Eye World
September 2000

Inside Lasik
First on the endothelial cell block

by Maxine Lipner

"Are practitioners captives of false beliefs when it comes to the excimer laser and its effect on the endothelium? Some new data are creating a reason to look at this issue more closely."

"While there is always concern about endothelial cell loss with the use of phakic intraocular lenses, photorefractive keratectomy and laser in-situ keratomileusis have generally been thought of as fairly risk-free in this regard. But some are beginning to believe that the excimer may not be as innocuous to the endothelium as most think."

Endothelial excimer lock-down?

Daljit Singh, MS, DSc, professor emeritus of Guru Nanak Dev University Medical College in Amritsar Punjab, India, was first drawn into this endothelium netherworld when he performed PRK for +8 D spherical error in the amblyopic eye of a young adult. "To my horror, the patient developed severe corneal edema that took more than a month to clear," Singh said. He hoped it was just a fluke, but later found that the patient had lost almost 50% of endothelial cells. When another hyperopic patient developed severe striate keratitis in the deeper layers of the cornea stroma, he examined her at the slitlamp microscope. "� The corneal swelling was toward the endothelial side, while the anterior surface was smooth," Singh said. "This last case opened my eyes to the possibility of endothelial cell damage being directly related to the use of the 193-nm laser for refractive purposes."

Singh subsequently studied 80 PRK patients in myopia groups who underwent the procedure with his MEL 60/94 Meditec excimer laser. A video of the endothelium was made immediately before PRK, then a bandaged contact lens was applied, and the endothelium was re-examined with a specular endothelial microscope at the conclusion of the procedure. "I found evidence of consistent damage to the endothelium, once the treated refractive error was higher than �5 D," Singh said. He submitted his study results, which showed up to 25% cell loss, to but the paper was rejected, which Singh believes was politically motivated. "The truth about corneal endothelium can upset the apple cart of PRK and LASIK surgery, and all the industry connected with it," he said."

Doing study time

"Neal A. Sher, MD, clinical professor of ophthalmology at the University of Minnesota and attending surgeon at Phillips Eye Institute, Minneapolis, is aware that past study results on endothelial changes after PRK and LASIK have been mixed. He thinks there may be merit to Singh's observations."

Ocular Surgery News
Special Meeting Report
Dec. 15, 1999

LASIK-dry eye connection gets attention at AAO-PAAO

"At this year's meeting, there was an emerging recognition of an important complication of laser in situ keratomileusis (LASIK) -- postoperative dry eye.

"During his keynote address in a session on LASIK complications and their management at the Refractive Surgery Subspecialty Day, Richard L. Lindstrom, MD, noted the the overall frequency of complications after LASIK is decreasing.  Severe vision loss after LASIK is now a rare occurrence."

"However, he said, dry eye is being seen with increasing frequency, is making patients very unhappy and must be recognized and treated aggressively.  In his practice in Minneapolis, he said, he often uses punctal occlusion to address patient complaints of dry eye."

Archives of Ophthalmology
August 1999

"A Cautionary Tale of Innovation in Refractive Surgery"

by George O. Waring III, MD, FRCOphth

"The use of lamellar keratotomy in hyperopic ALK and in keratomileusis raises a fundamental question about corneal biomechanics:  What is the minimal thickness of the cornea that can preserve corneal shape for the lifetime of the patients without development of progressive corneal steepening or frank ectasia?  No one knows."

Ocular Surgery News
Monographs
August 1, 1999

McCulley:  "Studies have shown that about 20% of people have less problems with light after corneal refractive surgery and 20% have more problems with light after corneal refractive surgery.  It is important that patients are told this additional information."

BBC Online
18th July 1999

"New scientific research from Germany shows that seven out of ten patients are left with defective vision after laser surgery."

"The CAA says "laser procedures may produce side effects of glare and distortion of vision .... the long-term effects are unknown and laser surgery is not recommended for aircrew."

