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Updated on March 14, 2007

Dr Colin Clement brings you the latest developments in keratoconus research

March 2007

Refractive surgery and Keratoconus

LASIK (LASer In situ Keratomileusis) is a popular, readily available laser refractive procedure for the correction of moderate stable refractive errors. Keratoconus has traditionally been viewed as a contraindication to LASIK, however recent work has focused on the use of LASIK in corneal grafts. This study, from New York (USA), examined the safety of performing LASIK refractive surgery in each eye of individuals whom previously had corneal transplants for keratoconus. The average period between transplant surgery and LASIK correction was 46 months. The 5 patients ranged in age from 23 to 37 years. All eyes were short sighted prior to LASIK correction with the largest amount of astigmatism being 4.50 dioptres. Uncorrected visual acuity pre-LASIK averaged 6/66, ranging from 6/18 to 6/120. In 1 patient, there was a complication during LASIK resulting in cancellation of the procedure. The other 9 LASIK procedures were uneventful. Mean follow-up after the LASIK was 9 months. Uncorrected visual acuity ranged from 6/6 to 6/9 with an average 6/7.5. In no eye was there a deterioration in visual acuity after LASIK.

This study has shown that LASIK, in young patients with previous corneal transplantation and stable moderate refractive error, is safe and can lead to improved uncorrected visual acuity. The LASIK complication rate in this series was 10%.

Eric Mann, MD, Gerald W. Zaidman, MD, and Salil Shukla, MD. Efficacy of Nonsimultaneous Bilateral LASIK After Nonsimultaneous Bilateral Penetrating Keratoplasty

Cornea  Volume 25, Number 9, October 2006

 


Crosslinking treatment of progressive keratoconus: new hope  

G Wollensak  

Current Opinion in Ophthalmology
2006: 17; 356 -360  

 

Anyone with a curiosity in the new cross-linking treatment for Keratoconus currently under trial in Melbourne would do well to read this excellent article recently published in Current Opinion in Ophthalmology. Gregor Wollensak has put together a brief and concise summary of the topic including the rationale behind the treatment, results of animal studies and, of most interest, the outcome of human trials. There are three studies now published on the outcome of crosslinking treatment for keratoconus in humans. I have already summarised the original study in 2003 by Wollensak et al. and this is included at this web site. In addition, There is now 5-year data available from the same study1 showing that 100% of the 61 eyes included did not progress after treatment and 31 of these (52%) actually regressed by an average 2.87 dioptres. In the other study from New York2, 27 eyes were treated and all stabilized with 12 (44%) demonstrating regression by an average 2 dioptres. Using a contact ultrasound device, they were also able to demonstrate increased corneal rigidity after treatment overall. Gregor Wollensak makes the point that the results of trials are in patients with progressive disease at the severe end of the spectrum. Whilst the results are encouraging, we have no way of knowing whether similar results may be achieved in those with less severe or stable disease. Future studies will no doubt explore these possibilities.

 

  1. D Sandner, E Sporl, M Kohlhaas et al. Collagen crosslinking by combined riboflavin/ultraviolet-A (UVA) treatment can stop the progression of keratoconus. Investigative Ophthalmology and Visual Science 2004: 45; E-abstract 2887

 

  1. E Braun, J Kanellopoulos, L Pe, M Jankov. Riboflavin/ultraviolet A-induced collagen cross-linking in the management of keratoconus. Investigative Ophthalmology and Visual Science 2005: 46; 4964

 

July 2006

Efficacy of contact lens storage solutions against different Acanthomoeba strains

 

K Hiti, J Walochnik, EM Haller-Schober, C Faschinger and H Aspock

Cornea 2006 Vol 25: 423 -

 

Acanthomoeba is a microbe found in water that is associated with serious corneal infection. Over 90% of acanthomoeba corneal infection is in contact lens wearers and may lead to corneal perforation and even permanent blindness. It is notoriously difficult to treat with multiple agents required for a minimum 12 months and often many years. Prevention of acanthomoeba infection is an important issue for all contact lens wearers.

