Understanding keratoconus: what have we learned from the New Zealand perspective?

Authors


Abstract

Although first described more than 150 years ago, keratoconus is still an enigmatic disease that remains an area of wide-ranging, dynamic, international research. This review considers data from New Zealand/Aotearoa, where keratoconus is both relatively common and extensively studied. New Zealand researchers have made several significant contributions to the international literature in this field, including identifying a higher prevalence of keratoconus in New Zealand per se and within Maori and Polynesian populations compared to many international studies. As reported in other studies, a higher proportion of asthma, allergy and eczema as potential risk co-factors are present in New Zealand subjects with keratoconus compared with estimates from the general population. The rates of family history of keratoconus are typically higher than those reported internationally, with higher rates in Asian, Pacific and Maori ethnicities. Interestingly, such a positive family history has been associated with less severe keratoconus on computerised topographic analysis. Investigations of corneal microstructure have revealed dramatic alterations in the keratoconic cornea, with reduced density and abnormal morphology of the corneal sub-basal nerve plexus and decreased keratocytic density. Laboratory studies of keratoconic corneal buttons have also furthered our understanding of the pathophysiology of this disease, demonstrating elevated levels of cathepsin enzymes and localised disruptions in Bowman's layer with incursion of cellular processes from anterior keratocytes. Over the past two decades keratoconus has consistently remained the leading indication for corneal transplantation in New Zealand, accounting for over 40 per cent of cases. Indeed, New Zealand appears to have the highest reported proportion of transplantation surgery for keratoconus worldwide. Current and future studies of keratoconus in New Zealand highlight an emphasis on elucidating the genetics of, and investigating novel therapeutic interventions for, this relatively common corneal disease.

Despite more than 150 years of investigation,[1] keratoconus still remains an enigmatic disease in terms of inheritance, prevention, associated risk factors, disease progression, treatment and underlying pathophysiology.[2] Our knowledge of this disease has expanded greatly in the last 30 years due to a combination of clinical and laboratory studies. Indeed, 80 per cent of all research publications listed by Medline with the keyword ‘keratoconus’ (3,035 of 3,772 articles) have been published since January 1980 and almost half since the year 2000 (accessed June 1, 2012). Thus keratoconus remains a disease topic of wide-ranging and dynamic research.

A relatively high prevalence of keratoconus has been noted in New Zealand for more than 30 years[3] and in recent years, key features of keratoconus have been recognised increasingly in the New Zealand population and by New Zealand researchers. Indeed, nearly 30 New Zealand studies have revealed aspects of the underlying pathophysiology and confirm that the disease may be more common and more severe in New Zealand/Aotearoa. This brief review considers the evidence that may be unique to, or generalisable from, these New Zealand studies of keratoconus.

Prevalence and Predisposition to Keratoconus in New Zealand

The prevalence of keratoconus has been reported to vary in different studies internationally, from 8.8 to 54.4 per 100,000.[4] In 1978, Sabiston[3] stated that ‘The occurrence rate in Hawkes Bay has been calculated to be one in two thousand of the population and is found to be equally present in both Maoris and Europeans.’ Although there are no further data directly studying the prevalence of keratoconus in New Zealand, a number of studies has investigated the nature of keratoconus in New Zealand populations.

One large practitioner-based survey revealed that most subjects with keratoconus in New Zealand were of European descent, with those of Maori or Pacific Island descent accounting for approximately 20 per cent of the cohort. Interestingly, this population distribution for keratoconus was similar to that observed for ethnicity proportions in the general New Zealand population.[5] In contrast, a recent study of patients with keratoconus attending subspecialty cornea and external disease clinics at the Department of Ophthalmology, Auckland District Health Board, revealed significantly higher proportions of Maori and Pacific patients and lower rates of European and Asian patients than the total population.[6] Both of these studies reported a male gender bias (58.5[5] and 54 per cent,[6] respectively).

It is important, when considering the relative likelihood of keratoconus in relation to ethnicity, the varied reasons subjects may chose to attend a hospital practice and these may be influenced by socio-economic or ethnic variables that may confound and influence these data.

Screening of New Zealand school children for topographic corneal anomalies (Figure 1) suggested that topographic images suggestive of early keratoconus affected 19 per cent of the screened cohort.[7] Although not directly comparable in terms of the age, type of populations screened, methods of screening and diagnostic criteria, studies from other countries have shown significantly lower prevalence of keratoconus (Israel, 2.34 per cent;[8] India, 2.3 per cent;[9] Denmark, 0.09 per cent;[10] USA, 0.05 per cent[11]).