"Consultant Ophthalmologist, William Jory, also has reservations.  He used to perform laser surgery until he heard worrying reserach presnted at international scientific meetings.  He says: "I have been able to demonstrate a loss of night vision in my laser cases, not all of them but a majoriuty, approximately 80 per cent."

FDA Consumer magazine
July-August 1998

Laser Eye Surgery: Is It Worth Looking Into?

by Carol Lewis

What Are the Risks of Laser Surgery?

"The risks outlined below apply to both PRK and LASIK procedures. The chances of having a serious vision-threatening complication are minimal, and there have been no reported cases of blindness following either PRK or LASIK, says James Salz, M.D., clinical professor of ophthalmology. However, FDA is aware of a few instances of severe eye injury requiring corneal transplant."

Journal of Refractive Surgery
March 1999

Change in Corneal Sensitivity following laser in situ keratomileusis

However, because of cutting the corneal flap and ablating titrated amounts of tissue, it does injure deeper layers of the cornea and creates a gap between the flap and the unlerlying bed.  Thus, LASIK can be expected to affect regeneration of involved nerve cells and tissues."

"One possible explanation is that in LASIK, because the corneal stroma is ablated after a corneal flap is created, more damage is caused to deeper corneal tissue than in the case of PRK, and there is more risk of damaging nerve fibers in forming a flap.  Moreover, because there is a temporary gap between the corneal flap and the bed, the transfer of cells and other materials may be impeded.  Such diffusion barriers can be expected to affect the recovery of nerve cells and corneal tissues."

Klin Monatsbl Augenheilkd
Oct. 1998

[Progressive corneal ectasia after laser in situ keratomileusis.]
[Article in German]

by Speicher L, et al

"Corneal ectasia can occur after LASIK even in low degrees of myopia of less than ten diopters."

Journal of Refractive Surgery
September/October 1998

The Call of the Sirens: Ethically Navigating the Sea of Nonvalidated Therapies

Michael R. Grimmett, MD, FACP, FACS

"Medical research and innovation are vital to the advancement of medicine and, ultimately, benefit society and individual patients. However, the ethical principles of beneficence, respect for persons, and justice must guide the development and implementation of new practices. Ethical codes governing clinical practice and research already warn practitioners to avoid the use of nonvalidated practices outside of controlled clinical trials. Nonetheless, lack of compliance with these codes places many patients at risk for harm. Ophthalmologists, as well as all physicians, must recommit themselves to these ethical principles and codes and establish more vigorous peer-review methods to protect patients from nonvalidated practices that are implemented without a scientific basis."

Ocular Surgery News International Edition
June 1998

Flying spot laser effective for mild to moderate myopia.

"One month after surgery, 3% of patients continued to have foreign body sensation."

American Institute of Biological Sciences
Scientific Peer Advisory and Review Services
Study Commissioned by the Department of Defense
United States of America

April 1998

Report of the Peer Review Panel on Photorefractive Keratectomy (PRK) Research

"Furthermore, the safety of LASIK surgery is completely unknown."

Recommendations

"The panel recommends that future studies sponsored by the DoD related to
corneal and ocular physiology be directed toward answering the following three
questions:
1. What is the cause of regression in patients�epithelial hyperplasia or
fibrosis�and how long does it take to stabilize�5 years to 10 years?
2. What is the importance of an abnormal basement membrane? Is there any
effect on long-term epithelial and keratocyte differentiation and functions, and what is
the risk to later infection?
3. What is corneal haze, how can it be measured objectively and how does it
correlate with visual outcomes including glare and low-contrast visual acuity?"

