cornea, conjunctiva and refractive surgery eupo 2009

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European University Professors of Ophthalmology Course book www.eupo.eu CORNEA, CONJUNCTIVA and REFRACTIVE SURGERY EUPO 2009

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European University Professors of Ophthalmology

Course book

www.eupo.eu

CORNEA, CONJUNCTIVA and REFRACTIVE SURGERY

EUPO 2009

European University Professors of Ophthalmology

Course book

CORNEA, CONJUNCTIVA and REFRACTIVE SURGERY

EUPO 2009

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European University Professors of Ophthalmology

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OPD­Scan™ Refractive Power/Corneal Analyzer

Autorefractometer Keratometer

++Topographer

+Pupillometer

+Aberrometer

Retinoscopy / Skiascopy­ Principle

Hyperopia­2 D

EmmetropiaMyopia 50 cm

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OPD­Scan™ Refractive Power/Corneal Analyzer

Autorefractometer Keratometer

++Topographer

+Pupillometer

+Aberrometer

Retinoscopy / Skiascopy­ Principle

Hyperopia­2 D

EmmetropiaMyopia 50 cm

(,D=>)D?" .,)D?"0#";;?;@%+?>=#<?);1AA=<>)D?"

Scanning Slit Retinoscopy / Skiascopy­ Principle(Example R2 D lens)

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OPD­Scan™ Refractive Power/Corneal Analyzer

Autorefractometer Keratometer

++Topographer

+Pupillometer

+Aberrometer

Retinoscopy / Skiascopy­ Principle

Hyperopia­2 D

EmmetropiaMyopia 50 cm

(,D=>)D?" .,)D?"0#";;?;@%+?>=#<?);1AA=<>)D?"

Scanning Slit Retinoscopy / Skiascopy­ Principle(Example R2 D lens)

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OPD­Scan™ Refractive Power/Corneal Analyzer

Autorefractometer Keratometer

++Topographer

+Pupillometer

+Aberrometer

Retinoscopy / Skiascopy­ Principle

Hyperopia­2 D

EmmetropiaMyopia 50 cm

(,D=>)D?" .,)D?"0#";;?;@%+?>=#<?);1AA=<>)D?"

Scanning Slit Retinoscopy / Skiascopy­ Principle(Example R2 D lens)

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OPD­Scan™ Refractive Power/Corneal Analyzer

Autorefractometer Keratometer

++Topographer

+Pupillometer

+Aberrometer

Retinoscopy / Skiascopy­ Principle

Hyperopia­2 D

EmmetropiaMyopia 50 cm

(,D=>)D?" .,)D?"0#";;?;@%+?>=#<?);1AA=<>)D?"

Scanning Slit Retinoscopy / Skiascopy­ Principle(Example R2 D lens)

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OPD­Scan™ Refractive Power/Corneal Analyzer

Autorefractometer Keratometer

++Topographer

+Pupillometer

+Aberrometer

Retinoscopy / Skiascopy­ Principle

Hyperopia­2 D

EmmetropiaMyopia 50 cm

(,D=>)D?" .,)D?"0#";;?;@%+?>=#<?);1AA=<>)D?"

Scanning Slit Retinoscopy / Skiascopy­ Principle(Example R2 D lens)

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Internal Aberration

'The Integration of Topography und Aberrometry in one unit makes it possible to calculate and display

Internal Aberrations'

“!"#$%"&'” (“)*+'&%” , “-.%"$&'”/.%0“1.#&'”20

(20%) (100%) (80%)Calculation Aberrometer Topography

OPD Station Software Upgrade –Holladay Report !"#"$%&'()

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Internal Aberration

'The Integration of Topography und Aberrometry in one unit makes it possible to calculate and display

Internal Aberrations'

“!"#$%"&'” (“)*+'&%” , “-.%"$&'”/.%0“1.#&'”20

(20%) (100%) (80%)Calculation Aberrometer Topography

OPD Station Software Upgrade –Holladay Report !"#"$%&'()

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Internal Aberration

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Internal Aberrations'

“!"#$%"&'” (“)*+'&%” , “-.%"$&'”/.%0“1.#&'”20

(20%) (100%) (80%)Calculation Aberrometer Topography

OPD Station Software Upgrade –Holladay Report !"#"$%&'()

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Internal Aberration

'The Integration of Topography und Aberrometry in one unit makes it possible to calculate and display

Internal Aberrations'

“!"#$%"&'” (“)*+'&%” , “-.%"$&'”/.%0“1.#&'”20

(20%) (100%) (80%)Calculation Aberrometer Topography

OPD Station Software Upgrade –Holladay Report !"#"$%&'()

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Internal Aberration

'The Integration of Topography und Aberrometry in one unit makes it possible to calculate and display

Internal Aberrations'

“!"#$%"&'” (“)*+'&%” , “-.%"$&'”/.%0“1.#&'”20

(20%) (100%) (80%)Calculation Aberrometer Topography

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“!"#$%"&'” (“)*+'&%” , “-.%"$&'”/.%0“1.#&'”20

(20%) (100%) (80%)Calculation Aberrometer Topography

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S/:%E:P3223;/5C%(/5:)31%.3;8/1/GC

d%\-53;%D5L)h=%7-5L)C%d

NON-INFLAMMATORY

CORNEAL PATHOLOGY

Prof.Dr.Murat Irkec, MD

Director, Corneal Service and Research Unit

Department of Ophthalmology

Hacettepe University Faculty of Medicine

Ankara - Turkey

Degeneration : deterioration and decrease in function

Degenerations may be :

!! Unilateral or bilateral

!! Often asymmetric

!! An inheritance pattern usually not found

!! Many occur later in life (normal aging)

!! Secondary to systemic or pathological process

!! Often eccentric or peripheral

!! Relation to vascularity

Classification of corneal degenerations

A. Primary

!! Iron lines

!! White limbal girdle of Vogt

!! Cornea farinata

!! Ant. and post. crocodile shagreen

!! Corneal arcus (arcus senilis)

!! Hassal-Henle bodies

Classification of corneal degenerations

!! Pinguecula

!! Pterygium

!! Spheroid degeneration

!! Salzmann s nodular degeneration

!! Terrien s marginal degeneration

!! Corneal amyloid

!! Lipid degeneration

!! Coat s white ring

!! Band keratopathy

!! Neurotrophic keratopathy

!! Exposure keratopathy

!! Recurrent erosion syndrome

B.Secondary

WHITE LIMBAL GIRDLE OF VOGT

!! White, cresentic, peripheral corneal opacities

in the interpalpebral area

!! Two clinical forms

Type 1: rare, early band keratopathy,

clear zone from limbus

Type 2: common, 100% after 80 years of age,

more common at the nasal limbus,

no peripheral clear zone from limbus

!! Histology: subepithelial hyaline and elastotic changes

Bowman s membrane and superficial stroma

replaced by basophilic granular deposits

VOGT’s LIMBAL GIRDLE TYPE 1

!! Early calcific band keratopathy

!! Narrow lucent area from the limbus

!! White band contains holes (Swiss cheese) !! Destruction and calcification of Bowman s layer