Figure 1.

Orbscan II tomographic maps of a keratoconic cornea, demonstrating inferior corneal steepening and thinning, with a posterior elevation of more than 40 μm

Of particular note, the odds of exhibiting suspect anomalous corneal topography were twice that for Maori/Polynesian than for non-Maori/Polynesian students (26.9 versus 12.9 per cent).[7] A recent study showed that Maori and Pacific Island ethnicity is associated with more severe disease, and a younger mean age at diagnosis than Caucasian and Asian subjects (17.1 ± 5.6 years versus 27.6 ± 11.6 years).[12]

Although not absolutely conclusive without further supporting studies, these initial studies generally tend to support the contention that keratoconus is both more common in New Zealand per se than in many countries internationally and also more common within Maori and Polynesian populations.

Environmental Factors

In a large New Zealand study, the mean age at diagnosis of keratoconus (self-reported) was 22.9 ± 9.9 years and over 90 per cent of cases were diagnosed between the ages of 11 and 40 years.[5] Similarly, a Scottish hospital-based study reported the mean age at diagnosis of keratoconus by the Hospital Eye Service was 24.05 ± 8.97 years (range, 10 to 59 years, median 21.8 years).[13] The disease has been reported to present at an earlier age in males than in females[5] and in subjects with a history of atopy.[12] Eye rubbing is a well-known association of atopy and there is an extremely wide variation in the reported incidence of eye rubbing in New Zealand studies of keratoconus (23.1,[12] 36,[6] 63[5] and 92 per cent[14]).

As reported in other international studies, a higher proportion of asthma, allergy and eczema (as associations and potential risk co-factors) is present in New Zealand subjects with keratoconus compared with estimates from the general population:[5] asthma 28.6 to 46.2 per cent,[6, 12, 14] eczema 24.4 to 26.9 per cent[6, 12, 14] and ocular allergy 27.8 to 34.6 per cent;[6, 12] however, atopy may merely be an association and the resulting eye rubbing is the more important environmental factor.

A family history of keratoconus has been reported in between 12.5 and 33 per cent of New Zealand studies (12.5,[6] 17.3,[12] 23.5[5] and 33 per cent[14]). Interestingly, Asian, Pacific, and Maori patients had significantly higher rates of a family history of keratoconus than those of European ancestry.[6] For comparison, the USA-based Collaborative Longitudinal Evaluation of Keratoconus (CLEK) study[15] reported a family history of keratoconus in 14 per cent of participants and the Scottish DUSKS study[13] noted a family history of keratoconus in five per cent, although among the small Asian (Indian sub-continent) subgroup, this figure rose to 25 per cent.

Severity of Keratoconus in New Zealand

Clinical evaluation of a large New Zealand keratoconic population has shown that 13 per cent exhibit corneal stromal scars, 38 per cent a Fleisher ring and 17 per cent Vogt's striae.[14] Cone morphology based on axial keratometric topographic maps has been predominantly defined as asymmetric bow-tie (29[6] and 42 per cent[14]), followed by round (18[6] and 31 per cent[14]) shape. Owens and Watters[14] observed that in some cases, the shape of the cone was fixation-sensitive and that each subject typically exhibited the same cone shape in both eyes;[14] however, complete enantiomorphism based on topography may only be observed in 12.5 per cent of patients with keratoconus[6] and the prevalence of forme fruste keratoconus has been estimated to be 12 per cent.[14]

Earlier studies using ultrasonic pachymetry showed that maximum loss of corneal thickness occurs in the area approximately 2.4 mm below the visual axis and the far superior cornea remains free from significant thinning, even in severe keratoconus.[16] Furthermore, a pachymetric inferior-superior (I-S) difference of 100 μm or greater is considered to be pathognomonic of keratoconus, and the results of this study led Watters and Owen[16] to propose three categories of I-S pachymetric differences: suspect/mild keratoconus with 80 to 100 μm, moderate keratoconus with 100 to 125 μm and advanced keratoconus with 125 μm or more.