"Other recommendations for areas meriting further study are as follows (in order
of their appearance in the Chapter 2):
1. What is the precise in vivo decrease in corneal thickness after PRK in patients,
and how does achieved photoablation correlate with intended correction?
2. What is the risk for the development of early cataract following single and
multiple PRK procedures?
3. What is the tolerance of the cornea to shear stresses after LASIK surgery?
4. What is the depth of injury to underlying cells�keratocytes and endothelial
cells�in patients, and how does the depth of injury correlate with the development of
haze and regression?
5. What is the risk of UV and solar radiation to haze and regression?
6. What is the effect of pregnancy and menopause on PRK?
7. Can growth factors or cytokines alter the post-PRK repair process?
8. What is the early inflammatory response and how does it correlate with haze
and regression?
9. What is the mechanism of collagen fibrillogenesis and how does it relate to
corneal haze?
10. What is the risk of corneal endothelial damage following LASIK?
11. What is the risk of corneal anesthesia following PRK, and how does
reinnervation modulate epithelial healing and long-lasting epithelial defects after PRK?
How does corneal anesthesia affect basal tear secretion and subsequent corneal drying
and damage?

"Although PRK and LASIK are widely accepted and being performed worldwide,
many controversies and gaps in knowledge exist with respect to safety, efficacy, and
techniques. The following information summarizes the controversies and gaps in
knowledge."

"Most studies have been relatively short term with PRK and limited with LASIK.
There is a significant gap in knowledge with respect to potential long-term complications
of both of these procedures."

"PRK in clinical ophthalmology and optometry is an evolving procedure. There is
a rapid growth in the frequency of PRK, especially when it is performed under a flap
(e.g., LASIK), that is attributed to its clinical appeal for both physician and patient.
However, there is even less information available about wound healing, clinical results,
and visual performance following LASIK."

"There are several concerns with using the excimer laser to photoablate the corneal surface, including (1) variation in photoablation rates, (2) uv radiation effects, (3) thermal effects, and (4) biomechanical effects."

"Excimer radiation does appear to produce oxidative damage to proteins in the
aqueous chamber and lens suggestive of cataractogenesis."

"In contrast to PRK, LASIK may achieve depths that could severely compromise
the cornea to blunt trauma; however, in one report there appeared to be no difference in
the effect of LASIK and PRK on the biomechanical stability of the cornea (Peacock et al.,
1997). Also, little or nothing is known about the integrity of the corneal flap and
whether healing after LASIK ever restores the ability of the anterior cornea to withstand
sheer stress, particularly those types of stresses that might be encountered by military
personnel. The panel recommends that further study of the sheer stress be conducted on
LASIK to establish the tolerance of LASIK flaps to withstand lateral force. These
studies, if conducted in animals, must be interpreted cautiously because animals show
considerably greater healing responses than humans that may restore some intralamellar
adhesive strength, which may not occur in patients."

"However, long-term ultrastructural
studies indicate that the basement membrane is abnormal and not completely reformed
by 18 months after surgery in primates (Hanna et al., 1990), raising concern as to
whether a normal basement membrane is ever re-established."

"Virtually nothing is known about the early changes following PRK in the human
population with regard to the depth and extent of keratocyte injury, if any. Following
LASIK, depth of injury may have more severe consequences where injuries may extend
to the corneal endothelium. With the recent advances in microscopy these studies could
be conducted to establish the extent of injury for patients. The panel recommends that
clinical studies should be conducted to evaluate acute depth of injury and establish both
the presence and the extent of risk to underlying cells, keratocytes, and endothelial cells."

"In general, corneal wound repair is a complex, multifactorial process for which
many of the cellular and molecular mechanisms controlling the wound healing process
are either not known or are only poorly understood."

"The consequence of incomplete regeneration of epithelial basement membrane remains unknown."

"Little is known about the effects of LASIK on the corneal endothelium. There is
some concern that LASIK may effect the endothelium adversely, particularly because
LASIK produces considerably deeper injury that may approach within 100 mm of
Descemet's membrane. The Panel recommends that basic studies be conducted to
further evaluate and define this risk."

"However, with ocular pathology that reduced letter acuity by about 0.5 log units, face
recognition (and word recognition) dropped by 1.0 log unit, indicating that face
recognition acuity will be affected more than letter acuity."

