Keratoconus and the Marfan paradox

KERATOCONUS AND THE MARFAN PARADOX:

“If keratoconus truly is a connective tissue dystrophy with biomolecular substratum, the keratoconus cornea would be, like the corneas in Marfan Syndrome, homogenously thin, flat and regular”

Marfan Syndrome (MFS) is a genetic disorder of connective tissue first described by Antoine Marfan, a French pediatrician in 1896. The changes seen in Marfan Syndrome result from the abnormal synthesis of collagen which alters the biomechanics of soft tissues in the human body (1).

The effects of Marfan Syndrome are widespread, affecting the skeletal, cardiovascular and ocular systems. A spectrum of ocular abnormalities is associated with this disease, including ectopia lentis (displaced lens), high myopia and retinal detachment (2), but it is the changes in the cornea that are intriguing, and have unfortunately not been accorded sufficient prominence in the literature.

As we will discover, much can be learned by studying and comparing in detail the corneas of patients with Marfan Syndrome with those with keratoconus.

Marfan Syndrome: The Facts

Marfan syndrome is a genetic disease caused by a mutation in the gene FBN1 that creates abnormalities in a protein called fibrillin-1, an essential component of connective tissue. This gene mutation in the fibrillin-1 molecule is responsible for the reduction in the strength of collagen present in the tissues of the body.

Connective tissue provides the framework that holds the body together and plays an important role in growth and development. It is found throughout the body, and patients with Marfan syndrome have problems with their connective tissue in a number of systems including the eye.

In about 75% of cases, the condition is inherited from a parent while 25% of the time it is a new mutation. Marfan Syndrome is an autosomal dominant disorder; autosomal dominance is one of several ways that a trait or disorder can be passed down (inherited) through families. Dominant inheritance means an abnormal gene from one parent can cause disease, even when the matching gene from the other parent is normal (because the abnormal gene dominates).

A person with Marfan syndrome is usually tall, thin, and has flexible joints. If a patient affected by the disease stretches out his arms from their sides, his arm span (from one end to the other) is greater than his height. They also typically have scoliosis (a curved or crooked spine). The most serious complications of Marfan Syndrome involve the heart and aorta with an increased risk of mitral valve prolapse and aortic aneurysm. The aorta is the main blood vessel that carries blood from the heart. An aneurysm corresponds to an enlarged or bulging aorta.

In summary, patients with Marfan syndrome suffer from multiple tissue disorders caused by an alteration of the collagen in connective tissue resulting in tissue softening.

The corneas of Marfan Syndrome patients are soft and weak (3,4), and this weakening is also seen in other ocular tissue such as the sclera, and the zonules, which are the suspensory ligaments that hold the crystalline lens. Scleral distension causes the eyeball to elongate and as a result myopia is common in patients with Marfan Syndrome. The loosening of the zonules often results in dislocation of the crystalline lens, a condition called “ectopia lentis”. Ectopia lentis is considered a key sign of Marfan syndrome and is often the first ocular sign of the disorder.

marfan flat keratometry defeatkeratoconus.com gatinelThese corneal topography maps were both obtained in eyes of Marfan Syndrome patients. In these softer eyes, loosening of the crystalline lens ligaments (zonules) has resulted in the partial displacement of the crystalline lens (bottom arrows: see the "notches” at the lens equator, which should not be visible normally). The corneal stroma is also softer and distended. Instead of being steeper as in keratoconic eyes, the corneal surface is flatter. Note the Sim Ks (simulated keratometry, which reports the values of the steepest and flattest corneal meridians respectively). Here, the mean keratometry is less than 41.5 D in both cases. This is typical of Marfan corneas, and in line with the progressive distension of the ocular tissues (cornea and sclera). From this observation we can conclude that corneas with altered corneal biomechanics do not become steeper centrally, but instead undergo progressive flattening.

Keratoconus: The Facts

Keratoconus, like Marfan Syndrome, is believed to result from abnormal collagen synthesis in association with genetic and cellular factors. However, unlike Marfan Syndrome, this belief is but a theory, as no specific genetic mutation or biomolecular changes have been identified.

The classic theory in question states that keratoconus is a dystrophy limited to the cornea, which incurs its softening, thinning and bulging. Most corneal specialists allude to some mysterious pathophysiological process starting at a cellular or molecular level, inducing a weakening of the corneal stromal tissue, and culminating in corneal thinning and protrusion. In this hypothesis, the first hit of keratoconus is ill-defined.