Reported cases of identical twins with keratoconus are rare internationally, and there is only one case report from New Zealand.[17] The corneal topography of identical twins with keratoconus revealed not only unequal severity of keratoconus but also non-identical cone types, although contact lens wear up to three days prior to performing corneal topography may have confounded these results. It appears that even in cases with a strong history of inheritance of keratoconus, the development of a particular cone classification may be dependent on other extraneous events.

A family history of keratoconus is the only variable to show strong evidence of an association with severity of keratoconus, with a positive family history actually being indicative of less severe disease.[6]

Clinical Studies of Pathophysiology

Owens, Watters and Gamble[18] studied the effect of SoftPerm contact lenses (composed of a rigid gas-permeable centre and a hydroxyethyl methacrylate soft periphery) on keratoconic corneas. In the keratoconic group, average central corneal swelling after one day was significantly less than the average swelling for the normal (control) subject group. For the keratoconic subjects, cone peak radii flattened by an average of 0.14 ± 0.25 mm within the first seven hours of wear, whereas the normal subjects flattened by 0.03 ± 0.25 mm at the selected equivalent location 1.5 mm below the central cornea. After one month, the measurements of corneal radii were not significantly different from baseline in either group. It is interesting to note that the pattern of corneal swelling in keratoconus was ring-shaped, the oedema surrounding the ectactic portion of the cornea. It was concluded that in the keratoconic eye, swelling following SoftPerm lens wear creates excessive touch over the ectactic area, potentially increasing the risk of scar tissue formation in these individuals.

Patel and McGhee[19] reported the first study to elucidate the distribution of sub-basal nerves in the keratoconic living human cornea and to correlate the two-dimensional distribution with computerised corneal topography. This study confirmed that the pattern and density of the sub-basal nerve plexus is altered in the keratoconic disease process, even during the early stages (Figure 2). Sub-basal nerve fibre bundles exhibited abnormal configurations at the apex of the cone, where the sub-basal nerve plexus appeared to consist of a tortuous network of nerve fibre bundles, many of which formed closed loops. At the topographic base of the cone, nerve fibre bundles appeared to follow the curvilinear contour of the base, with many of the bundles appearing to run concentrically with the cone in this region.

Figure 2.

Wide field montages of laser scanning in vivo confocal microscopic images of the living human sub-basal nerve plexus. The healthy cornea exhibits a radiating pattern of nerves, contrasting with the keratoconic cornea, which has a low density of tortuous nerves.

This strong evidence for the involvement of these nerves in the disease process was further supported by studies investigating corneal sensation using the quantitative non-contact pneumatic corneal aesthesiometer[20] and in vivo confocal microscopy.[12, 20] Sub-basal nerve density and basal epithelial density were shown to be significantly lower in keratoconic compared to healthy corneas; however, although central corneal sensation was significantly lower in contact lens-wearing keratoconics compared to normal subjects, there was no significant difference in corneal sensation between the non-contact lens wearing keratoconic and normal groups.

In vivo confocal microscopic studies in New Zealand have also confirmed significantly lower keratocytic densities in subjects with keratoconus in comparison with age-matched controls.[12, 21] In particular, the reduction in density of keratocytes was significant in the anterior stroma of keratoconic subjects with contact lens wear and in the posterior stroma of all keratoconic subjects (with or without contact lens wear).[21]

New Zealand Laboratory Studies of the Pathophysiology of Keratoconus

Laboratory studies of keratoconic corneal buttons obtained at corneal transplantation have furthered our understanding of the cellular architectural changes and pathogenesis of this disease. In their unique examination of the peripheral keratoconic cone, Sherwin and collegaues[22] observed localised disruptions of Bowman's layer with discrete incursion of fine cellular processes from the anterior keratocytes into this structure, often in association with a localised indentation of the basal epithelium. Analysis of cathepsin levels within individual keratocytes showed that a small proportion of the keratocytes in the anterior stroma had strongly elevated levels of cathepsin enzymes compared to a constitutively expressed esterase enzyme. High levels of cathepsin have been implicated as one of the possible causes of matrix degradation in keratoconus. Therefore, the authors hypothesised that it was degradative enzyme activity from these abnormal cells that was causing localised structural degradation of both Bowman's layer and the stroma, which may be further exacerbated by physical stresses such as intraocular pressure and eye rubbing.[22]