Ocular Surgery News
April 15, 1998

LASIK: Retreating the back of the flap

by Michael C. Knorz, MD

"Laser in situ keratomileusis (LASIK) has become the most frequently used refractive surgical procedure. It guarantees fast visual recovery, and residual refractive errors can be treated easily by lifting the flap."

"I have been involved with LASIK from the early days. Back in 1993, we used a flap thickness of 130 µm. Later on, a flap thickness of 160 µm became the accepted standard. A thicker flap is more stable and, therefore, both easier to handle and less likely to wrinkle and cause irregular astigmatism. A disadvantage of the thicker flap is that it leaves less stroma to be ablated. The thickness of the stromal bed, however, is the most important factor to prevent progressive corneal ectasia causing significant visual loss."

"I have seen some cases of keratectasia, which usually develop 1 to 2 years after the initial surgery. It usually presents as a very steep central island, as the cornea is thinnest in the center and, therefore, most likely to become ectatic centrally. In all cases, the thickness of the stromal bed was less than 200 µm, in some cases even less than 150 µm. In order to prevent late keratectasia, we must leave a stromal bed of at least 200 µm, probably even 250 µm."

Ocular Surgery News
April, 1998

CRS-USA data indicate postop LASIK complications most threatening to vision

Postoperative results

"A second way of looking at complications is to consider the postoperative cause of the case at the 3-month follow-up. Postoperative complications were generally not caused by the keratome and more often resulted in a loss of visual acuity, Dr. Kezirian said.
Postoperatively, the study found an overall complication rate of 5.8%. Complications included corneal edema (0.6%), corneal scar (0.1%), persistent epithelial defect (0.5%), significant glare (0.2%), persistent discomfort or pain (0.5%), interface debris (3.2%), interface epithelium (0.6%) and cap thinning (0.1%). Some single cases with complications were reported as two events."

Ocular Surgery News
March 15, 1998

Evolving Trends, Techniques, & Pearls in Cataract and Refractive Surgery.

"Kelley:  I think the key time to irrigate is before you lift it.  The fornix is going to be swimming with debris otherwise, and you can irrigate a lot and still miss particles."

"I have found that most of the time when you irrigate straight away, the water goes under but the debris stays put.  You have to actually tilt their head and irrigate towards the ear."

"Machat:  If a patient has a little bit of debris it is not the end of the world.  It mainly affects your referrals, it does not affect their vision."

"I find that when I cut the flap there is debris on the microkeratome and it literally becomes ingrained and sticks vigorously, and it is tough to get rid of that.  Sometimes I will see something and lift the flap and scrape it to get it off, but I try to keep my irrigating time down to around 10 seconds."

Ocular Surgery News
March 15, 1998

Other Products in the Development Pipeline

Company: Chiron Vision
Product: Company submitted application for Technolas for photorefractive keratectomy for 1 D to 10 D of myopia and for up to 4.5 D of astigmatism.

Aust. Fam. Physician
March 1998

Laser refractive surgery

by Loughnan, M.

"The most important influence on the refractive outcome of such procedures is the pre-operative refraction.  The best outcomes are seen with treating low degrees of myopia and/or astigmatism.  Outcomes for treating high degrees of myopia or astigmatism are often disappointing."

Ocular Surgery News
March 15, 1998

Diagnosing and topically quenching dry eyes

"Eye drops, whether preservative-free or not, don't always work or provide enough relief. Other topical therapies are tried before considering surgical options. Other nonsurgical treatments include moisture goggles, ointments and plastic eye shields."

"Because of the thick consistency and vision blurring effects of ointment, this therapy is primarily reserved for night time use. Also, night time might actually be the root of the dry eye syndrome. "A lot of patients sleep with their eye open just a crack," Dr. Krall said. "When these patients first open their eyes in the morning, they rip off epithelium." Dr. Krall said, depending on the severity of the syndrome, he may use lubricating drops and ointment at night."

"Moisture chamber, or goggles are awkward, but are quite effective. "These are mainly for the severe dry eye patient," Dr. Friedlaender said. "Sometimes I'll suggest that these severe dry eye patients sleep with swim goggles on." It sounds a little peculiar, but it is something that works pretty well to create a moisture effect."

