocular surface in terms of corneal staining, goblet cell density, and squamous metaplasia using standard Schirmer testing and impression cytology; these tests were performed on mild to severe keratoconus patients who had no history of contact lens wear, ocular surgery or other active systemic or eye conditions [14]. They found that nearly 46.6% of the eyes had punctate keratopathy and 70.6% had a tear breakup time <10 seconds; squamous metaplasia was an average of 10 times greater in the keratoconus eyes verses control eyes, and goblet cell density was half that of control eyes [14]. The significance of the squamous metaplasia is that an actual transformation of tissue has occurred. Goblet cells are important in producing mucins: glycoprotein secretions known to create a hydrophilic ocular surface and therefore aid in tear film stability [15-16]. An interesting finding in Dogru’s study was that Schirmer testing revealed no significant differences between the keratoconus eyes and control eyes, suggesting an absence of aqueous-deficient dry eyes [14]. Dogru suggested the possibility of new approaches in therapies for keratoconus patients. These therapies include topical retinoids, which have been shown to aid in producing basement membrane components, and topical 15-(S)-hydroxyeicosatetraenoic acid for increasing mucin secretions [12]. This study and others to be discussed may be suggestive of tissue and tear function abnormalities in keratoconus.
Genetic Studies
Numerous genetic studies have been performed with the hope of discovering a gene that is solely responsible for keratoconus. Noting that keratoconus has systemic and familial associations, genetics most likely plays a role in the etiology [17]. Furthermore, the variability displayed in families, the asymmetry with which the eyes are affected, and discordance between mono- and dizygotic twins supports a genetic component [18-20]. There are a few cases of monozygotic twins in which one had clinical signs of keratoconus, and the other lacked any signs – even with topography – owing evidence that environmental aspects play a role as well [19]. Both dominant and recessive inheritance patterns have been seen in families, and the variable expression of keratoconus remains puzzling [21-23]. However, the development of corneal topography now enables a method of early detection in the condition, which further helps to clarify pedigrees and prevalence in families as it is used to test family members and show similarities in the cone presentation (e.g., central, inferior) [24,25].
Keratoconus has proven associations with Down syndrome (10-300 fold increase in prevalence), Leber’s congenital amaurosis, atopy and connective tissue disorders; these associations can be important in providing chromosomal information since these disorders have a defined genetic origin [26]. The most compelling systemic association is with mitral valve prolapse, as Beardsley and Sharif found 44% and 58% prevalence in their subjects respectively, possibly indicating a link with collagen abnormality [26-28].
Unfortunately, some genetic studies in the past used inconsistent methods, and many were conducted mostly on caucasians[29-30]. Rabinowitz recently recruited hispanic, black, and asian subjects in addition to whites and found some consistency in linkage between whites and hispanics [17]. He found evidence of linkage to keratoconus on chromosomes 4, 5, 9, 12, and 14 for whites “and/or all pedigrees”, and additionally chromosome 17 for Hispanics only [17]. Specifically, Rabinowitz targeted three candidate keratoconus genes from these chromosomes: lysyl oxidase, a gene responsible for collagen cross-linking; cell death-inducing DEFA-like effector b, thought to be involved in apoptosis; and gelsolin, a gene also associated with another corneal dystrophy [17]. Although his study could only conclude that many loci are involved in keratoconus, it was the first of its kind with a large sample size (351 subjects phenotyped) to identify linkage in populations other than whites, and will most likely challenge other scientists to recruit a variety of subpopulations [17]. In addition, Rabinowitz has shown linkage to other chromosomes – 3, 13, 15, 16, 17, 20, and 21 (significant in trisomy 21), yet the exact genetic cause for keratoconus is still not clear in that genes were not found at the precise loci [31,32].
Although associated with polymorphous corneal dystrophy, the visual system homeobox 1 gene (VISX1) has been widely speculated as a possible mutation involved in keratoconus [33-35]. Aldave et al recently disproved this in a study of four specific mutations, showing that VSX1 gene mutations are not associated with the etiology of keratoconus [35].
Udar et al recently studied superoxide dismutase 1 (SOD1) along with Christina Kenney’s group as a possible candidate gene in keratoconus [32]. Superoxide dismutase on chromosome 21 is an enzyme known to be involved in antioxidant activities by reducing accumulating free radicals [32]. Although mutations in the gene were found, the evidence was not conclusive, and no causal relationship between these mutations of SOD1 and keratoconus could be confirmed; further studies were suggested with other variants of the gene [32].
Inflammation and Immune Response
Although keratoconus is defined throughout the literature and textbooks as a noninflammatory condition, several studies support the possibility of inflammatory and immune molecules at work in this condition.