 

This study was undertaken to assess whether a number of contact lens storage solutions can prevent acanthomoeba survival. Ten solutions in total were tested. Contact lens solutions were added to a known concentration of acanthomoeba suspension for either 1 or 8 hrs before the suspension was cultured for the presence of microbes. Results are shown in the table below:

 

Table 1. Viability of Acanthomoeba Cysts after 1-hour exposure time

 

Contact Lens Storage Solutions

Acanthamoeba Viable

Boston Advance

No

Meni Care Plus

No

ReNu Multi Plus

Yes

Bausch&Lomb st A

Yes

Concerto soft

Yes

ACTI-MED

Yes

SOLO-care Plus

Yes

Optifree Express

Yes

Contra Clair

Yes

Regard

Yes

 

Table 2. Viability of Acanthomoeba Cysts after 8-hour exposure time

 

Contact Lens Storage Solutions

Acanthamoeba Viable

Boston Advance

No

Meni Care Plus

No

ReNu Multi Plus

No

Bausch&Lomb st A

No

Concerto soft

Yes/No*

ACTI-MED

Yes/No*

SOLO-care Plus

Yes/No*

Optifree Express

Yes/No*

Contra Clair

Yes

Regard

Yes

 

  • Effect dependant on concentration and strain of acanthomoeba.

 

Boston Advance (rigid contact lenses) was found to be the most effective in that it destroyed the cysts of all strains at all concentrations within 1 hour. Meni Care Plus was almost as effective but failed to kill 1 strain at the highest concentration. Storage solutions for soft contact lenses were ineffective overall in destroying cysts.

 

In summary, this study found Boston Advance  and Meni Care Plus to be the most effective storage solutions of those tested for destroying acanthomoeba. Importantly, none of the authors have a commercial interest in any of the storage solutions so the results are not likely to be biased by this. Readers should bear in mind that acanthomoeba may still cause infection from the water associated with hand washing regardless of whether the lens/solution is sterile.

 

 


There has been considerable interest in the corneal collagen crosslinking treatment since the announcement that trials of the treatment are starting is Australia. Below is a summary of the only published research on this treatment.

Riboflavin/Ultraviolet-A-induced Collagen Crosslinking for the Treatment of Keratoconus

 

Gregor Wollensak, Eberhadr Spoerl Theo Seiler

American Journal of 2003: Vol 135; pp620 – 7

 

A novel treatment for Keratoconus has shown promise in a pilot study of 22 patients in Germany. These patients, between the ages of 13 – 58 years, had moderately to advanced progressive keratoconus affecting both eyes. Treatment involved the application of riboflavin drops to the cornea followed by exposure to focused ultraviolet A light for 30 minutes. In theory, this has been shown to increase collagen crosslinking and help reinforce the cornea. Only 1 eye in each patient was treated with the fellow eye acting as a control for comparison. The treatment did not prevent hard contact use afterwards.

 

Participants were observed for an average of 2 years after the treatment. Sixty-five percent showed a significant improvement in visual acuity without contact lenses. Also, on average the prescription of participants improved by 1.14 dioptres. Importantly, 70% of participants demonstrated regression of their Keratoconus after treatment with a further 22% remaining stable. By comparison, 22% of untreated eyes demonstrated marked progression of keratoconus during the study period. No adverse side effects of treatment were reported by the study participants.

 

This study has demonstrated promising results for a treatment that for the first time may prevent or reverse the effects of Keratoconus. It is a particularly appealing treatment as it is relatively simple to administer and may be performed as a day only procedure with little or no side effects. This study is not without its problems however. In particular, the investigators were not blinded to the identity of the patients and so this may be a source of bias in the way the results are reported. Equally, the follow-up of some of the patients may be inadequate. Despite this, however, the results are encouraging and provide the basis for further work on this treatment option. A larger trial of this treatment is currently under way in Melbourne and we look forward to the results with anticipation.

Older Research

November 2004

Some interesting work that has emerged from the USA points to eye rubbing as being an ever-important factor in the development of keratoconus. Jafri and colleagues from the Emory University School of Medicine in Atlanta have reported 5 cases of individuals that developed keratoconus in one eye only. The unique feature in each case was a history of significant rubbing of the affected eye but not the other eye. The authors believe that eye rubbing is the most significant predictor of keratoconus and explains the association between keratoconus and atopic diseases such as hay-fever and sinusitis. Jay Krachmer MD (Dept of Ophthalmology, University of Minnesota) has written an excellent editorial on the implications of this report for those who are interested in further reading.Jafri B, Lichter H and Stulting RD.

