Lindstrom's Perspective

Wide range of keratoconus treatments available, on the horizon

In this commentary, I will share a few thoughts and opinions from a clinician who has shared in the care of thousands of keratoconus patients over 45 years.

Most textbooks put the incidence of keratoconus at one per 2,000. That would translate to 180,000 patients in the United States and about 1,800 in the 50-mile circle around my city, Minneapolis/St. Paul. I believe there are many more keratoconus patients than one per 2,000. As a busy corneal refractive surgeon, up to 10% of the patients who present for laser refractive surgery demonstrate findings that discourage me from proceeding. These patients often exhibit an asymmetrical bow-tie topography along with a thin cornea. Sometimes there is a little skew deviation and the cornea may be somewhat steep. Their inferior/superior keratometry reading difference is often greater than 1.6 D. I will label many as forme fruste keratoconus or keratoconus suspect in my medical record. Today we have no great way to measure corneal stiffness/elasticity, but in the future Brillouin spectroscopy may allow us to determine which of these patients are truly at increased risk for ectasia, especially if we were to perform laser refractive surgery.

If only half of the patients who make me too nervous to proceed with LASIK have a risk for developing keratoconus, that would represent an incidence of 5%, or 18 million, rather than 180,000. Likely the true incidence is somewhere in between. We need better diagnostics to identify the at-risk patient. Someday it may make sense to treat them before they develop any ectasia.

There is an interplay between genetics and environment in many disease processes. Keratoconus is usually considered a corneal dystrophy, but it is much less symmetrical than other corneal dystrophies such as lattice, macular and granular corneal dystrophy. There are at least six genes that have been shown to be associated with keratoconus, and identical twins often both develop the disease even when raised in different homes. There are also definite examples of families with multiple generations developing keratoconus. The famous identical twin studies performed at the University of Minnesota were quite convincing to me that genetics trumps environment in most cases, with identical twins separated at birth developing the same personality traits and diseases, pursuing the same occupations and even wearing the same clothes 40 years later even though reared in totally different environments. Still, there is good evidence accumulating that for the keratoconus cornea, environment may trump genetics.

In particular, eye rubbing and contact lens wear, which arguably is a form of eye rubbing, seem to play a role in the development of many, if not most, keratoconus cases. The pathophysiology of the disease, which shows progressive dissolution of Bowman’s layer with secondary thinning and ectasia, is consistent with chronic surface trauma as an etiological factor. Inflammation with release of cytokines and proteases secondary to surface trauma from chronic eye rubbing seems a logical etiology. In addition, the asymmetry of disease present in nearly all patients with more severe ectasia on the side more rubbed or on the side upon which the patient buries their eye into the pillow during sleep suggests a traumatic etiology.

My current thought is that the etiology is not eye rubbing alone, but eye rubbing in the genetically predisposed patient. I think post-LASIK ectasia is in the same bucket, corneal refractive surgery in the genetically predisposed eye. Counseling to avoid eye rubbing, treatment of any associated allergy or ocular itching/irritation that encourages eye rubbing, and in select cases an eye shield at night can be helpful. Unfortunately, I have found that getting eye rubbers to stop rubbing their eyes is as difficult as treating a serious chemical dependency. The keratoconus patient also often develops one or more personality disorders, making treatment more difficult, and some may need psychiatric intervention. The negative impact of this disease on quality of life is not to be underestimated.

In regard to other therapy, during the first 30 years of my career it was glasses, then contact lens wear, and when patients reached the stage where they either could not see well with any contact lens or wear it enough hours in the day to be functional, we recommended keratoplasty. Today I have several combined procedures that do not include keratoplasty. For the patient with mild keratoconus, corneal cross-linking alone is usually sufficient. I treat young patients immediately upon making the diagnosis and do not wait to confirm progression. In patients older than 40 years, I will often follow them with repeat topography for maximum keratometry, measure keratometry readings and do repeat manifest refractions. If any of these tests suggests progression in either eye, I will usually recommend CXL in both eyes.

In mild early keratoconus with good best corrected vision, I always start with CXL alone. I have tried PTK/PRK combined immediately with CXL, and in my hands the incidence of corneal haze is too high for my comfort, even with the use of mitomycin C. Many world experts disagree and routinely perform combined PRK/PTK with CXL, but I do not.

My CXL today is epithelium-on, and we have adopted a technique that allows good loading of a custom compounded riboflavin formulation through the intact epithelium. This approach is much easier on the patient than epithelium-off CXL, and after nearly 10 years of epithelium-on CXL, my need to perform repeat treatments is under 1%. The corneal flattening is somewhat less with epithelium-on CXL than I have observed with epithelium-off CXL, but I am primarily doing CXL to prevent disease progression.