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VOGT’s LIMBAL GIRDLE TYPE 2

!! Asymptomatic and incidental

!! Lesion is subepithelial

!! Elastotic degeneration and calcium at the level of Bowman’s layer

CORNEAL ARCUS

!! Gerontoxon in the aged (Arcus senilis)

!! Ant. embryotoxon in the young (A. juvenilis)

!! Lipid deposition in the peripheral cornea

!! Cholesterol, cholesterol esters,

phospholipids,neutral glycerides

!! Lipid is extracellular

!! Lipids are of vascular origin

!! Men affected more than women

!! Increased risk of CAD (<40 years)

!! Hyperlipoproteinemia type 2 and3

IRON LINES

!! Iron deposition in the epithelium

!! Several types due to different causes

!! Hudson-Stahli lines (Fleischer, Ferry & Stocker)

!! Prevalence and intensity increase with age

!! Source of iron unknown

!! May be physiological (young people)

!! No sex predilection

!! Asymptomatic and require no treatment

SPHEROID DEGENERATION

!! Climatic droplet keratopathy

!! More than one form

!! Primary age-related

!! Secondary form

!! Traumatic corneal scars

!! Herpetic keratitis

!! Chronic corneal edema

!! Lattice dystrophy

!! Chronic open-angle glaucoma

!! Conjunctival degeneration

!! Pinguecula

SPHEROID DEGENERATION

!! Prevalence related to geography

!! Males affected more than females

!! Usually bilateral, may be unilateral

!! Clinically yellow-gold subepithelial droplets

!! Advance from periphery to the center

!! Foreign body sensation,irritation, VA decrease possible

!! EC proteinaceous material at Bowman’s membrane level and anterior stroma

!! Treatment:

PTK, lamellar KP, lamellar keratectomy

BAND KERATOPATHY

!! Common secondary degeneration

!! Calcium phosphate deposition in the anterior cornea

!! Caused by local or systemic factors

!! Calcium deposition :

!! Intracellular in systemic Ca metabolism abnormalities

!! Extracellular in local ocular disease

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BAND KERATOPATHY

Classification

Chronic ocular diseases

!! Uveitis (juvenile chronic arthritis)

!! Glaucoma

!! Corneal edema

!! Interstitial keratitis

!! Phthisis

Ocular trauma

!! Climatic exposure

!! Mercurial containing preservatives

BAND KERATOPATHY

Classification

Systemic abnormalities

!! Hypercalcemia

!! Hyperphosphatemia

Heredity

!! Norrie’s disease

!! Autosomal recessive band keratopathy

BAND KERATOPATHY

!! Confined to the interpalpebral fissure

!! Peripheral clear zone at the limbus

!! Begins nasally and temporally

!! Swiss cheese appearance (corneal nerves)

!! Histology:

!! Epithelial BM- basophilic staining

!! Bowman s layer /ant. stromal lamellae

- Ca++ deposition and fragmentation

!! Subepithelial fibrous pannus

!! Scarring

BAND KERATOPATHY

!! Ulceration of the corneal epithelium !discomfort

!! Reduced vision (visual axial involvement)

!! Treatment:

Epithelial removal !chelation with Na2EDTA

!mechanical debridement with a blade or burr

LIPID DEGENERATION

!! Accumulation of cholesterol and fatty acid deposits

!! Primary form - rare, usually bilateral

no stromal vascularization

!! Secondary form - more common, leakage from

stromal vessels

LIPID DEGENERATION

!! Deposits around an area of vessels:

!! Crystalline or diffuse

!! Yellow or cream

!! Discrete or fan-like

!! Sudden appearance from NV + VA

!! Causes of corneal NV in lipid degeneration:

!! Corneal trauma

!! Infectious keratitis (HSV or HZV)

!! Interstitial keratitis

!! Spontaneous regression (occasionally)

!! Treatment:

!! Argon laser to the feeding vessel

!! Penetrating keratoplasty

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SALZMANN’S NODULAR DEGENERATION

!! First reported in 1925

!! Rare, noninflammatory, slowly progressive

!! Degeneration characterized by bluish white

nodules elevated above corneal surface (forming circular array)

!! Irregular astigmatism

!! Hyperopic refractive shift

!! Foreign- body sensation

!! Corneal scarring and decreased VA

!! Glare

SALZMANN’S NODULAR DEGENERATION

Late sequelae of previous corneal inflammation

!! Phylectenular keratitis (common)

!! Trachoma (common)

!! Vernal disease (common)

!! Exposure keratopathy

!! Interstitial keratitis

!! Chronic keratitis

!! Idiopathic (rare)

!! Following contact lens wear

!! Postcorneal surgery

!! Epithelial basement membrane dystrophy

Etiology

SALZMANN’S NODULAR DEGENERATION

!! A fibrillar, hyaline degeneration of collagen–

cellular debris.

!! The number of fibrocytes in the affected areas can vary (numerous cells that are active to scarce

degenerating cells)

SALZMANN’S NODULAR DEGENERATION

!! Clear area between the nodules

!!Thinning of the overlying epithelium

!! Basal epithelial cell degeneration

!! Replacement of Bowman s layer by (eosinophilic) material

SALZMANN’S NODULAR DEGENERATION

Treatment Modalities

!! Manual removal

!! PTK with or without MMC

!! Lamellar/penetrating keratoplasty

Bowers Jr PJ et al. J Cataract Refract Surg 2003

Marcon AS, Rapuano CJ Cornea 2002

!! All Salzmann cases are individual in

their appearance and experience is

needed to reach optimal surgical

technique

Schematic drawing of the surgical procedure

!! Tissue removal with a surgical knife

!! Laser ablation to smooth the surface

!! Masking fluid employed several times

Laser ablation

Manual removal

From: Sujata D et al. J Cataract Refract Surg 2005

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SALZMANN’S NODULAR DEGENERATION

Before Treatment After Treatment

From: Sujata D et al. J Cataract Refract Surg 2005

PTK appears to be an effective and

safe procedure for treatment of Salzmann's nodular degeneration

SALZMANN’S NODULAR DEGENERATION

!! Certain lesions cannot be removed by a blade only

!! Lamellar or penetrating keratoplasty require donor

material and are more invasive

!! PK rarely recommended due to good endothelium

!! Lamellar grafting is useful when PTK is not successful

!! Interface haze is a problem in lamellar keratoplasty

!! Mitomycine-C may prevent recurrence, but is toxic

Please keep in mind

TERRIEN’S MARGINAL DEGENERATION

!! Slowly progressive thinning of peripheral cornea

!! Most common in men (3:1)

!! Patient age: 10-70 years

!! Most cases are bilateral (+ asymmetry)

!! Early stages generally asymtomatic

!! Sometimes mild irritation in early stages

!! Induced against- the -rule astigmatism (late stages)

!! Spontaneous or traumatic corneal rupture (rare)

TERRIEN’S MARGINAL DEGENERATION

Deposition of refractile yellowish-white opacities

(superiorly peripheral anterior stroma)

Development of gutter

(parallel to the limbus) Superior or more extensive

corneal thinning

TERRIEN’S MARGINAL DEGENERATION

!! Gutter is steep centrally, shallow peripherally (1)

!! Gutter is 1-2 mm in width

!! The epithelium remains intact

!! Superficial vessels fill the gutter to the central edge

!! Deposition of lipid at the central edge

!! Pseudopterygium development (2)

