Dr. Paul S. Anderson
Keratoconus is a progressive thinning and anterior protrusion of the cornea that results in steepening and distortion of the cornea, altered refractive powers, and reduced vision. Keratoconus has a complex multifactorial etiology, with environmental, behavioral, and multiple genetic components contributing to the disease pathophysiology.  In more advanced cases, corneal scarring from corneal edema and decompensation further reduces visual acuity. Symptoms are highly variable and depend on the stage of progression of the disorder.1,2 There is a large variance in the reported prevalence of keratoconus ranging from 8.8 to 54.4 per 100,000.3–5 This variation is in part due to the different diagnostic criteria used in various studies.3–5 keratoconus is known to affect all ethnicities. For example, incidence of KTCN in Asians is 25 per 100,000 (1 in 4000) per year, compared with 3.3 per 100,000 (1 in 30,000) per year in Caucasians. 
Keratoconus is associated with other disorders (more than two dozen syndromes are associated) including Down syndrome, Leber congenital amaurosis, connective tissue disorders, including osteogenesis imperfecta, GAPO syndrome, and some subtypes of Ehlers–Danlos syndrome . Aside from these correlations keratoconus is likely a multifactorial – polygenic and heavily epigenetically influenced condition [1,2]. To date, no mutations in any genes have been identified for any of the discussed keratoconus loci. Other reports indicate mutations in SOD1 (MIM 147450, locus 21q22.11) andVSX1 (KTCN1, MIM605020, locus 20p11.2) genes as enrolled in the etiology of keratoconus, however, none of the subsequent studies have confirmed role of these changes. Other candidate genes for keratoconus, such as COL6A1, COL8A1, MMP9, and MMP2, have been examined and excluded as causative genes. These results support the theory of multiple gene involvement rather than a single major gene in the development and progression of keratoconus .
Mitochondrial injury and sensitivity may be involved in the genetic, epigenetic and ReDox basis of keratoconus. Abu-Amero et.al. summarize the data thus: “Under electron microscopy, swelling of the mitochondria was observed in keratoconus corneal tissues. Keratoconus corneas exhibited more mitochondrial DNA (mtDNA) damage than normal corneas. Keratoconus fibroblasts had increased basal generation of reactive oxygen species and were more susceptible to stressful challenges (low-pH and/or H2O2 conditions) than were normal fibroblasts. Additionally, cultured keratoconus fibroblasts have an inherent, hypersensitive response to oxidative stress that involves mitochondrial dysfunction and mtDNA damage” .
ReDox (in this paper referring to the balance between the various fat and water soluble compartment reductive-oxidative balance factors) – Oxidative stressors are also implicated and make complete logical sense as contributors to keratoconus pathogenesis [3,18]. Earlier biochemical data reported low G6PD levels in the cornea  which would lead to an oxidative ReDox balance. G6PD deficiency is known to cause cellular erythrocyte sensitivity to pro-oxidative states due to a lack of glutathione recycling enzyme substrate. It is also a precursor to generalized slow glutathione recycling throughout the body. More recent reviews  have reported additional biochemical pre-sets which would also lead to poor ReDox balance coupled with poor structural integrity:
- Decreased levels of G6PD.
- Relative decrease in hydroxylation of lysine and glycosylation of hydroxylysine.
- Decrease in total collagen and a relative increase in structural glycoprotein.
- In patients with keratoconus, keratin sulphate is decreased and its structure is modified.
- The ratio of dermatin sulphate to keratin sulphate is increased in keratoconus.
Therapies in the past have involved the use of rigid style contact lenses (Originally PMMA and now RGP styles or “piggyback” procedures using a soft lens topped by a rigid style lens.) This use of contact lenses had two goals, one being a splint effect on the cornea and the other being creating a contiguous fluid meniscus under the lens which is the only way to create maximum refractive correction and visual acuity. [16,17] Other therapies involved corneal transplant procedures (keratoplasty) which now are performed in either full or part thickness manners based on severity of condition.
Corneal collagen crosslinking procedures: [4-14] Collagen crosslinking, an investigational treatment in the United States, was first performed in Europe in the late 1990s for the treatment of ectatic corneal conditions. The treatment combines riboflavin and ultraviolet A (UVA) light, allowing the formation of reactive oxygen species, with the goal of halting the progression of corneal disease. For riboflavin to act as a catalyst in this process, it must first be absorbed into the corneal stroma. Because the corneal epithelium acts as a barrier to riboflavin absorption, it can be removed before treatment with UV light. Two procedures: The Dresden technique, or “epi-off” crosslinking, is initial removal of the central 9 mm of epithelium, followed by 30 minutes of riboflavin administration. Subsequently, UVA light is applied for 30 minutes, followed by bandage contact lens placement. Dr. Brian Boxer Wachler was the first to perform transepithelial crosslinking, or “epi-on” crosslinking, in 2004. Because the epithelium is not removed, riboflavin loading requires more time than with epi-off techniques. Epi-on crosslinking has several distinct advantages: faster visual recovery; reduced pain; and reduced risks for delayed epithelial healing, infection, and visually significant corneal haze .
Intacs (trademark) are curved, tiny segments that are placed in between the layers of the cornea during a 10 minute, painless procedure. Patients typically describe the procedure as “easier than getting my teeth cleaned at the dentist.” You won’t feel the Intacs after it’s tucked under the cornea, just as you do not feel a dental filling for a cavity. The segment’s specific design makes them an integral and common treatment for keratoconus and keratoectasia. The goal of Intacs® is to improve vision by reducing the distorted corneal shape caused by the bulging cornea . Intacs can be used with collagen crosslinking procedures.