I wait 12 months and in select patients will do my version of a keratoconus combined procedure by performing a PRK with MMC. For me, this staged approach results in less haze and reduces the likelihood of an overcorrection. I also do Intacs (SightLife Surgical) in patients with more severe keratoconus. My indication is a patient who I cannot correct to 20/40 or better with spectacles. I have done both single and dual Intacs placements, and the literature suggests the outcomes are similar with both approaches. I currently favor placing two Intacs. My keratoconus triple procedure would be to perform Intacs followed by CXL 2 to 4 weeks later followed by PRK/PTK at 1 year or more after Intacs/CXL if needed.

Now, stepping even more into the investigational arena, I also have a keratoconus quadruple procedure. In this approach I combine Intacs and conductive keratoplasty off label in an attempt to reduce astigmatism and flatten the cornea. There are about 30 U.S. surgeons using CK alone or in combination with Intacs for the keratoconus patient. I am one of them. Application of the CK spots is an art, and I do not charge for it. Decades ago, Antonio Gasset, MD, proposed controlled thermal keratoplasty for treating more severe keratoconus, and this current application of CK is a more modern form of thermal keratoplasty. I then follow with CXL 2 to 4 weeks later and in select cases perform a PRK/PTK with MMC 1 year or more later.

I am still performing keratoplasty for select patients with severe keratoconus, usually in the presence of significant thinning, surface scarring and contact lens intolerance. I look forward to the day when keratoplasty for keratoconus is reduced to an extremely rare procedure or perhaps even becomes extinct.

On the horizon in the United States and available in Europe is custom topography-driven CXL. I think this approach will be a meaningful advance over what we are doing today. In addition, there are several drops that show promise to stiffen the at-risk cornea without requiring our still somewhat invasive approach to CXL. That would be a great advance and might allow us to titrate the treatment regimen based on severity.

It is gratifying that we have much improved treatments for the victims of this debilitating disease. One of our current challenges in the U.S. is lack of patient access and poor insurance coverage with lack of affordability for the procedures currently available. I sincerely hope this barrier to treatment does not persist.

Disclosure: Lindstrom reports relevant financial disclosures for Avedro, Bausch + Lomb, Refractec, SightLife Surgical and J&J Vision.

In this commentary, I will share a few thoughts and opinions from a clinician who has shared in the care of thousands of keratoconus patients over 45 years.

Most textbooks put the incidence of keratoconus at one per 2,000. That would translate to 180,000 patients in the United States and about 1,800 in the 50-mile circle around my city, Minneapolis/St. Paul. I believe there are many more keratoconus patients than one per 2,000. As a busy corneal refractive surgeon, up to 10% of the patients who present for laser refractive surgery demonstrate findings that discourage me from proceeding. These patients often exhibit an asymmetrical bow-tie topography along with a thin cornea. Sometimes there is a little skew deviation and the cornea may be somewhat steep. Their inferior/superior keratometry reading difference is often greater than 1.6 D. I will label many as forme fruste keratoconus or keratoconus suspect in my medical record. Today we have no great way to measure corneal stiffness/elasticity, but in the future Brillouin spectroscopy may allow us to determine which of these patients are truly at increased risk for ectasia, especially if we were to perform laser refractive surgery.

If only half of the patients who make me too nervous to proceed with LASIK have a risk for developing keratoconus, that would represent an incidence of 5%, or 18 million, rather than 180,000. Likely the true incidence is somewhere in between. We need better diagnostics to identify the at-risk patient. Someday it may make sense to treat them before they develop any ectasia.

There is an interplay between genetics and environment in many disease processes. Keratoconus is usually considered a corneal dystrophy, but it is much less symmetrical than other corneal dystrophies such as lattice, macular and granular corneal dystrophy. There are at least six genes that have been shown to be associated with keratoconus, and identical twins often both develop the disease even when raised in different homes. There are also definite examples of families with multiple generations developing keratoconus. The famous identical twin studies performed at the University of Minnesota were quite convincing to me that genetics trumps environment in most cases, with identical twins separated at birth developing the same personality traits and diseases, pursuing the same occupations and even wearing the same clothes 40 years later even though reared in totally different environments. Still, there is good evidence accumulating that for the keratoconus cornea, environment may trump genetics.