Asymmetric keratoconus attributed to eye rubbing.
Cornea 2004: 23 (6); 560 – 564.Krachmer JH.
Eye rubbing can cause keratoconus. Cornea 2004: 23 (6); 539 – 540.View the journal at www.corneajrnl.com

Presently the treatment options in Keratoconus are very limited. For those with early and/or mild disease, contact lenses are used to correct any visual imperfections. Corneal transplants have been reserved for those with more severe disease. There is now hope that another treatment option may become available with the discovery of a technique for improving cornea rigidity without the need for surgery. The treatment involves applying a riboflavin solution to the surface of the cornea then exposing the cornea to UVA radiation. Wollensak and colleagues found that by applying this treatment to rabbits they were able to improve collagen fiber diameter in the cornea. It is hoped that this will increase the biomechanical stiffness of the cornea and correspondingly reduce the rate of progression in keratoconus. More work is needed to see whether this will become a viable treatment option. See the editiorial by Herbert Kaufman MD for a good overview of this topic.

Wollensak G, Wilsch M, Spoerl E and Seiler T. Collagen fiber diameter in the rabbit cornea after collagen crosslinking by  riboflavin/UVA.
Cornea 2004: 23 (5); 503 – 507.Kaufman HE. Strengthening the cornea. Cornea 2004: 23 (5); 432

View the journal at www.corneajrnl.com

The main reason for corneal transplant failure is rejection of the graft. In patients at particularly high risk of failure, rejection can occur in as many as 50% after a few years. Any measure to reduce the rate of rejection could have a significant impact on the success of corneal transplant surgery as a whole. A group from Karl-Franzens University Medical School in Graz, Austria have recently discovered that by storing the corneal tissue in a dextran-free medium for 7 days or more, the rate of corneal rejection was significantly reduced. This effect was most marked in the group at highest risk of rejection. It is hoped that a simple measure such as this will make corneal transplant surgery even more successful than it already is.

Simon M, Fellner P, El-Shabrawi Y and Ardjomand N. Influence of donor storage time on corneal allograft survival. Ophthalmology 2004: 111 (8); 1534 – 1538

June 2004

You may be surprised to know that up to 15% of individuals affected by kerataconus only have it in 1 eye initially. Intuitively one might think that it was only a matter of time before the other eye becomes involved. Not so, according to new research that has come out of Los Angles. A group at UCLA have followed the progress of 778 patients with keratoconus in one eye only. They found that only 50% of the good eyes went on to develop keratoconus up to 16 years after the initial diagnosis. If you consider that most people are diagnosed with keratoconus during puberty or early 20s and progress until their 30s, this means that those with Keratoconus in one eye only have a 1 in 2 chance of developing it in the other eye. The study also concluded that greatest risk of keratoconus also developing in the good eye is during the first 6 years of the onset. Despite monitoring the effects of age, gender, race and use of contact lenses on whether the good eye developed keratoconus or not, no link was found.

Xiaohui L, Rabinowitz YS, Rasheed K and Huiying Y. Longitudinal study of the normal eyes in unilateral keratoconus patients. Ophthalmology 2004; 111 Issue 3: 440-446

In the January edition of Clinical and Experimental Ophthalmology appeared a forum discussion on the issue of directed tissue donation as it relates to corneal transplantation. For those not familiar with this issue, directed tissue donation is where the donor places conditions on the use of their organs, for example that it be used in someone of a non-ethnic background. A panel of experts from Australia, New Zealand and the UK discuss the pros and cons in a lively and very interesting discussion. Those against directed tissue donation do so principally for 2 reasons: that it condones racist behaviour and attitudes within our community; and that it would bring negative attention to the corneal transplant program with risk of having it shut down. Those in favour, and who appear to be the minority, argue that directed tissue donation indirectly benefits all as the non-recipients move up the transplant list. Further to this, some experts argue that it is indefensible to decline a directed tissue donation in a climate of chronic under supply of donor organs. For the record, the current position of the cornea transplant services around Australia is that directed tissue donation is not allowed.