With a paucity of concrete evidence, should keratoconus still be considered a dystrophy of abnormal collagen synthesis?

We present to you The Marfan Paradox:
A perfect counter-example to highlight the irrelevance of the current theories of keratoconus pathogenesis

 

The MARFAN PARADOX

NB: This paradox is apparent only for those who consider that the primary cause of keratoconus is a tissue abnormality, which would be sufficient to induce corneal deformation characteristic of keratoconus without the need for repeated external trauma.

If the classic genetic and biomolecular theories of keratoconus genesis hold true, Marfan Syndrome would be the archetype of a “softening and bulging phenomenon involving the blood vessels and organs of the human body including the cornea.”

Moreover, the incidence of keratoconus (or a similar corneal deformation) should be very high in patients with Marfan Syndrome.

However, this is certainly not the case! On the contrary, instead of being steeper and irregular, the corneas of Marfan Syndrome patients are flatter and regular, with their diameters often enlarged (5,6). Marfan corneas are thinner (7), as they are in keratoconus patients, but this thinning is homogeneous and not focal.

In short, despite the global tissue softening, the thinner and weaker corneas of Marfan Syndrome patients exhibit characteristics opposite to the corneas in keratoconus patients.

Marfan corneas are soft but they are NOT KERATOCONIC

 

The Marfan Paradox exists because the medical community has wrongly assumed that a softer cornea must bend and bulge.

In Marfan corneas, the exact opposite happens: whilst it undertakes the effect of the intraocular pressure at its posterior surface, the softer cornea tends to gradually stretch and distend.

This causes its curvature to reduce progressively, and its apparent diameter to increase. As stated above, a similar process occurs at the level of the aorta, resulting in excessive bulging and distension. These mechanisms are consistent, as when the aorta enlarges, the radius of curvature of its wall also increases.

dilatation aorta marfan defeatkeratoconus.com paradox flat corneaThe dilation of the ascending aorta in Marfan Syndrome is characterized by fragmentation and loss of elastic and smooth muscle fibers in the vessel wall. When the aorta dilates, the radius of curvature of its wall increases, which means that its curvature decreases. This is consistent with the mechanisms involved at the ocular level. The progressive distension of the eyeball affects the sclera (myopic shift) and the cornea, which thins and flattens progressively. This comparison raises the question of defining keratoconus as “ectatic”. Truly ectatic corneas may be thin and flat. In keratoconus, the cornea is thin but steep, and this thinning and steepening are focal. The molecular mechanisms and the signalling pathways which would select part of the corneal shell to thin and deform specifically and “spontaneously” under the sole influence of the forces of intraocular pressure have not been defined. Rather, the influence of an external mechanical force like eye rubbing is better at accounting for the characteristics seen in keratoconic corneas.

The Marfan paradox and its surprising topographical features can be accepted a priori if one examines the effect of intraocular pressure on the posterior surface of the cornea in detail. Apparatus for measuring intraocular pressure typically include mechanisms to increasingly deform the cornea by applying a progressively increasing force onto it. This force (eg: a puff of air) is responsible for an inward deformation of the corneal surface, which, for the same intraocular pressure, would be easier to induce if the cornea is thinner or biomechanically weaker. Because the force from the intraocular pressure is evenly distributed against the posterior surface of the cornea and the inner surface of the sclera, a softer eyeball will undergo a progressive distension of its shell, which causes the local corneal radii of curvature to increase (and the corneal curvature to decrease), with concomitant progressive thinning.

Hence, in the absence of a localized or focal additional force or trauma as in Marfan Syndrome, the biomechanical weakening of Marfan corneas results in a flatter corneal surface. This distension of the eyeball also contributes to its increase in axial length, and most Marfan patients indeed suffer from axial myopia. Abnormally flat corneas and axial myopia both correspond to the ocular diagnostic criteria for Marfan syndrome.

With this in mind, the term “corneal ectasia” may better describe the condition observed in eyes with Marfan Syndrome than in keratoconus.  In the latter, the corneal wall is more warped than ectatic, at least in early and mild forms of the disease.