Building on these observations, a subsequent study explored the sequence of events occurring as the disease progresses, particularly in relation to the corneal nerves,[23] which crossed Bowman's layer and lay very close to both keratocyte and epithelial cell nuclei. The authors postulated that these nerves may form a trans-Bowman's communication pathway, albeit cellular rather than extracellular. Keratocytes expressing high levels of cathepsin B and G and varying degrees of corneal damage at these sites of nerve crossing were also observed.[23]

The question of recurrence of keratoconus has been investigated by examining and characterising the pathology of keratoconus in a series of corneal buttons removed during repeat penetrating keratoplasty. This study confirmed little sign of recurrence of keratoconus in corneal allograft tissue, providing further weight to the argument that keratoconus is induced in the tissue of genetically susceptible individuals with associated environmental factors rather than manifesting in transplanted tissue.[24]

Corneal Transplantation for Keratoconus in New Zealand

Data from the New Zealand National Eye Bank over the past two decades have consistently revealed keratoconus as the leading indication for corneal transplantation, accounting for 45.6 per cent[25] of cases from 1991 to 1999 and 41.1 per cent of cases from 2000 to 2009.[26] When the various indications for corneal transplantation are compared internationally, New Zealand appears to have the highest reported proportion of transplantation surgery for keratoconus worldwide[27-30] (Table 1).

Table 1. An international comparison of the leading indications for corneal transplantation
IndicationNew ZealandNew ZealandAustraliaUSAUKChina
1991–1999[25]2000–2009[26]1985–2009[27]2001–2005[28]2007–2008[29]1997–2002[30]
Keratoconus45.6 per cent41.1 per cent31.0 per cent16.0 per cent21.7 per cent12.9 per cent
Bullous keratopathy17.9 per cent13.9 per cent25.0 per cent28.4 per cent14.7 per cent6.9 per cent
Regraft8.7 per cent17.0 per cent19.0 per cent22.0 per cent22.3 per cent4.5 per cent

Several possible reasons for this have been suggested. Maori and Pasifika comprise over 20 per cent of the New Zealand population and reports suggest a higher incidence of keratoconus in these ethnic groups. It has also been suggested that New Zealand has a particularly progressive form of keratoconus different from that seen elsewhere, with a more rapid progression of the disease to a stage that requires transplantation.[12, 26]

Keratoconus also accounts for the bulk of indications for paediatric (age 14 years or less) corneal transplantation in New Zealand (67.2 per cent), a figure notably higher than those reported internationally (0–11 per cent).[31]

Fan and collegaues[32] examined the occurrence of intraocular pressure (IOP) elevation in patients following primary penetrating keratoplasty for keratoconus. The incidence of post-keratoplasty elevated IOP was substantial between one week and 12 months post-keratoplasty at 32 per cent, with 11 per cent of eyes developing mild, 12 per cent moderate and nine per cent severe IOP elevation. A steroid-related elevation of IOP was considered to be the most likely mechanism for this rise. None of the patients required surgical management of elevated IOP and none of the eyes required ongoing treatment with an ocular anti-hypertensive agent once the corticosteroids were withdrawn and the IOP normalised. Interestingly, in this study the IOP responders were significantly less likely to be of Maori or Pacific ethnicity.[32]

Conclusions

New Zealand researchers have made unique contributions to the international literature in the field of keratoconus. So far, the majority of these studies have focused on the epidemiology, clinical characteristics and pathophysiology of this disease. Current studies in New Zealand have moved toward investigating novel therapeutic interventions. A recently completed randomised controlled trial of corneal collagen cross-linking in Auckland, has shown this procedure to be a safe and effective intervention to halt or minimally reverse the progression of keratoconus in the majority of eyes. In vivo confocal microscopy of treated corneas confirmed a return to pre-operative values in terms of sub-basal innervation and keratocytic density within 12 months. New Zealand researchers are also making inroads into the development of a potential, novel therapeutic strategy for early keratoconus with the transplantation of spheroid cultured stromal cells. The application of stromal cell transplants, if effective in keratoconus, will assist in addressing the increasing demand for donor corneal tissue by potentially using the peripheral donor corneal tissue that is now discarded following transplantation. Because stromal cell transplantation would be used for treating early keratoconus, it has the potential to reduce the morbidity associated with severe keratoconus.

The relatively high prevalence of keratoconus, apparently more severe and progressive, and the frequency of corneal transplantation in New Zealand place researchers in this country in a unique position to investigate the causes and treatment of this disease.

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