Keratoconus - developing a new theory for keratoconus research in the future

The prevailing orthodoxy that keratoconus is primarily a structural corneal disease may need to be re-evaluated in the light of ongoing research into the pathogenesis of the condition, according to Michael Assouline MD, PhD. The Laplace-Gauss law, which describes the physics of thin wall spheres, implies that the ratio of thickness to radius of curvature of the cornea is constant for a stable intracorneal pressure and wall tension. This suggests that the development of keratoconus (a focal deformation with reduced thickness and radius of curvature) may not require a mechanically defective corneal tissue. “My own theory after more than 25 years studying keratoconus is that the disease may actually be primarily neurosensory rather than corneal. There is evidence of retinal or optic dysfunction in keratoconus, with dysregulation of the emmetropisation process of the eye similar to that which occurs in axial myopia,” Dr Assouline told delegates attending the French Implant and Refractive Surgery Association (SAFIR) annual meeting in Paris. EVIDENCE-BASED MEDICINE Dr Assouline, in private practice at the Centre Iéna Vision and Clinique de la Vision, Paris, said that there is a definite lack of evidence-based medicine for keratoconus, with many unanswered questions relating to the disease’s etiology and best therapeutic strategy. Of nearly 4,613 papers published on keratoconus in the scientific literature, only 11 were prospective, randomised studies that could be deemed to offer conclusive evidence, he said. “The problem is that we often don’t know whether we are treating the cause or the consequence of the disease,” he said. “Furthermore, there is no consensus on the main outcome variable for treatments,” he added. Information is also lacking on the pathogenesis of the condition, said Dr Assouline, with a complex combination of genetic, environmental and cellular factors all potentially playing a role in the development of the disease. Of a list of 17 or more potential candidate genes for keratoconus, the variants of one gene in particular – VSX1 (visual system homeobox 1) – crops up with more frequency than any other, said Dr Assouline. “Interestingly, VSX1 does not code for corneal products, but plays a key role in the differentiation of bipolar dopamine cells in the retina which are implicated in the integration of visual signalling,” he said. NEW AVENUES Dr Assouline’s hypothesis is that a variation in VSX1 or some other genes triggers a dysfunction of bipolar cells and a disrupted emmetropisation process that may ultimately lead to keratoconus. “The mutation affects the way that the visual message is coded by the retina, regulating either the axial growth of the eye through an amplification loop in cases of high myopia, or through a weakening of the cornea amplified by eye rubbing in keratoconus,” he said. Dr Assouline noted that because spherical aberration and coma associated with keratoconus cannot be corrected with glasses, most subjects experience ocular strain and accommodative blepharitis, which favours chronic eye rubbing and micro trauma to the cornea. Summing up, Dr Assouline said he hoped his hypothesis would open new avenues in keratoconus research in the future. “I think we may need to consider keratoconus not as a primary disease of the corneal tissue but more as a regulation problem with the emmetropisation process of the eye,” he said. Population studies show that the prevalence of keratoconus is variable in different parts of the world, with a lower incidence in Europe and northern regions compared to the Middle East, which Dr Assouline identified as the global “epicentre” of the disease. PROTO-WRITING Relating this to the high myopia “epicentre” in Southeast Asia, Dr Assouline pointed out that both regions, Mesopotamia and Southeast Asia, witnessed the birth of proto-writing, often as micrographic systems (such as in Chaldean tablets or Chinese “Oracle” bones) some 4,000 years ago. Dr Assouline suggested that these variations in the emmetropisation process of the eye, producing human phenotypes with an aptitude for very near work, but detrimental to distance vision, may have facilitated the emergence of writing culture and subsequent highly organised societies. Michael Assouline: dr.assouline@gmail.com

Tags: corneal disease, etiology, pathogenesis