Atopy, a genetically determined state in which the body elicits an exaggerated response to a foreign stimulus, is known to be associated with increased levels of immunoglobulin E (IgE) [15,36]. In 1982, Kemp and Lewis reported elevated serum levels of IgE in 59% of 27 keratoconus patients selected at random [37]. Rahi et al reported increased serum levels of IgG and IgM in keratoconus patients, while Kemp and Lewis found no statistically significant difference in these immunoglobulins in keratoconus patients compared to controls in their study [37,38].
Although an association between eye rubbing in patients with allergic conditions has been widely reported by several studies, many clinicians and researchers view it as a difficult correlation to make due to the nature of self-reported episodes. It is feasible, however, that these patients rub may their eyes as a result of an already present allergic reaction taking place.
In 2005, Lema and Durán studied one eye each from 28 patients diagnosed with keratoconus [36]. They targeted specific cytokines, cell adhesion molecules, and matrix metalloproteinase 9 (MMP-9). Cytokines, cell adhesion molecules and MMP-9 were chosen for their association with chronic inflammation [36]. Tear samples of 15 ųLs were collected from keratoconus subjects who had not worn contact lenses, and had no active inflammatory systemic or ocular conditions, and then processed with ELISA kits. Three molecules were found to be at levels significantly higher than normal in keratoconus patients: IL-6, TNF-α, and MMP-9. In addition, the levels of each molecule were strongly correlated with the severity of keratoconus. Following regression analysis, however, only MMP-9 was found to be an independent variable associated with the degree of keratoconus. Lema made a compelling remark: “It can be concluded…that keratoconus cannot be defined any more as a noninflammatory disorder” [36].
In his review article from 2001, Simon Collier addresses MMPs and their possible role in keratoconus [39]. He specifically addresses the absence of upregulation of MMP-9 by Fini, Kenny, and Zhou by suggesting that techniques could be a possible source of conflict [39-42]. Collier additionally notes that MMP-9 should be induced by IL-1, and Fabre et al noted that keratoconus fibroblasts release fourfold the number of these same IL-1 receptors compared to normal corneas [39,43]. It would stand to reason therefore, that MMP-9 could indeed be overexpressed in keratoconus. Furthermore, Li and Pflugfelder report that MMP-9 may be “a most amplifying factor for corneal inflammation” [44].
Other researchers have seen expression of similar molecules in keratoconus patients. Collier et al were first in demonstrating the expression of membrane-type 1 (MT1) MMP in vivo in keratoconus corneas compared to controls [45]. Ohuchi and D’Ortho had found previously that MT1-MMP can activate gelatinase A to digest type IV collagen of the basement membrane; MT1-MMP has the ability to degrade several extracellular matrix molecules including collagen types I-III [46,47].
It is important to note that the cornea is 70% collagen by weight and is mostly comprised of Type I collagen [39]. The ectasia and thinning found in keratoconus is mostly due to a damaged extracellular matrix and a decrease in types I and IV, along with an increase in type IX collagen – not otherwise found in the basement membrane of the cornea. [39,48]. Collier et al further hypothesized that MT1-MMP could be released in response to an inflammatory-related or pathological event, and that it most likely has a significant role in the etiology if not the progression of keratoconus [45].
Abalain et al studied levels of telopeptides, or collagen degradation products from 26 keratoconus subjects and 36 controls [48]. This study allowed contact lens wear and an average of 2-7 ųL was collected; active inflammation, ocular surgery and topical ocular medications were exclusions [48]. The concentration of telopeptides was found by ELISA kits, and keratoconus patients were found to have 3.5 times the amount of telopeptides compared to normals; contact lens wear did not significantly modify the amounts [48]. It was hypothesized that corneal thinning may result from proteolysis of collagen rather than a decrease in the synthesis of extracellular components [48].
Degradative Enzymes/Oxidative Processes
In a hallmark review paper, Christina Kenney and Donald Brown describe a “cascade hypothesis of keratoconus” in which enzymes in two pathways could lead to oxidative damage [49]. She notes a decrease in the inhibitors of destructive enzymes are decreased in keratoconus corneas; they are alpha one (α1) proteinase inhibitor, alpha two (α2) macroglobulin, and tissue inhibitor metalloproteinase one (TIMP-1); the latter of which can inhibit cell apoptosis (programmed cell death) and affect cell growth [15,42,49,51]. Matthews et al noted that relative concentrations between TIMP-1 and TIMP-3 could be determinants in the balance of cell overgrowth and apoptosis in keratoconus [52].
Importantly, apoptosis occurs in normal cellular turnover as well as diseases and wound healing [49]. Edwards et al hypothesized that apoptosis could also occur from the release of inflammatory cytokines from injured corneal and conjunctival epithelial cells [26].