1

2

TERRIEN’S MARGINAL DEGENERATION

!! Most cases are non-inflammatory

!! Rare cases with corneal and conjunctival

vascular congestion (with moderate to severe pain)

!! Mixed lymphocytic and neutrophil reaction (stroma)

!! Relatively young patients

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TERRIEN’S MARGINAL DEGENERATION

Pathology

A. Limbal side B.Central

!! Stromal thinning

!! Thickened epithelium

!! Loss of Bowman s layer

!! <25% of the resident cells express MHC Class II antigens

!! CD4/CD8 cell ratio!1:1

!! <5% of the infiltrating cells CD22(+) (B cells)

TERRIEN’S MARGINAL DEGENERATION

Differential Diagnosis

!! Arcus senilis (early)

!! Mooren’s ulcer

!! Furrow degeneration

!! Marginal pellucid degeneration

!! Inflammatory peripheral keratitis

!! Peripheral corneal melting (autoimmune)

MOOREN S ULCER

!! Chronic, painful corneal ulceration

!! Two different clinical types:

!! Benign- usually unilateral, older patients

!! Progressive type- 25% of all cases,young patients

!! Starts in the peripheral cornea !circumferential spread

sclera centrally

MOOREN S ULCER

!! Inappropriate immunologic responses

!! Cornea infiltrated by lymphocytes and plasma cells

!! 75% to 100% of the resident cells express

MHC class II antigens

!! CD4/CD8 cell ratio ! 2.4:1

!! 25% to 50% of the infiltrating cells CD22 (+) !B cells

Cheng CL et al. Ophthalmology 2005

TERRIEN’S MARGINAL DEGENERATION

Treatment

!! Observation

!! Astigmatic control with spectacles or contact lenses

!! Surgical treatment:

!! Excision of ectatic tissue and direct closure

!! Eccentric penetrating keratoplasty

!! Crescentic onlay lamellar keratoplasty

Compressive

C-shaped lamellar

keratoplasty

RIGHT EYE BCVA: 6/10 (-5.00 @ 35o)

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RIGHT EYE BCVA: 6/10 (-5.00 @ 35o) SEMILUNAR ONLAY LAMELLAR

KERATOPLASTY

OD

BCVA: 6/10 (+1.50 -6.00 @ 60o)

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in recent years, not only in oncology, but also, for example,in ophthalmology. Drugs such as Bevacizumab (Avastin®),Ranibizumab (Lucentis®), and Pegaptanib (Macugen®) arenow mainstay for treatment of age-related maculopathy, themost common form of adult blindness in industrializedcountries.

There are no licensed antiangiogenic drugs available foruse against human corneal neovascularization yet, so to fi-nally close the circle from the cornea as an in vivo model to thecornea as a place of angiogenic diseases, we can at least usenovel antiangiogenic drugs off-label in patients with sight-threatening corneal angiogenesis. We can now also try topromote corneal graft survival by novel antihem- and espe-cially antilymphangiogenic drugs.17–19

The aim of this review therefore is to (a) highlight the im-portant contributions to angiogenesis research made by Ju-dah Folkman and co-workers, using the cornea as an in vivomodel system, (b) to outline the progress in lymphangiogen-esis research that has been made, again using the cornea asan in vivo model, and (c) finally closing the loop to discusshow this progress in research done at the cornea as a modelcan be used at the cornea as a place for clinically relevant and

sight-threatening neovascular diseases, using, for example, Be-vacizumab (Avastin®) eye drops. In our opinion, this is aperfect example for a successful translational research story,started by Judah Folkman more than 30 years ago, that nowslowly comes back from bench to bedside to treat patientswith sight-threatening corneal neovascularization and topromote corneal transplant survival.

The Cornea as the In Vivo Model System to Study the Mechanisms of Angiogenesis

Judah Folkman established the basis for research into an-giogenesis, not only for tumor angiogenesis, but by using thecornea as a model system also for corneal angiogenesis al-ready in the early 1970s. Since then, the corneal angiogene-sis assay has been one of the best in vivo assays for the eval-uation of factors influencing angiogenesis.20 One reason thatmakes the cornea an ideal object for observing neovascular-ization is its normal lack of vascularity, maintained by different molecular mechanisms (Fig. 1). New vessels caneasily be identified and quantified with the help of comput-erized image analysis programs (Fig. 4). Therefore, the

REGENFUSS ET AL.192

FIG. 1. The normal cornea, the transparent “windscreen” of the eye, is devoid of both blood and lymphatic vessels andtherefore is an ideal model system to study the mechanisms of hemangiogenesis and lymphangiogenesis (A). There is asharp transition from physiologically vascularized conjunctiva to avascular cornea (arrowhead in A and arrows in B. (B)Corneal flatmount stained with CD31 (Ref. 1. Reproduced with permission. © 2006, National Academy of Sciences).

FIG. 2. Pathologic, clinically invisible corneal lymphangiogenesis associated with pathologic, clinically visible angiogen-esis (A) in a vascularized human cornea, as detected by novel specific immunohistochemical markers for lymphatic endo-thelium such as LYVE-1 (B). Lymphatic vessels stained in red, blood vessels stained in green with CD31.

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in recent years, not only in oncology, but also, for example,in ophthalmology. Drugs such as Bevacizumab (Avastin®),Ranibizumab (Lucentis®), and Pegaptanib (Macugen®) arenow mainstay for treatment of age-related maculopathy, themost common form of adult blindness in industrializedcountries.

There are no licensed antiangiogenic drugs available foruse against human corneal neovascularization yet, so to fi-nally close the circle from the cornea as an in vivo model to thecornea as a place of angiogenic diseases, we can at least usenovel antiangiogenic drugs off-label in patients with sight-threatening corneal angiogenesis. We can now also try topromote corneal graft survival by novel antihem- and espe-cially antilymphangiogenic drugs.17–19

The aim of this review therefore is to (a) highlight the im-portant contributions to angiogenesis research made by Ju-dah Folkman and co-workers, using the cornea as an in vivomodel system, (b) to outline the progress in lymphangiogen-esis research that has been made, again using the cornea asan in vivo model, and (c) finally closing the loop to discusshow this progress in research done at the cornea as a modelcan be used at the cornea as a place for clinically relevant and

sight-threatening neovascular diseases, using, for example, Be-vacizumab (Avastin®) eye drops. In our opinion, this is aperfect example for a successful translational research story,started by Judah Folkman more than 30 years ago, that nowslowly comes back from bench to bedside to treat patientswith sight-threatening corneal neovascularization and topromote corneal transplant survival.

The Cornea as the In Vivo Model System to Study the Mechanisms of Angiogenesis

Judah Folkman established the basis for research into an-giogenesis, not only for tumor angiogenesis, but by using thecornea as a model system also for corneal angiogenesis al-ready in the early 1970s. Since then, the corneal angiogene-sis assay has been one of the best in vivo assays for the eval-uation of factors influencing angiogenesis.20 One reason thatmakes the cornea an ideal object for observing neovascular-ization is its normal lack of vascularity, maintained by different molecular mechanisms (Fig. 1). New vessels caneasily be identified and quantified with the help of comput-erized image analysis programs (Fig. 4). Therefore, the

REGENFUSS ET AL.192

FIG. 1. The normal cornea, the transparent “windscreen” of the eye, is devoid of both blood and lymphatic vessels andtherefore is an ideal model system to study the mechanisms of hemangiogenesis and lymphangiogenesis (A). There is asharp transition from physiologically vascularized conjunctiva to avascular cornea (arrowhead in A and arrows in B. (B)Corneal flatmount stained with CD31 (Ref. 1. Reproduced with permission. © 2006, National Academy of Sciences).