Sherwin T, Coster DJ, La Nauze J, Merry A, Pendergrast D and Armitage WJ. Is directed donation misguided? Clinical and Experimental Ophthalmology 2004; 32: 5-8

Imagine the disappointment of having a successful corneal graft for keratoconus that has been stable for many years, only to develop a cataract in that same eye and develop impaired vision again. Of course a cataract operation could easily rectify this problem but what effect will this surgery have on your longstanding corneal graft? Some ophthalmologists from Philadelphia, USA examined this very question in a group of patients who had had stable corneal grafts for an average 8.4 years but up to 36 years. After cataract surgery, they closely monitored the progress of patients for an average 44 months and found that graft rejection occurred in only 3%. All the remaining patients had clear corneal grafts and improved vision after the cataract surgery. It is concluded that cataract surgery on individuals who have had a corneal graft is safe and does not cause graft failure in the vast majority.
Nagra PK, Rapuano CJ, Laibson PL, Kunimoto DY, Kay M and Cohen EJ. Cataract extraction following penetrating keratoplasty. Cornea 2004: 23; 377-379

Other news and research off the Net
compiled by Keratoconus Australia and contributors

Keratocyte apoptosis after corneal collagen cross-linking using riboflavin/UVA treatment
Cornea. 2004 Jan 23(1):43-9Wollensak G, Spoerl E, Wilsch M, Seiler T.Department of Ophthalmology, Technical University of Dresden, Dresden, Germany. gwollens@hotmail.com

PURPOSE: Combined riboflavin/UVA treatment inducing collagen cross-links in the cornea has been shown to increase the biomechanical rigidity of the cornea and has been used successfully in the treatment of progressive keratoconus. The current study was undertaken to investigate the possible cytotoxic effect of combined riboflavin/UVA treatment on corneal keratocytes in vivo. METHODS: Thirty-four New Zealand white rabbits were treated with 0.1% riboflavin solution and surface UVA irradiances ranging from 0.75 to 4 mW/cm2 (1.35- 7.2 J/cm2) for 30 minutes. The animals were euthanized either 4 (n = 6) or 24 (n = 28) hours postoperatively. Four additional control eyes underwent epithelial debridement alone. The corneas of the enucleated eyes were evaluated in routine histologic sections. In addition, the TUNEL technique and transmission electron microscopy were used for the detection of keratocyte apoptosis. RESULTS: In the control eyes with corneal epithelial debridement only, apoptotic keratocytes were found in the anterior 50 microm of the corneal stroma 4 hours postoperatively. However, riboflavin/UVA-induced apoptosis was only visible in the rabbit eyes enucleated 24 hours postoperatively. In these eyes, we found apoptosis of keratocytes down to a variable stromal depth depending on the applied UVA irradiance. A cytotoxic UVA irradiance for keratocytes in the range of 0.5-0.7 mW/cm2 could be deduced. CONCLUSIONS: Riboflavin/UVA treatment leads to a dose-dependent keratocyte damage that can be expected in human corneas down to a depth of 300 microm using a surface UVA dose of 5.4 J/cm2. Future studies should be done to examine the keratocyte repopulation and exclude possible adverse sequelae of keratocyte loss like stromal scarring or thinning.PMID: 14701957 [PubMed - indexed for MEDLINE](Note: Keratocytes are corneal cells and apoptosis means programmed cell death. It seems that the process speeds up the program. Dr. Bezalel Schendowich)The journal Eye and in Ocular Surgery News May 2004