Department of Health and Human Services
Public Health Service
Food and Drug Administration

Ophthalmic Devices Advisory Panel
Ninetieth Meeting
Volume II, Open Session

Feb. 13, 1998

"We assessed patient symptoms following these procedures, and we have listed here the incidence of settings in which the patients felt that they had these symptoms to a bothersome degree.  That would include bothersome glare, bothersome halos, difficulty with night driving, ghosts of double images, foreign body sensation, anxiety, and pain."

Journal of Refractive Surgery
August 1997

"Laser in situ keratomileusis for Myopia of -1 to -3.50 Diopters"

"Mild discomfort was felt by all patients but the majority reported no peri-operative or postoperative pain."

Journal of Refractive Surgery
May/June 1997

"Quality of Vision and Freedom from Optical Correction after Refractive Surgery"

"Unfortunately, published data on how many patients wear spectacles and contact lenses after refractive surgery is almost nonexistent - a remarkable indictment of clinical repoorting from the refractive surgical community, since the most important criterion of success for patients who have refractive surgery is freedom from corrective lenses."

"It is not only the refractive outcome after surgery that determines spectacle wearing status, but also the stability of refraction over time."

Journal of Cataract and Refractive Surgery
April 1997

Perez Santonja JJ, et al

"Laser in situ keratomileusis to correct high myopia."

"Current surgical algorithms must be modified to improve predictability in higher corrections.  Longer follow-up is necessary to evaluate long-term incidence of vision-threatening complications."

Ocular Surgery News
November 1, 1996

Physician-led company gets IDE for LASIK.

Ocular Surgery News
International Edition
November 1, 1996

Clear-lens extraction, LASIK successfully treat high myopia, but not without risk

Both procedures offer predictable results, but both carry threat of serious complications.

by Harvey Black

"LASIK is a much more difficult surgery to perform than lens removal, Dr. Kim said. "Most surgeons can do cataract surgery. LASIK is a whole new ball game," he said."

Complications exist with LASIK, as well. Endothelial cell loss, which occurred in one patient, is an example. "In this patient, only 180 µm was left after stromal ablation. You need more than 180 µm after stromal ablation to protect the endothelium," he said.

http://www.fda.gov/cdrh/ode/2093.pdf

Checklist of Information Usually Submitted in an Investigational Device
Exemptions (IDE) Application for Refractive Surgery Lasers

Food and Drug Administration
Diagnostic and Surgical Devices Branch
Division of Ophthalmic Devices
Office of Device Evaluation
Document Issued on: October 10, 1996

"3.2.6.2 Complications
A. Corneal edema between one week and one month after the procedure
B. Peripheral corneal epithelial defect at one (1) month or later (for LASIK, location of the defect
to be identified as on, off, or across the flap)
C. Epithelium in the interface (LASIK only)
D. Recurrent corneal erosion at one month or later (PRK only)
E. Foreign body sensation at 1 month or later
F. Pain at one month or later
G. Ghost/double images in the operative eye
H. Flap is not of the size and shape as initially intended or microtome stopped in mid-cut
(LASIK only)"

3.3 Risk/Benefit Analysis

"The risks of performing (PRK / LASIK) on sighted eyes include improper correction,
decrease in best corrected visual acuity, glare, halo, foreign body sensations, corneal
scarring, corneal ulceration or perforation, intraocular infection, corneal decompensation,
persistent corneal edema, hyphema, hypopyon, endophthalmitis, microbial keratitis or
cataract. Also the long term risks of the procedure are unknown. The LASIK procedure
has additional risks related to the characteristics of the microkeratome. There should be a
discussion of steps taken to mitigate the risks of PRK or LASIK."

Ocular Surgery News
October 1, 1996

FDA should expedite approval of expanded laser uses

"Many ophthalmologists regard LASIK as the off-label laser refractive surgical procedure with the greatest potential to cause harm to a patient.  Extended visual disability and profound, permanent impairment of vision have followed globe perforation with the microkeratome."