FIG. 2. Pathologic, clinically invisible corneal lymphangiogenesis associated with pathologic, clinically visible angiogen-esis (A) in a vascularized human cornea, as detected by novel specific immunohistochemical markers for lymphatic endo-thelium such as LYVE-1 (B). Lymphatic vessels stained in red, blood vessels stained in green with CD31.

PSU6+ Z6( A"561'13%84( 8'%*%8"''7( %*)%.%#'&( 81$*&"'( '72-6"*3%13&*&.%.( "..18%"5&0(?%56( -"561'13%84( 8'%*%8"''7()%.%#'&("*3%13&*&.%.(HQ1)%*)")?"0'4("#%@+5)-4."*)',#*+"A)"0)5+$+'$+5)/B)*,?+()0>+'%&')%..4*,-%0$,'-+.%98"'(2"$B&$.(=1$('72-6"5%8(&*0156&'%/2(./86(".( _`O9D(H!LS(^72-6"5%8()&..&'.(.5"%*&0(%*($&04(#'110()&..&'.(0$"%*+5)%*)C#++*)6%$-)2789=

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cornea offers a good possibility for studying corneal he-mangiogenesis and recently also lymphangiogenesis in vivo.During the last 30 years, Folkman and others achieved manyresults by the help of a corneal angiogenesis assay.

In 1971, Judah Folkman published a paper in the New En-gland Journal of Medicine, where he proposed that, by im-planting a tumor into the corneal stroma, tumor growth isdepending on angiogenesis.9 He hypothesized that a tumorcan only grow beyond a certain size if it gets connected tothe blood system by neovascularization.9 For this hypothe-sis, he had to face a lot of skepticism at this time, but overthe years Folkman and his co-workers supplied evidence forthe theory that now is widely accepted.

In 1972, Michael Gimbrone and Folkman presented newdata collected with the rabbit eye in vivo model to supportthe theory. They demonstrated that small tumor fragmentsimplanted in the anterior chamber did not become vascu-larized and remained at a small size, whereas fragments, im-planted directly on the surface of the iris, introduced neo-vascularization and tumor size increased exponentially.21

Based on these data, they considered the possibility to con-trol tumor growth by preventing tumor-induced angiogen-esis.

In 1974, Gimbrone et al. reported a new experimentalmodel using the rabbit cornea, supporting again that tumorgrowth is angiogenesis dependent. After intrastromal tumorimplantation in the avascular cornea, the tumor size pri-marily increased at a linear rate. But once the tumor got vas-cularized, tumor growth was exponential.22 Using thismodel, several substances isolated from neonatal scapularcartilage,8 shark cartilage,10 and the vitreous7 were found tohave inhibitory effects on the growth of new blood vessels,thereby restricting tumor growth. Similar effects could beshown for medroxyprogesterone, dexamethasone, or corti-sone locally applied in sustained release polymer to rabbitV2 carcinoma that was implanted in the rabbit cornea.23

CORNEAL (LYMPH)ANGIOGENESIS 193

FIG. 3. Concurrent induction of inflammatory hemangiogenesis (B: blood vessels; stained in green: CD31) and lymphangio-genesis (L: lymphatic vessels; stained in red: LYVE-1) in a murine model of corneal inflammatory neovascularization (A–D) (Ref.55. Reproduced with permission. © 2004, American Society for Clinical Investigations). Central, normally avascular cornea is atthe top, physiologically vascularized conjunctiva at the bottom of each picture (segment of murine corneal flatmount).

FIG. 4. Using the cornea to analyze pharmacologic effectsof antiangiogenic and antilymphangiogenic drugs is enabledby precise, stepwise morphometry in the normally avascu-lar cornea with absent vascular background “noise” (A–G).

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cornea offers a good possibility for studying corneal he-mangiogenesis and recently also lymphangiogenesis in vivo.During the last 30 years, Folkman and others achieved manyresults by the help of a corneal angiogenesis assay.

In 1971, Judah Folkman published a paper in the New En-gland Journal of Medicine, where he proposed that, by im-planting a tumor into the corneal stroma, tumor growth isdepending on angiogenesis.9 He hypothesized that a tumorcan only grow beyond a certain size if it gets connected tothe blood system by neovascularization.9 For this hypothe-sis, he had to face a lot of skepticism at this time, but overthe years Folkman and his co-workers supplied evidence forthe theory that now is widely accepted.

In 1972, Michael Gimbrone and Folkman presented newdata collected with the rabbit eye in vivo model to supportthe theory. They demonstrated that small tumor fragmentsimplanted in the anterior chamber did not become vascu-larized and remained at a small size, whereas fragments, im-planted directly on the surface of the iris, introduced neo-vascularization and tumor size increased exponentially.21

Based on these data, they considered the possibility to con-trol tumor growth by preventing tumor-induced angiogen-esis.

In 1974, Gimbrone et al. reported a new experimentalmodel using the rabbit cornea, supporting again that tumorgrowth is angiogenesis dependent. After intrastromal tumorimplantation in the avascular cornea, the tumor size pri-marily increased at a linear rate. But once the tumor got vas-cularized, tumor growth was exponential.22 Using thismodel, several substances isolated from neonatal scapularcartilage,8 shark cartilage,10 and the vitreous7 were found tohave inhibitory effects on the growth of new blood vessels,thereby restricting tumor growth. Similar effects could beshown for medroxyprogesterone, dexamethasone, or corti-sone locally applied in sustained release polymer to rabbitV2 carcinoma that was implanted in the rabbit cornea.23

CORNEAL (LYMPH)ANGIOGENESIS 193

FIG. 3. Concurrent induction of inflammatory hemangiogenesis (B: blood vessels; stained in green: CD31) and lymphangio-genesis (L: lymphatic vessels; stained in red: LYVE-1) in a murine model of corneal inflammatory neovascularization (A–D) (Ref.55. Reproduced with permission. © 2004, American Society for Clinical Investigations). Central, normally avascular cornea is atthe top, physiologically vascularized conjunctiva at the bottom of each picture (segment of murine corneal flatmount).

FIG. 4. Using the cornea to analyze pharmacologic effectsof antiangiogenic and antilymphangiogenic drugs is enabledby precise, stepwise morphometry in the normally avascu-lar cornea with absent vascular background “noise” (A–G).

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temic and topical application of Bevacizumab significantly in-hibited the outgrowth of blood and lymphatic vessels.17 Al-though the binding affinity for murine VEGF is very low, sig-nificant binding could be detected by Western blot analysis,ELISA, and a surface plasmon resonance assay.17 Based onthese in vivo results, Avastin eye drops, now in use off-label inpatients with progressive corneal angiogenesis, should also in-hibit human corneal lymphangiogenesis.