The Keratoconic Cornea and the necessary external mechanical factor:

In contrast to the Marfan cornea, the typical topographic pattern of a keratoconic cornea includes steepening and irregularity of the corneal surface and changes in the corneal thickness, including central or paracentral accelerated thinning.

Invoking an external source of trauma to the cornea (such as eye rubbing) as a pathogenetic cause provides a better explanation to these findings than the as yet unravelled processes of molecular change mysteriously affecting only parts of the cornea and preserving the other tissue components of the body.

The force exerted against the corneal shell by the pressure of the fingers, particularly the knuckles, may be considerable. Repetitive force can cause stretching and disorganization of the corneal collagen lamellae. An acute rise in intraocular pressure from sudden reduction in eye volume from the compression of the globe by the fingers could also stretch the scleral shell and lead to an axial myopic refractive shift. Despite contradicting reports, the axial length of keratoconus patients seems to be slightly but significantly higher than in non-keratoconus patients.

These striking differences between the topography of an authentic biomechanical decompensation from a molecular collagen abnormality (as in Marfan Syndrome) and what is observed in keratoconus suggest that the exertion of an external mechanical force may be necessary to account for the apparition and progression of the focally ectatic process.

In short, a “soft” cornea does not undergo the typical topographic changes that are observed in keratoconic eyes without an external mechanical factor.

 

What can be learned from the Marfan paradox:

The Marfan paradox is clear evidence that the current theories that assume the corneal changes in keratoconus to be caused primarily by some unknown biological mechanism are invalid. If these theories were true, the keratoconus cornea would flatten harmoniously and enlarge, not steepen irregularly. Mechanical trauma inflicted to the apical area of the cornea (as in eye rubbing)  better accounts for the focal weakening and irregular steepening seen in keratoconic eyes.

It is time to re-think the etiology of keratoconus

These observations should invite ophthalmologists to revise their assumptions on the mechanisms leading to the apparition of what is described as “keratoconus”.

What could cause such intense focal impairment at the level of the corneal apical region?

The cases presented in this website all reveal a history of eye rubbing antecedent to the first sign of keratoconic changes in the eye. The striking correlation between the intensity of eye rubbing and sleeping position with the severity and laterality of keratoconus all point to eye rubbing as the necessary first hit for keratoconus to occur.

Based on the current evidence, eye rubbing as the root cause best explains the changes seen in keratoconus.

Annex: Side by side comparison between the main features observed in Keratoconic vs Marfan eyes:

marfan vs keratoconus defeatkeratoconus.comSide by side comparison between the main features of Marfan syndrome and keratoconus.

References:

 

  1. Dietz H. Marfan Syndrome. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mefford HC, Stephens K, Amemiya A, Ledbetter N, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. 2001 Apr 18 [updated 2017 Oct 12].

  2. Konradsen TR, Zetterström C. A descriptive study of ocular characteristics in Marfan syndrome. Acta Ophthalmol. 2013;91(8):751-5.

  3. Kara N, Bozkurt E, Baz O, Altinkaynak H, Dundar H, Yuksel K, Yazici AT, Demirok A, Candan S. Corneal biomechanical properties and intraocular pressure measurement in Marfan patients. J Cataract Refract Surg. 2012;38(2):309-14

  4. Beene LC, Traboulsi EI, Seven I, Ford MR, Sinha Roy A, Butler RS, Dupps WJ Jr. Corneal Deformation Response and Ocular Geometry: A Noninvasive Diagnostic Strategy in Marfan Syndrome. Am J Ophthalmol. 2016;161:56-64

  5. Sultan G, Baudouin C, Auzerie O, De Saint Jean M, Goldschild M, Pisella PJ; Marfan Study Group. Cornea in Marfan disease: Orbscan and in vivo confocal microscopy analysis. Invest Ophthalmol Vis Sci. 2002;43(6):1757-64

  6. Luebke J, Boehringer D, Eberwein P, Reinhard T. Corneal K-Values as a Diagnostic Screening Tool for Marfan Syndrome. Cornea. 2017;36(6):700-703

  7. Sultan G, Baudouin C, Auzerie O, De Saint Jean M, Goldschild M, Pisella PJ; Marfan Study Group. Cornea in Marfan disease: Orbscan and in vivo confocal microscopy analysis. Invest Ophthalmol Vis Sci. 2002;43(6):1757-64

 

 

 

 

 

 

 

 

 

 


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