Summary – Integrative Medical Options:
Based on current data and understanding regarding keratoconus it is reasonable that a broad approach based on the specific status of the patient should be followed. Genetic influences are likely contributory, but aside from ReDox, Mitochondrial and G6PD status it is unknown how broad this area really is. The best likely place to hold the genetic basis is that it is impactful on the disease but likely highly affected by epigenetic stressors.
As improvement in nutritional and epigenetic factors are possible and have no potential negative impact on standard therapies, forming a treatment plan that involves standard diagnosis and treatment (based on current medical standards) coupled with integrative therapies is likely to produce the most positive benefits. The therapeutic considerations below attempt to include the interventions most likely to support these goals.
ReDox balance and support:
- The overall ReDox state is governed by the interplay between fat soluble (cell and mitochondrial membranes, lipid molecules such as cholesterol etc.) and water soluble (plasma, cytosol etc.) compartments. While there are myriad potential supports the base of ReDox balance is tocopherols, balanced omega fats and triglyceride molecules (phosphatidyl choline, serine etc.) for lipid membranes and glutathione and ascorbate activity for the water soluble compartments.
- Ascorbate and tocopherols are straight forward in their administration, and support the recycling of other ReDox agents.
- Glutathione can be administered parenterally or as an oral liposome as well as supported by lipoic acid, l-glutamine and N-acetyl-cysteine as precursors. Additionally the cycling and support of glutathione requires specific nutrients, without which glutathione activity decreases. These include magnesium, selenium, zinc, and vitamins B-2, B-3 and B-5 [25-31].
- As SOD and other Phase-2 pathways have been linked to poor corneal integrity [2,3] and as all the pathways mentioned require them assurance of balanced trace mineral supplementation is required.
- There is support in the data for the use of balanced antioxidant supplementation to improve low G6PD function (in people with genetic G6PD issues). Four papers show positive effects [20-23] while one negative paper which used an imbalanced therapy is in the literature .
- Essentially the tenants of therapy outlined in ReDox balance and support above are the same outlined in these studies.
Sulfation balance and support:
- Assurance of molybdenum repletion and in the case of molybdenum sufficiency on testing short term oral supplementation of 200-500 mcg molybdenum to provide support for sulfite oxidase activity.
- Sulfite oxidase activity reduces sulfite forms and provides sulfate substrate for sulfation operation.
- In addition to the above ReDox therapies assurance of ascorbate, proline, lysine, manganese and other cofactor availability is important.
- Hyaluronic acid (HA) and its enzyme hyaluronidase were discovered in 1934 and 1940 respectively. They were known to have activity and effect in the eye, and soon became the subject of much investigation starting with a publication by Godtfredsen in the British Journal of Ophthalmology . Even in 1949 it was known that HA was implicit in the integrity of the eye and over the years has been shown to be useful as a topical medication for corneal repair  as well as an injected medication for retinal disorders.
Parenteral riboflavin therapy:
- While biologically plausible the idea of parenteral riboflavin administration is at this time speculative.
- The use of riboflavin as delivered in the modern “collagen crosslinking” therapies described above [4-14] is said to be required topically as the oral administration would never suffice and deliver the agent to the stroma. That said, the use of riboflavin as a parenteral while treating the above ReDox and other factors makes the inclusion of parenteral riboflavin reasonable on those grounds.
- In addition to the above it should be noted that the reason that riboflavin was considered only available after surgical or other epithelial disruption is that the corneal epithelium is mostly impervious to topical riboflavin administration in its normal state. The normal nutrient delivery to the stroma however is actually via aqueous humor filtration and diffusion through the endothelium of the cornea . This would indicate that both oral and parenteral administration of riboflavin would have both access and potential increased delivery to the stroma (the parenteral routs obviously providing a higher concentration).
- Nowak DM and Gajecka M. The Genetics of Keratoconus. Middle East Afr J Ophthalmol. 2011 Jan-Mar; 18(1): 2–6. doi: 10.4103/0974-9233.75876. PMCID: PMC3085147
- Abu-Amero KK, Al-Muammar AM and Kondkar AA. Genetics of Keratoconus: Where Do We Stand? Journal of Ophthalmology. Volume 2014, Article ID 641708, 11 pages. http://dx.doi.org/10.1155/2014/641708
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- Wittig-Silva C, Whiting M, Lamoureux E, Lindsay RG, Sullivan LJ, Snibson GR. A randomized controlled trial of corneal collagen cross-linking in progressive keratoconus: preliminary results. J Refract Surg. 2008;24:S720-S725. Abstract
- Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol. 2003;135:620-627. Abstract
- Rama P, Di Matteo F, Matuska S, Paganoni G, Spinelli A. Acanthamoeba keratitis with perforation after corneal crosslinking and bandage contact lens use. J Cataract Refract Surg. 2009;35:788-791. Abstract
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- Al-Aqaba M, Calleinno R, Fares U, et al. The effect of standard and transepithelial ultraviolet collagen cross-linking on human corneal nerves: an ex vivo study. Am J Ophthalmol. 2012;153:258.e2-266.e2.
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- Hatch KM and Trattler WB. Corneal Crosslinking: Epi-on or Epi-off? http://www.medscape.com/ viewarticle/763924
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