The cornea proved also to be very helpful in defining gen-eral mechanisms of inflammatory lymphangiogenesis.Maruyama and colleagues could identify a novel mechanismwhereby inflammatory lymphangiogenesis takes place,which also adds to the important role macrophages play ininflammatory lymphangiogenesis: Macrophages not only re-lease a whole cocktail of lymphangiogenic growth factors,55

but also physically integrate into newly formed lymphaticvessels.16

Translation of Antihem- and AntilymphangiogenicTherapies into Clinical Use Against CornealNeovascularization

As outlined above, tremendous progress has been madein recent years in understanding the basic mechanisms of

corneal angiogenesis, and very recently also corneal lymphangiogenesis. In parallel, great efforts have beenmade to translate the discoveries in angiogenesis researchinto clinical medicine, primarily in the field of oncology,but also in ophthalmology. VEGF inhibitors such as Bevacizumab (Avastin®), Ranibizumab (Lucentis®), andPegaptanib (Macugen®) are now the mainstay for treatingneovascular forms of age-related maculopathy. They are also widely used off-label for treating diabetic reti-nopathy, retinal venous occlusions, and neovascular glau-coma.

What about inhibiting corneal neovascularization in theclinic? What about translating antiangiogenesis from theprime in vivo model (i.e., the cornea) into clinical therapy?Angiogenesis inhibition at the anterior segment obviouslylags behind antiangiogenesis at the posterior pole of the eye,primarily because of industry support for treatment of age-related maculopathy and the burden of blinding retinal dis-ease for an aging society (age-related maculopathy now isthe most common blinding disease in the elderly in indus-trialized countries). Nonetheless, there are numerous indi-cations for antiangiogenic therapy at the anterior segment,and some have already been addressed in clinical trials orusing the above mentioned anti-VEGF inhibitors off-label.

CORNEAL (LYMPH)ANGIOGENESIS 195

FIG. 5. Inhibition of hemangiogenesis and lymphangiogenesis promotes graft survival after low-risk corneal transplan-tation (Ref. 57. Reproduced and modified with permission. © 2004, IOVS). Inhibition of postoperative hemangiogenesis(green: CD31) and lymphangiogenesis (red: LYVE-1) using a VEGF-A cytokine trap significantly promotes graft survival ina murine model of corneal transplantation. (A) Control. (B) VEGF trap. (C) Survival proportions.

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Indications for antiangiogenesis at the anterior segment in-clude:

1. Inhibition of corneal neovascularization (either beingsight-threatening or being harmful for corneal graft sur-vival),

2. Inhibition of aggressive corneal neovascularization inrecurrent pterygia,

3. Inhibition of corneal conjunctivalization in patientswith limbal stem cell deficiency (e.g., after chemicalburns, or after limbal stem cell transplantation),

4. Modulation of neovascularization and wound healingafter filtering surgery for glaucoma patients, and

5. Inhibition of iris neovascularization causing neovascu-lar glaucoma.

In the following, we will focus on current options and fu-ture perspectives of angiogenesis inhibition at the cornea. Asoutlined above, the normal cornea is devoid of both bloodand lymphatic vessels and actively maintains that avascu-larity against a plethora of minor angiogenic stimuli that thecornea, due to its exposed anatomic position, is constantlyexposed.1 This so-called “angiogenic privilege” of the corneais, for example, responsible for the surprising fact thatcorneal refractive surgery never causes corneal angiogene-sis.

The mechanisms of this corneal angiogenic privilege areredundantly organized and very elaborate, an indicationhow important evolutionary corneal avascularity was. Thereare several lines of defense against corneal neovasculariza-tion:

a. Endogenous inhibitors of angiogenesis are located atthe inner and outer borders of the cornea. These in-clude inhibitors such as angiostatin, endostatin, throm-bopondins, and PEDF, and there are certainly more in-hibitors to be identified.59,60

b. Several highly sophisticated receptor decoy mecha-nisms contribute to corneal avascularity: there is an en-dogenous natural “trap” for VEGF-C and –D (i.e., theectopically expressed VEGF receptor 3 in the cornealepithelium) (Fig. 6).1 Complementary to that trap thereis a soluble form of VEGFR1 also expressed in cornealepithelium which neutralizes VEGF-A.2 In addition,there is a corneal Interleukin 1 receptor antagonist.61

c. The cornea actively tries to prevent hypoxia-driven up-regulation of VEGF, first by low if any expression ofHIF 1 alpha, and second by expression of IPAS, an in-hibitor of hypoxia-driven HIF 1 alpha-signaling.62

Nonetheless, several corneal diseases can lead to patho-logical corneal neovascularization. These can be groupedinto diseases causing corneal inflammation (e.g., bacterialand viral forms of keratitis), diseases interfering with the lim-bal barrier between normally avascular cornea and physio-logically vascularized conjunctiva (Fig. 1; e.g., chemicalburns or inherited forms of limbal deficiency) and finally dis-eases presumably leading to corneal hypoxia (i.e., contactlenses with low oxygen penetration).19 Corneal neovascu-larization is associated with the second most common causeof blindness worldwide (trachoma) and also with the mostcommon form of corneal blindness in industrialized coun-tries (herpetic keratitis). In fact, corneal neovascularizationdoes not only seem to be a sequel of certain inflammatorycorneal diseases, but also may be causative for autoimmuneforms of herpetic keratitis.19

The clinical sequelae of corneal angiogenesis are severalfold: blood vessels growing into the normally avascularcornea reduce corneal transparency and thereby visual acu-ity. Blood vessels do not only cause blindness by themselves,but also by secondary changes caused by immature cornealblood vessels, that is, lipid deposition in the cornea (lipidkeratopathy, Fig. 2), corneal edema and bleeding into thecornea.19 Furthermore, pathologic blood, and especially lym-

REGENFUSS ET AL.196

FIG. 6. Ectopically expressed VEGF receptor 3 in the corneal epithelium (A) (arrows) acts as a natural sink for angiogenicgrowth factors VEGF-C and -D and maintains corneal avascularity by preventing the ligation of these factors to their naturalreceptors on vascular endothelium in the adjacent conjunctiva (B) (Ref. 1. Reproduced and modified with permission. © 2006,National Academy of Sciences); B: with friendly permission from Peter Mallen, Schepens Eye Research Institute, Boston).

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phatic vessels growing into the cornea, significantly impairthe prognosis of a corneal transplantation performed intosuch a cornea afterwards.3,4,57 Whereas non-HLA-matchedgrafts placed into an avascular, so-called low-risk recipientbed enjoy a 5-year survival of around 90%, the survival ratein pathologically prevascularized, so-called high-risk recip-ient corneas drops to below 50%. Several of these high-riskeyes are not even operated on because of the poor progno-sis.3,4,57

Recently, in addition to corneal hemangiogenesis, wecould demonstrate the presence of pathological and clinicallynonvisible corneal lymphatic vessels in human vascularizedhigh-risk corneas.5 Immunologically, these lymphatic vesselsact as the afferent arc of the immune reflex circle and enabledirect access of donor-derived antigen-presenting cells andantigenic material to the regional lymph node, where an im-mune responses is mounted. Consequently, pre-existingpathologic blood (and clinically invisible lymphatic vessels)constitute the strongest predictor for immune rejections af-ter keratoplasty. In addition, we could recently demonstratethat also corneal hem- and lymphangiogenesis occurringonly after keratoplasty (both in the low-risk as well as in thehigh-risk setting) significantly increase the risk of immunerejections.56,57 Consequently, novel antihem-/anti-lymhan-giogenic therapies could significantly promote the survivalof corneal grafts, both in the murine model of low-and high-risk keratoplasty.15,57,56 This proved the general feasibilty ofthe new therapeutic concept of immunomodulation byanti(lymph)angiogenic therapy.