PAGE BREAK

In particular, eye rubbing and contact lens wear, which arguably is a form of eye rubbing, seem to play a role in the development of many, if not most, keratoconus cases. The pathophysiology of the disease, which shows progressive dissolution of Bowman’s layer with secondary thinning and ectasia, is consistent with chronic surface trauma as an etiological factor. Inflammation with release of cytokines and proteases secondary to surface trauma from chronic eye rubbing seems a logical etiology. In addition, the asymmetry of disease present in nearly all patients with more severe ectasia on the side more rubbed or on the side upon which the patient buries their eye into the pillow during sleep suggests a traumatic etiology.

My current thought is that the etiology is not eye rubbing alone, but eye rubbing in the genetically predisposed patient. I think post-LASIK ectasia is in the same bucket, corneal refractive surgery in the genetically predisposed eye. Counseling to avoid eye rubbing, treatment of any associated allergy or ocular itching/irritation that encourages eye rubbing, and in select cases an eye shield at night can be helpful. Unfortunately, I have found that getting eye rubbers to stop rubbing their eyes is as difficult as treating a serious chemical dependency. The keratoconus patient also often develops one or more personality disorders, making treatment more difficult, and some may need psychiatric intervention. The negative impact of this disease on quality of life is not to be underestimated.

In regard to other therapy, during the first 30 years of my career it was glasses, then contact lens wear, and when patients reached the stage where they either could not see well with any contact lens or wear it enough hours in the day to be functional, we recommended keratoplasty. Today I have several combined procedures that do not include keratoplasty. For the patient with mild keratoconus, corneal cross-linking alone is usually sufficient. I treat young patients immediately upon making the diagnosis and do not wait to confirm progression. In patients older than 40 years, I will often follow them with repeat topography for maximum keratometry, measure keratometry readings and do repeat manifest refractions. If any of these tests suggests progression in either eye, I will usually recommend CXL in both eyes.

In mild early keratoconus with good best corrected vision, I always start with CXL alone. I have tried PTK/PRK combined immediately with CXL, and in my hands the incidence of corneal haze is too high for my comfort, even with the use of mitomycin C. Many world experts disagree and routinely perform combined PRK/PTK with CXL, but I do not.

PAGE BREAK

My CXL today is epithelium-on, and we have adopted a technique that allows good loading of a custom compounded riboflavin formulation through the intact epithelium. This approach is much easier on the patient than epithelium-off CXL, and after nearly 10 years of epithelium-on CXL, my need to perform repeat treatments is under 1%. The corneal flattening is somewhat less with epithelium-on CXL than I have observed with epithelium-off CXL, but I am primarily doing CXL to prevent disease progression.

I wait 12 months and in select patients will do my version of a keratoconus combined procedure by performing a PRK with MMC. For me, this staged approach results in less haze and reduces the likelihood of an overcorrection. I also do Intacs (SightLife Surgical) in patients with more severe keratoconus. My indication is a patient who I cannot correct to 20/40 or better with spectacles. I have done both single and dual Intacs placements, and the literature suggests the outcomes are similar with both approaches. I currently favor placing two Intacs. My keratoconus triple procedure would be to perform Intacs followed by CXL 2 to 4 weeks later followed by PRK/PTK at 1 year or more after Intacs/CXL if needed.

Now, stepping even more into the investigational arena, I also have a keratoconus quadruple procedure. In this approach I combine Intacs and conductive keratoplasty off label in an attempt to reduce astigmatism and flatten the cornea. There are about 30 U.S. surgeons using CK alone or in combination with Intacs for the keratoconus patient. I am one of them. Application of the CK spots is an art, and I do not charge for it. Decades ago, Antonio Gasset, MD, proposed controlled thermal keratoplasty for treating more severe keratoconus, and this current application of CK is a more modern form of thermal keratoplasty. I then follow with CXL 2 to 4 weeks later and in select cases perform a PRK/PTK with MMC 1 year or more later.

I am still performing keratoplasty for select patients with severe keratoconus, usually in the presence of significant thinning, surface scarring and contact lens intolerance. I look forward to the day when keratoplasty for keratoconus is reduced to an extremely rare procedure or perhaps even becomes extinct.

On the horizon in the United States and available in Europe is custom topography-driven CXL. I think this approach will be a meaningful advance over what we are doing today. In addition, there are several drops that show promise to stiffen the at-risk cornea without requiring our still somewhat invasive approach to CXL. That would be a great advance and might allow us to titrate the treatment regimen based on severity.

PAGE BREAK

It is gratifying that we have much improved treatments for the victims of this debilitating disease. One of our current challenges in the U.S. is lack of patient access and poor insurance coverage with lack of affordability for the procedures currently available. I sincerely hope this barrier to treatment does not persist.

Disclosure: Lindstrom reports relevant financial disclosures for Avedro, Bausch + Lomb, Refractec, SightLife Surgical and J&J Vision.