When Imaging Isn’t Enough
Molecular biomarker analysis could improve the diagnosis and management of keratoconus, and might only require tear fluid
Swaminathan Sethu, Natasha Pahuja, Rohit Shetty |
From least to greatest severity, keratoconus can be managed with interventions ranging from spectacles, contact lenses, intracorneal ring segments, corneal collagen crosslinking (CXL) or corneal transplants – usually with reasonable success. But a significant proportion of patients continue to deteriorate or progress to severe disease, despite getting the best possible treatment. Why? In many cases, the problem begins with diagnosis. This shows us two clear unmet needs: early detection of keratoconus, and a better understanding of why some patients don’t respond to treatment.
Current diagnostic and management strategies depend primarily on advanced clinical imaging modalities like corneal topography. But imaging isn’t enough – all an image can do is show you the pathological changes to the cornea that keratoconus has already caused. It tells you nothing of the factors that may drive ectasia, and doesn’t answer the question of what predisposes some patients to an unfavorable prognosis. Unless visible structural changes are present, corneal imaging can tell clinicians nothing about the presence of subclinical forms of keratoconus. So although clinical imaging is an indispensable tool for diagnosis, it provides very limited insight into disease pathogenesis.
What are the alternatives? Molecular profiling and characterization have proven to be beneficial in unraveling the pathogenic mechanisms of many diseases, and has certainly changed the way we understand keratoconus. For over a century, it was assumed that keratoconus was a non-inflammatory disease, but recent molecular evidence from laboratories around the world, including ours, have shown otherwise (1–3). There is growing evidence that links dysregulated inflammatory events, altered corneal structural components, and aberrant stromal and epithelial remodeling in the keratoconic cornea. We and others have shown that increased inflammatory cytokine expression, higher matrix metalloproteinases and lower lysyl oxidase activity exist during the pathogenesis of keratoconus, and that as the dysregulation of these factors increase, so does the observed severity of disease.
We recently demonstrated that treating the inflammation present in the cornea of patients with keratoconus can stabilize the disease (1). With our current knowledge, it would be prudent to integrate clinical imaging and molecular biomarkers in the diagnosis and management of keratoconus. The ability to gain a relevant sample, which is relatively easily collected and profiled, is a critical consideration in biomarker screening. Tear fluid-based biomarkers could be the solution – they have proven useful in monitoring various diseases, including neurodegenerative conditions, metabolic disorders, and cancer. As keratoconus is a localized disease that involves only the anterior segment of the eye, it’s hoped that tear fluid-based molecular profiling would offer a much-needed and noninvasive method of studying disease pathogenesis. We believe that the ideal situation would be disease-specific biomarker testing in tear fluid, using a rapid, point-of-care diagnostic kit, both for screening, and even as a tool in a primary care setting.
Knowing the molecular status of the disease would also be beneficial in planning treatment; the inflammation could be managed prior to performing surgical procedures, ensuring the best possible outcomes. In early disease, the topical management of inflammatory factors might even be sufficient. Topical eye drops could be developed for specific molecular targets, which might be effective at improving the condition without exposing the patient to significant side-effects. Another important aspect of developing a more effective strategy for the management of keratoconus is to improve our knowledge of the underlying disease pathogenesis, its triggers and risk factors, like allergies, eye rubbing and nutritional deficiencies.
By combining our knowledge from clinical imaging and emerging insights using molecular diagnostics, we are entering a new age of diagnostic and management paradigms for keratoconus – and as we improve our approach, we can provide more effective care to patients, and reduce the morbidity and the associated economic burden of the disease.
- R Shetty et al., Invest Ophthalmol Vis Sci, 56, 738–750 (2015). PMID: 25648341.
- I Lema et al., Br J Ophthalmol, 93, 820–824 (2009). PMID: 19304583.
- SA Balasubramanian et al., Acta Ophthalmol, 90, e303–309, (20120). PMID: 22413749.