Therefore, we and others have focused on how to targetpathologic corneal hem- and especially lymphangiogenesis,both causing blindness as well as deteriorating corneal graftsurvival (both pre-and post corneal transplantation). For thelatter purpose, specific inhibitors of lymphangiogenesis aredesirable, since these would probably not interfere withcorneal wound healing. Because especially in the context ofcorneal inflammation, hem- and lymphangiogenesis areclosely interrelated,55 it was so far difficult to specifically tar-get lymphangiogenesis without affecting hemangiogenesis.As outlined above, we and others have recently describedseveral new pharmacological approaches to (relatively)specifically target inflammatory corneal lymphangiogenesis.These approaches include:

a. Blocking peptides against integrins expressed on lym-phatic vascular endothelial cells.58 We could show thatblocking peptides against integrin alpha 5, being ex-pressed on lymphatic vascular endothelium in vivo, atcertain concentrations relatively specifically block lym-phangiogenesis without affecting hemangiogenesis.58

b. Blocking antibodies against the lymphatic vascular en-dothelial specific VEGF receptor 3 also have beenshown to relatively specifically block inflammatorylymphantiogenesis without affecting hemangiogene-sis.48

None of these approaches have yet entered clinical trialsfor use in patients, but they are promising tools for a (rela-tive) specific blockade of lymphangiogenesis in the contextof corneal transplantation to promote graft survival.

The current options for corneal angiogenesis inhibition inthe clinic primarily include indirect antiangiogenic agents

such as anti-inflammatory steroids and cyclosporine A. Theonly specific antiangiogenic treatment options available are:

a. The off-label use of anti-VEGF agents such as Beva-cizumab (Avastin®), Ranibizumab (Lucentis®), and Pe-gaptanib (Macugen®), which have been licensed for either anticancer and/or intravitreal use against age-related maculopathy, and

b. The use of antisense oligonucleotide eye drops againstinsulin receptor substrate 1 (IRS-1) in the frameworkof a European multicenter study.

In direct continuation of Folkman and colleagues’ experi-mental studies on the role of VEGF in corneal neovascular-

CORNEAL (LYMPH)ANGIOGENESIS 197

FIG. 7. Avastin (Bevacizumab) eye drops potently stop pro-gressive corneal angiogenesis, lead to partial regression ofimmature blood vessels and reduced perfusion of matureblood vessels (Ref. 10. Reproduced with permission. © 2007,Springer Verlag). (A) prior to and (B) 4 weeks after addi-tional therapy with Avastin eye drops five times a day in apatient with progressive corneal neovascularization afterlimbal stem cell deficiency.

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ization, anti-VEGF pharmacological strategies such as Beva-cizumab (Avastin®) translate that concept into clinical ap-plication. Indeed, initial experimental studies using severalanimal models do support an important inhibitory effect ofBevacizumab, Lucentis, and Macugen on corneal neovascu-larization (Fig. 7).63–70 Avastin eye drops and Lucentis eyedrops in addition have been shown to inhibit corneal lym-phangiogenesis in animal models.17,70

The initial clinical experience of using Avastin eye dropsor subconjunctival injections also suggests that approach tobe a promising tool to target pathologic corneal neovascu-larization in the clinic.18,71–74 Our initial patients beingtreated with Avastin eye drops off-label for pathologiccorneal neovascularization unresponsive to conventionaltherapy showed a significant, but also very variable, re-sponse to additional Avastin eye drops when neovascular-ization was analyzed morphometrically on standardizeddigitized slit-lamp pictures.18 All other published case re-ports or small case series support the concept of Avastin eyedrops or subconjunctival applications being relatively effec-tive (no controlled trials available yet) and relatively safe (noproper safety studies available yet).48,71–74 Therefore,prospective randomized studies are necessary to define in-dications, safety, and effectiveness of that approach in in-hibiting corneal neovascularization.

For the other two off-label available anti-VEGF agents,there is much less known about their effect on human corneal

neovascularization. Preclinical data show both of them being active against corneal neovascularization, withRanibizumab, as said above, also being active against corneallymphangiogenesis.70 A prospective, multicenter, random-ized European phase IIb study at the moment is investigat-ing the efficacy and tolerability of an antiangiogenic antiseneoligonucleotide against IRS-1 applied as eye drops twicedaily. Initial interim results suggest the compound to be safeand effective.

What about the safety of topical neutralization of VEGF atthe ocular surface? Although the limited evidence from pub-lished off-label clinical use of anti-VEGF therapies (primar-ily Bevacizumab)18,48,71–74 as well as from in vivo and in vitrosafety studies suggest this specific antiangiogenic approachto be safe, several potential complications have to be kept inmind and observed thoroughly in future studies. If onededucts potential side effects from the known physiologicalfunctions of VEGF in the cornea or in the anterior segmentof the eye, several potential side effects come into play, es-pecially given the “nonangiogenic” effects of VEGF, that is,its neurotrophic effect, its role in wound healing and in-flammation:

a. Neurotrophic keratopathy: the cornea is one of themost densely innervated tissues of the human bodyand we know now that VEGF is a potent neurotrophicgrowth factor.75 Physiologically, there are trace

REGENFUSS ET AL.198

FIG. 8. Essential role of VEGF-A in immune amplification as evidenced from inflammatory corneal neovascularizationmodels (Ref. 55. Reproduced with permission. © 2004, American Society for Clinical Investigation). Early depletion of ei-ther VEGF-A or macrophages completely stops the immune-amplification cascade, leading to inflammatory corneal hem-and lymphangiogenesis. VEGF-A has an indirect lymphangiogenic effect via macrophage recruitment.

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A

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A

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A

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A

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1438 www.thelancet.com Vol 367 April 29, 2006

We compared a combination of measures of refraction and visual acuity. Fortunately, these variables are primary outcomes in almost all studies of laser vision correction. Manifest refraction spherical equivalent is the amount of refractive error that remains after ablation, and combines both the spherical and astigmatic correction. Manifest refraction spherical equivalent thus measures the ability of the laser refractive procedure to reach the target refraction. We analysed postoperative manifest refractive spherical equivalents to determine the percentage of patients whose residual refractive error fell within about 0·50 D or about 1·0 D of the target error. Visual acuity is a subjective measure of the patient’s ability to resolve objects (usually letters) at under defi ned lighting conditions. Although this measure does not necessarily replace the patient’s visual function in his or her environment, it does provide a standardised way to assess the success of the procedure. The number of patients with uncorrected visual acuities of 20/20 (normal perfect vision) or more and of 20/40 (functional vision usually allowing the patient to drive without glasses) or more was analysed in this review. A loss of best spectacle-corrected visual acuity of more than two

lines on the Snellen chart was used to measure negative outcomes for the procedures. Our results are shown in fi gures 1–3. Published results were obtained by the following criteria: (1) randomised prospective study (n!25, follow-up period !3 months), (2) controlled prospective study (n!50, follow-up period !3 months), and (3) case series (n!100, follow-up period !6 months). However, it should be noted that even though the Snellen chart-based visual acuity has been judged as the standard method of assessing the outcomes of ophthalmic surgery, the variables mentioned above might not be enough to assess the satisfactory functional visual outcomes after refractive surgery. Laser refractive surgery can cause higher-order aberrations, such as glare, halo, or night-vision disturbance, and other variables such as contrast sen sitivity, and scotopic and mesopic vision. Wavefront aberrometres will probably have a greater role in measuring outcomes.