Review of Ophthalmology
March 1995

by Johhny Khoury, MD, et al

Understanding Wound Healing after Refractive Surgery

"Descemet's Membrane and the endothelium.  Because of its low wavelength, excimer laser energy cannot penetrate corneal tissue beyond a few microns.  However, there is a possibility of endothelial damage due to shock waves, fluorescence, secondary irradiation and posterior migration of toxic byproducts."

Review of Ophthalmology
October 1994

News and Trends

"Exaggerated" RK Advertising Prompts FTC Investigation.

"Although an FTC spokesman refused to comment, the investigation was reported in the newsletter of the American Cataract and Refractive Surgery.  David Karcher, Executive Director of ASCRS, says that the FTC has observed "a few cases where RK surgeons have gone over the line," which piqued its interest in RK advertising.  Mr. Karcher says that 10 refractive surgery practices across the US are the focus of the FTC's attention."

Review of Ophthalmology
September 1994

How to Answer the Irregular Astigmatism Challenge

W. Andrew Maxwell, MD, PhD, Fresno, Calif.

Here's how to diagnose and manage this frustrating refractive complication.

"Though advances in wound architecture now allow for "astigmatism neutral" sutureless cataract incisions, the growht in refractive surgery and especially in lamellar procedures seems likely to perpetuate the incidence of induced irregular astigmatism for years to come."

American Journal of Ophthalmology
March, 1994

Keratorefractive Surgery, Success, and the Public Health

by Dr. Leo J. Maguire

"We need to think in detail about corneal optics after refractive surgery because the
normal cornea is relatively trouble-free.  The cornea after refractive surgery is not
trouble-free.  It frequently has a more aberrated optical performance than its pre-
operative counterpart.  It is often unstable during diurnal cycles and in time periods
measured in months and years.  Its optical performance can even change
instantaneously with changes in pupil size."

"In 1988 Consumer Reports magazine reviewed the data on radial keratonomy
and advised its readers against the procedure.  They reconfirmed that judgment
in their 1992 health letter."

"When the cornea is irregular over the entrance pupil, the image generated by
the cornea loses contrast and edge definition.  Glare and ghost images can occur
that are particularly disturbing under conditions of low illumination."

"These effects occur in disturbingly high numbers of cases.  For example, a
recent topographic study found that only 42% of 97 consecutive cases of
excimer laser photorefractive keratectomy for myopia showed a uniform
pattern of refractive power within the ablation zone; 10% had distortion severe
enough to cause spontaneous complaints of aberration in central vision."

"Unfortunately many authorities continue to assume that these procedures are
an unqualified success as long as uncorrected visual acuity is 20/40 or better."

Summit Technology
SEC Filing
Quarterly Report, Circa 1997

Safety and Efficacy Concerns

"Concerns with respect to the safety and efficacy of the Company's Excimer System to perform Laser Vision Correction include predictability and stability of results.  Potential complications and side effects include:  post-operative discomfort (which can include pain, itching, tearing, and dryness of the eye); corneal haze during healing (an increase in the light scattering properties of the cornea); glare/halos (undesirable visual sensations produced by bright lights); decreases in contrast sensitivity (which can lead to night vision difficulties); temporary increase in intraocular pressure and/or pupil enlargement in reaction to post-procedure medication; modest fluctuations in refractive capabilities during healing; modest decreases in best corrected vision (i.e., vision with corrective eyewear); unintended over- or under-corrections; disorders of corneal healing (including so-called "central islands"); corneal scars; corneal ulcers; induced regular or irregular astigmatism (which may cause blurred or double vision and/or shadow images); drooping of the eyelid; and iris inflammation.  There can be no assurance that long-term follow-up data will not reveal additional complications that may have a material adverse effect on acceptance of Laser Vision Correction which in turn would have a material adverse effect on the Company's business, financial condition and results of operations."