Keratoconus higher among Asians than white patients

A study in Britain finds Asians were significantly more likely than white patients to have keratoconus in a retrospective study at an English hospital.  T. Georgiou and colleagues in Leeds, England, conducted a retrospective study of new patients diagnosed with keratoconus or malformation of the cornea at their hospital between 1994 and 2000. A catchment population of 176, 774 for the hospital was used to calculate the incidence of keratoconus in three ethnic populations: white (82%), Asian (17%) or other (1%).  A total of 74 cases of keratoconus were diagnosed in this 6-year period. Of these patients, 29 (39%) were white and 45 (61%) were Asian. This factored to an incidence of keratoconus of 1 in 4,000 per year for Asians, compared with 1 in 30,000 per year for whites (P < .001), the researchers said. Asians presented with keratoconus significantly younger than white patients. The incidence of atopic disease was found to be significantly higher in whites compared to Asian keratoconic patients, according to the study.  The researchers said that Asians, mostly of northern Pakistani origin, were significantly more likely to present with keratoconus than whites. The authors noted that this community has a tradition of interfamilial relationships, especially first-cousin marriages. The higher incidence in this population was highly suggestive of a genetic factor being significant in the etiology of keratoconus, the researchers said. The incidence of keratoconus was higher than in previous studies, the researchers said.  Atopic disease was significantly less common in Asians than white people, supporting the theory of a different etiology in these patients, the authors said.  The study is published in the April issue of the Eye.

Corneal epithelial sheet grafts from corneal stem cells

From the US NKCF: The research article mentions only the epithelial cell layer being grown. It mentions that the 12 successful cases had damaged epithelial stem cells in the limbus.  The recent newspaper articles give the impression whole corneas are grown.This is very important research for those with traumatic/burn injuries of the cornea. The epithelial layer is the very outermost layer of the cornea. This layer is essential to the health of the normal cornea and to the stability of a grafted cornea.  Often, in injuries to the cornea (trauma/caustic burns) the cells at the very periphery of the cornea are damaged. These cells are essential to the healing of the graft.  Without these specialized cells the cornea will not remain healthy, the graft will not survive. "Between December 2002 and this past January, Okano and Nishida recruited 12 patients with damaged epithelial stem cells in the limbus. Such patients comprise about 20 percent of those awaiting cornea transplants.Okano and Nishida declined to say how the patients lost their sight, saying they would do so in their scientific paper on the human trials. But people who need such transplants mostly have been blinded by disease, burns or contact with caustic chemicals.      Epithelial stem cells constantly generate new cells to cover the body's outer surface and line the inner walls of the mouth, lungs and stomach. In the eye, the stem cells replace dead corneal cells. The cornea can become cloudy or be overrun by capillaries from the white of the eye if those stem cells die. If the new procedure has a 100% success rate, why will it take two years before it becomes available?   The article states: ......limited trials of unapproved techniques are allowed in Japan, approval for large-scale human clinical trials could take months and full approval for medical use is at least two to three years away, Okano said. Below is the abstract from the medical journal:  Transplantation. 2004 Feb 15;77(3):379-85. 

Functional bioengineered corneal epithelial sheet grafts from corneal stem cells expanded ex vivo on a temperature-responsive cell culture surface.

Nishida K, Yamato M, Hayashida Y, Watanabe K, Maeda N, Watanabe H, Yamamoto K, Nagai S, Kikuchi A, Tano Y, Okano T.Department of Ophthalmology, Osaka University Medical School, Suita, Japan.

BACKGROUND: Limbal stem-cell deficiency by ocular trauma or diseases causes corneal opacification and visual loss. Recent attempts have been made to fabricate corneal epithelial graft constructs, but the technology is still evolving. We have developed a novel cell-sheet manipulation technology using temperature-responsive culture surfaces to generate functional, cultivated corneal epithelial cell sheet grafts.  METHODS: Human or rabbit limbal stem cells were cocultured with mitomycin C-treated 3T3 feeder layers on temperature-responsive culture dishes at 37 degrees C. Cell sheets were harvested from the dishes after 2 weeks by reducing temperature to 20 degrees C. Histologic analyses, immunoblotting, and colony-forming assay were performed to characterize the cell sheets. Autologous transplantation was undertaken to reconstruct the corneal surfaces of rabbits with experimentally induced limbal stem cell deficiencies.  RESULTS: Multilayered corneal epithelial sheets were harvested intact simply by reducing the temperature, without the use of proteases. Cell-cell junctions and extracellular matrix on the basal side of the sheet, critical to sheet integrity and function, remained intact. A viable population of corneal progenitor cells, close in number to that originally seeded, was found in the sheets. Harvested sheets were easily manipulated, transplantable without any carriers, and readily adhesive to corneal stroma so that suturing was not required. Corneal surface reconstruction in rabbits was highly successful. 