LASIK outcomesLow to moderate myopia (conventional laser ablation)Those with low (–4 D or less) or moderate (–4 D to –7 D) myopia represent the largest population of patients undergoing laser refractive surgery. They represent the

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Figure !: Visual outcomes of LASIK for myopia at 3–6 months after surgeryUCVA=uncorrected visual accuity. MRSE=manifest refraction spherical equivalents. For every assessment, results for low myopia with error 0 to –7 D (individual ranges and grouped) compared with high myopia with refractive error –7 D to –12 D.37–45, 50–61

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Review

www.thelancet.com Vol 367 April 29, 2006 1439

largest proportion of the general population; also, patients with higher myopia might not qualify as candidates for laser surgery. In view of the preponderance of low to moderate myopia, it is not surprising that the fi rst FDA-approved use of the excimer laser for LASIK was for these patients.

Grouped data from the FDA-approved laser platforms (LADAR Vision, Alcon, Fort Worth, TX, USA; EC5000, NIDEK, Gamagori, Japan; S2 & S3, VISX, Santa Clara, CA, USA; Technolas 217a, Bausch & Lomb, Rochester, NY, USA; Allegretto Wave, WaveLight, Sterling, VA, USA)37–42 for low to moderate myopia showed manifest refraction spherical equivalent within about 1·00 D of 96% and within about 0·50 D of 81%. Similarly, uncorrected visual acuities better than 20/40 were measured in 96%, although 72% of patients had vision equal to or better than 20/20. A loss of best spectacle-corrected visual acuity of more than two lines was noted in just under 1·0% of patients.

Comparison of the FDA data with other studies revealed similar outcomes with respect to e! cacy. Combined data from the non-FDA dataset show manifest refraction spherical equivalent within about 1·00 D of 94% and within about 0·50 D of 79%. About 95% of patients were 20/40 or better and 67% were

20/20 or better uncorrected. These other studies did, however, have a higher rate of best spectacle-corrected visual acuity loss totalling more than 2·3%. These overall excellent success rates explain the popularity of laser refractive surgery.

High myopia (conventional laser ablation)With the larger degree of refractive error and the concomitant need to remove more tissue in higher myopia, this group of patients is often analysed separately when measuring outcomes of refractive surgery. In the high myopia group, FDA data showed manifest refraction spherical equivalent within about 1·00 D of 80% and within about 0·50 D of 61%. Although 89% of patients were 20/40 or better, less than half (48%) achieved 20/20 or better. A loss of best spectacle-corrected visual acuity of greater than two lines was recorded in only 1% of patients.

Similarly, combined data from the non-FDA dataset showed manifest refraction spherical equivalent within about 1·00 D of 79% and within about 0·50 D of 59%. 94% of patients were 20/40 or better; 64% were 20/20 or better. Compared with FDA data, a loss of best spectacle-corrected visual acuity of more than two lines was noted in a higher rate of 2% of patients.

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Comparison of low to moderate versus high myopiaIn general, we might expect less accuracy and larger wound-healing e! ects with the deeper ablations. As the depth decreases, the cornea might also be destabilised, and this instability can further retard the ability to reach a target refraction. With the FDA data, a comparison of manifest refraction spherical equivalent between low-to-moderate and high myopia after LASIK shows a larger residual refractive error in high myopia. The di! erence between the low-to-moderate myopia of 96% within about 1·00 D and high myopia with 80% was even more indicative when accuracy to within manifest refraction spherical equivalent of about 0·50 D was analysed (81% for the lower myopic group and 61% for the higher myopic group).

This trend was also noted in the analysis of FDA data on fi nal uncorrected visual acuities. For the less myopic group, acuity of at least 20/40 was achieved in 96% of patients as compared with only 89% of the high myopia group. Again, the di! erence is even more pronounced when better acuities are examined. Less than half (48%) of patients with high myopia achieved acuities of 20/20 or better with LASIK; however, almost 72% of lower myopia achieved this excellent acuity level. Similar analysis of non-FDA data provided similar outcomes.

The cut-o! point between low-to-moderate and high myopia has been used in published work as a distinction, but these degrees of myopia are somewhat arbitrary. In a subgroup analysis of the FDA data, we noted that correlation between the degree of initial refractive error and the level of residual myopia and poorer acuity was fairly linear, even with the low-to-moderate group. In general, patients with higher degrees of myopia should be told that their likelihood of reaching perfect vision is less than in patients with lower myopia.

The rate of best spectacle-corrected visual acuity loss was essentially the same for all myopic groups. This fi nding suggests that although the improvement in vision and refractive error might be less for high myopes, the procedure is still likely quite safe in this group. Long-term studies are needed to ascertain the true risk for the high myopes who undergo greater tissue removal. This greater tissue removal might be expected to destabilise the cornea and allow for ectasia and worsening of outcome in susceptible individuals. Data collected at 10-year or 20-year follow-up would allow for a better analysis of this potential occurrence.

Wavefront-guided LASIK (custom laser ablation) for myopiaWavefront aberrometers represent a major advance in our ability to measure subtle, yet visually substantial, optical defects. The outcomes for wavefront-guided LASIK in myopia have been investigated by the FDA for three separate laser platforms. In view of the fewer numbers of non-FDA studies, the di! ering outcome measurements, and follow-up for these studies, only the FDA data are presented here.

Grouped data from the FDA-approved wavefront-guided laser platforms (LADAR Vision; Technolas 217z; and Star S4 and Wavescan Wavefront System, VISX, Santa Clara, CA, USA, and Bausch & Lomb Technolas 217z)43–45 for low to moderate myopia showed manifest refraction spherical equivalent within about 1·00 D in 96% of eyes and within within 0·50 D in 81%. Uncorrected visual acuities better than 20/40 were measured in 98%, and 89% of patients had vision equal to or better than 20/20. A loss of best spectacle-corrected visual acuity of more than two lines was recorded in only 0·5% of patients. Wavefront-guided LASIK seems to be most successful in patients who have low myopia, especially for uncorrected visual acuities better than 20/20. 95% of the patients up to –2 D achieved 20/20 or better, as did 91% in the range –2 to –4 D.