Gondhowiardjo et al noted a decrease in aldehyde dehydrogenase Class 3 (ALDH3) and superoxide dismutase, the necessary enzymes to process reactive oxygen species (ROS), and Kenney surmises that this leads to large amount of cytotoxic by products in keratoconus corneas eventually leading to corneal thinning and loss of vision [49,53,54].
Kenney recommends that clinicians educate patients on sources of reactive oxygen species such as ultraviolet (UV) light, trauma caused by excessive eye rubbing and poorly fit contact lenses, and uncontrolled allergies. In addition she recommends UV protection in both contact lenses and glasses, and prescribing of topical non-steroidal anti-inflammatory medications (NSAIDS) and allergy medications, as well as preservative-free artificial tears in the management of keratoconus patients [49].
CASE REPORT
Pertinent History and Chief Complaint
Patient AC, a 26-year-old white female, was referred to the clinic by a local practitioner for contact lens fitting in March, 2007. She had been fitted with soft toric contact lenses in December of 2006, and was reporting fluctuating and decreased vision with both her contact lenses and spectacles over the previous two years.
AC’s occupation was programmer, and her systemic history was unremarkable; she reported taking oral birth control medication. Other pertinent patient and family history was unremarkable. The patient’s comprehensive examination in December, 2006, revealed that pupils, motilities, and color vision were within normal limits in both eyes, although local stereopsis was reduced at 50”. Vision with her current spectacles was 20/30 OD and 20/40 OS. The manifest refraction determined was -2.75 -4.75 x 057 (20/30) in the right eye, and -3.75 -4.50 x 132 (20/30) in the left eye. The soft toric contact lens prescription had not been finalized, but trials of Vertex Toric had been dispensed: Median base curves, 14.4mm diameter and powers of -3.00-2.75 x045 in the right eye, and -3.50 -3.75 x155 in the left eye. The previous practitioner had noted no abnormalies with biomicroscopy, and non-contact tonometry revealed introcular pressures of 6 mmHg in both eyes at 5pm. Confrontations and amsler grid testing were reported within normal limits in both eyes. Dilation with 1% Tropicamide revealed that all aspects of the posterior pole and peripheral fundus examination were within normal limits in each eye. Their impression was myopic astigmatism and slightly reduced acuities in each eye, and plan was to refer to OSU clinic for further contact lens fitting.
Contact Lens Fitting – First Visit (4/06/07)
- Entrance Distance Visual Acuity (Snellen, with CL’s)
OD: 20/25
OS: 20/50 (PH 20/30)
- Pupils: 5/5 Round/reactive to light with no afferent pupillary defect OU
- Current Soft Contact Lens Assessment
OD / OS
Movement / Minimal / Minimal
Centration / Slightly inf / Slightly Inf
Coverage / Adequate / Adequate
Rotation / 9º Nasal / 10º Nasal
- Manifest Refraction (D)
OD: -2.75 -4.50 x04820/25
OS: -4.00 -4.50 x13220/30 PHNI
- Simulated Keratometry Readings (Medmont – see pp. 11-12)
OD: 48.8 D @ 134 / 42.7 D @ 044 Trace distortion of mires
OS: 49.4D @ 048 / 42.10D @138Trace distortion of mires
- Biomicroscopy:
OD / OS
Lids/Lashes / Make-up debris / Make-up debris
Conjunctiva / Trace injection / Trace injection
Cornea / See drawing / See drawing
Iris / Blue/clear / Blue/clear
Anterior Chamber / Von Herrick G4 / Von Herrick G4
Corneas:
- Contact Lens Fitting OD (9.5mm diameterPMMA fitting set, with 8.1mm Optic Zone (OZ) and 8.40/10.5 secondary and peripheral curves)1 drop Proparacaine instilled OD prior to fitting
1)BC = 7.3/-3.00 (Approximately Average of K readings)
Fit / Lid Attached (LA)Central Flourescein Pattern / Central Pooling
Edge Lift / Minimal 360º
Other / Mid peripheral bearing
2)BC = 7.5/-3.00 (Slightly flatter since central pooling)
Fit / LACentral Flourescein Pattern / Feather touch
Edge Lift / Minimal 360º
Other / Slight Mid peripheral bearing
Spherical over-refraction (SOR) -5.00D (vertexed power -4.75, 20/20)
- Contact Lens Fitting OS (9.5mm diameterPMMA fitting set, with 8.1mm OZ and 8.40/10.5 secondary and peripheral curves)
1 drop Proparacaine instilled OD prior to fitting
1)BC = 7.2/ -3.00 (Approximately Average of K readings)
Fit / LACentral Flourescein Pattern / Central pooling
Edge Lift / Minimal 360º
Other / Central Bubble
2)BC = 7.5/-3.00 (Since central pooling/bubble)