CONCLUSIONS: Cell sheet engineering technology allows us to create intact, transplantable corneal epithelial cell sheets that retain stem cells from limbal stem cells expanded ex vivo. Our research indicates highly promising clinical capabilities for our bioengineered corneal epithelial sheet.

OCULAR SURGERY NEWS EUROPE/ASIA-PACIFIC EDITION   June 2004 Researchers narrow hunt for keratoconus gene A region in the genome where the mutated gene is probably located has been identified, researcher says.
by Michela Cimberle BARCELONA – Researchers hope to discover the keratoconus gene soon, according to François Malecaze, MD. “We have identified a region in the genome where the mutated gene of keratoconus is probably located. The next step will be to sequence the suspected gene in order to find the mutated nucleotide, which will be a definite indication that this is the gene we were looking for,” Dr. Malecaze said during an instructional course at the winter meeting of the European Society of Cataract and Refractive Surgeons. The discovery of the keratoconus gene will affect the diagnosis and treatment of the disease. It could also help solve one of the problems in selecting patients for refractive surgery, he said. Important consequences Dr. Malecaze said there are four reasons that make the search for the keratoconus gene a major goal in ophthalmology.
“The first reason is because keratoconus is often familial. Previous studies suggested that 10% of keratoconus cases have a familial connection. However, more recent studies that take into account forme fruste keratoconus have shown that the prevalence of familial keratoconus is higher,” he said.
The second reason is because the pathogenesis of keratoconus is still unknown. The classical biochemical strategies to find the cause of the disease have not been successful so far, and genetics might explain the phenomena underlying this kind of corneal deformation, he said.
“The third reason is that the discovery of the keratoconus gene will dramatically improve the diagnosis of the disease, which is not always an easy task,” Dr. Malecaze said.
In some cases, even the most sophisticated corneal topographers do not guarantee a reliable differential diagnosis between forme fruste keratoconus and pseudokeratoconus.
“Even the quantitative indices don’t always allow a clear-cut decision, which is crucial when we screen patients for refractive surgery,” he pointed out. In the literature, most cases of post-LASIK ectasia were reported in connection with topographically suspected keratoconus corneas.“In the future, once the gene of keratoconus is discovered, a simple blood sample will allow a diagnostic decision,” Dr. Malecaze said.
Last, this discovery will lead to new, more specific therapeutic strategies that are based on a better knowledge of the biology and pathophysiology of the disease, he said.The full article is available on the OSN websiteOCULAR SURGERY NEWS EUROPE/ASIA-PACIFIC EDITION   April 2004

Tap water identified as source of U.K. bacterial keratitis cases

In a study, the majority of homes in which Acanthamoeba were isolated were occupied by a contact lens wearer by Michael Piechock Certain household water storage systems used in the United Kingdom harbor free-living amoeba, including Acanthamoeba, U.K. scientists found. Further, their study showed a direct epidemiological link between the water storage units and the incidence of Acanthamoeba keratitis, particularly among contact lens wearers. Dr. Simon Kilvington and colleagues at several institutions in the United Kingdom conducted the retrospective study, which sampled water from various taps in the homes of 27 patients with culture-proven Acanthamoeba keratitis. According to the study, free-living amoeba (FLA) were isolated from at least one water sample from 24 of 27 (89%) homes. Of these, eight samples contained Acanthamoeba, and all were taken from taps supplied by roof storage cisterns. Roof cisterns in the United Kingdom were used in the past to store water for times when the public water main was interrupted. They are used today mainly for supplying water to toilets and bathroom cold water taps, the authors wrote. The authors noted that 23 of the study participants wore contact lenses, although none admitted to using such water for lens cleaning or storage, “suggesting that Acanthamoeba keratitis can arise from indirect exposure to contaminated tap water.” “It is recommended that wearers adhere strictly to the manufacturer’s recommended lens hygiene procedures and use only sterile, approved solutions,” the authors said. “In addition … manipulation and storage of [contact lenses] … should take place away from sources of potential contamination.”

The full article is available on the OSN website