Comparison of wavefront-guided versus conventional laser ablation for myopiaWhether the additional information obtained with wavefront-guided treatments is translated into better ablations and improved acuity compared with conventional LASIK can be determined by comparing the FDA trials data. A marked di! erence in uncorrected visual acuities of 20/20 or better was seen between wavefront-guided and conventional treatments. In wavefront-guided LASIK, 89% of patients achieved this level of vision. By contrast, with conventional treatment, patients reached 20/20 or better only 72% of the time. These di! erences were not seen with the 20/40 or better acuity outcome.

There are no substantial di! erences in postoperative manifest refraction spherical equivalent between conven-tional and custom treatments. How can one reconcile the similar refractive outcomes in both treatments with the

Custom FDA studiesNon-custom FDA studiesOther studies (non-custom)

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Review

1442 www.thelancet.com Vol 367 April 29, 2006

or better than 20/20. A loss of best spectacle-corrected visual acuity of more than two lines was recorded in 0% of patients.

Outcomes of LASIK for presbyopiaPresbyopia is an age-related refractive condition in which the eye is no longer able to focus over a broad enough range to allow for both functional near and distance vision. Laser vision correction is unable to correct this condition per se, but can be harnessed to create corneal multifocality and pseudoaccommodation. Attempts to create multifocal corneas using new ablation profi les during LASIK surgery are under investigation in France and South America,72,73 and hold promise as future techniques to treat presbyopia.

LASIK surgery can, however, treat the symptoms of presbyopia through the use of a technique termed monovision.74–76 In monovision, the distance refraction for one eye is emmetropic and the distance correction for the second eye is myopic; one eye is set for distance vision and the other for nearer vision. In phakic patients who still have some degree of accommodation, albeit insu! cient for their needs, the near eye need not be corrected (or left untreated) at a level of myopia for near alone (about –2·75 D), but instead can be only mildly near-sighted. The outcomes for monovision treatment are dependent not only on the ability of the laser to accurately reach the target refraction, but also on the patient’s ability to adjust to anisometropia and the slight decrement in visual acuity and depth perception that arises from the di" erent focal points in each eye. Therefore, the preoperative use of monovision contact lenses might be useful.

There are no FDA trials for the use of LASIK for monovision. Non-FDA data suggest that about 80% of patients will make the adjustment to monovision, and that most patients will adapt to monovision within 3–4 weeks. Perhaps the most important factor for obtaining good outcomes with this technique is proper selection of patients and adequate counselling before the procedure. Patients must understand that improved functional vision, if it does arise, will come only after the adaptation period, and that it comes at some price to both near and distance acuity. When the patient is unhappy,

the undercorrected eye can undergo either enhancement (re-treatment) or initial treatment (when the myopic eye was untreated) to balance the eyes. The patient will then need to use reading glasses for near tasks.

Outcomes of surface ablations (photorefractive keratectomy and LASEK)Surface ablation (photorefractive keratectomy) was the fi rst ablative refractive surgical technique approved by the FDA. Although photorefractive keratectomy came into some disfavour during the late 1990s, surface ablation has seen a partial resurgence for the treatment of refractive error in patients with thinner corneas and low to moderate myopia, as a result of the avoidance of lamellar fl ap creation and its associated risks. The improvements in the laser systems can also improve outcomes achieved by surface ablation. The LASEK procedure represents a modifi cation of the original photorefractive keratectomy procedure in which the patient’s epithelium is retained (by making an epithelial fl ap) instead of removed.

The original FDA studies for photorefractive keratectomy were undertaken in 1995,77 and used laser systems that did not have capabilities of lasers today—eg, advanced soft-ware, accurate eye-tracking, and larger ablation zones. In view of the limitations of the lasers used in these studies, analysis of the FDA data alone for photorefractive keratectomy is not likely to yield useful results for today’s patients. No FDA trial for the LASEK procedure has been done.

The available data suggest that surface ablation achieves results similar to LASIK. Table 1 provides cumulative data for photorefractive keratectomy and LASEK techniques.30,50–52,56,57,78–91 Combining all myopia, photo-refractive keratectomy achieves best spectacle-corrected visual acuity of 20/20 or more in 61% of patients and of 20/40 or more in 94%, and LASEK achieves best spectacle-corrected visual acuity of 20/20 or more in 74% of patients and of 20/40 or more in 94%. For manifest refraction spherical equivalent, photorefractive kerate ctomy has a postoperative value of about 0·50 D in 71% of cases and LASEK in 74% of cases. From a refractive standpoint, the techniques seem very similar.

Myopia Hyperopia

PRK50–52,56,57,78–85 LASEK78,79,85–88 PRK30,89–91 LASEK89

Visual range –1 to –13·0 D –1 to –12·5 D +1 to +5 D +2 to +5 D

UCVA =20/20 2559/4184 (61·1%) 471/637 (73·9%) 474/630 (75·2%) 79/108 (73·1%)

UCVA =20/40 3877/4112 (94·3%) 361/382 (94·5%) 594/682 (87·1%) 98/108 (90·7%)

Within about 0·5 D of MRSE 2965/4158 (71·3%) 451/610 (73·9%) 481/682 (70·5%) 82/108 (75·9%)

Within about 1·0 D of MRSE 3748/4158 (90·1%) 482/538 (89·6%) 581/682 (85·2%) 99/108 (91·7)

Loss of =two lines of BCVA 3/517 (0·6%) 13/610 (2·1%) 14/682 (2·1%) 0/108 (0·0%)

UCVA=uncorrected visual acuity. MRSE=manifest refraction spherical equivalent. BCVA=best spectacle-corrected visual acuity. Data are number (%) unless otherwise indicated. For PRK studies, data published after January, 2000, only were collected.

Table !: Cumulated outcomes of photorefractive keratectomy (PRK) and LASEK for myopia and hyperopiaN$/5#+W<+G'7'5$0#,+ 1'0)17#3+ 1;+ F*101"#;"$)0.2#+ %#"$0#)017D+ iB:Tj+ $(,+ &QKOT+ ;1"+ 7D1F.$+++ $(,+*DF#"1F.$

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Review

www.thelancet.com Vol 367 April 29, 2006 1443

In comparative studies, LASIK and surface ablation have similar outcomes. The lower values for best spectacle-corrected visual acuity and manifest refraction spherical equivalent listed above for the surface ablation techniques might be the result of inclusion of high myopia. These higher myopia treatments, as discussed in the LASIK outcomes section, in general have poorer and less predictable results. Deep ablations for high myopia via surface ablation also have a greater tendency to produce stromal haze during the wound-healing process and thus might lead to poorer results. Indeed, most surgeons prefer not to do surface ablations in higher myopia; when they do treat these patients on the surface, they often use wound-healing biomodulators such as mitomycin C. We advise caution in using these biomodulators, since each has its own complications, and the long-term sequelae of their use for refractive surgery are not well understood. Indeed, evidence suggests the loss of stromal keratocytes after application of mitomycin C.92

Complications and managementSerious complications from refractive surgery are rare, as evidenced by the low rate of loss of best spectacle-corrected visual acuity. However, as with any surgery, complications might occur either intraoperatively or postoperatively.93 Risk-benefi t calculations of surgery are somewhat di! erent for refractive surgery, since procedures are generally done electively in healthy eyes with excellent visual potential.

Intraoperative complicationsThe creation of an intralamellar fl ap during the LASIK procedure increases the risk of intraoperative complica-tions. The complications of LASIK are listed in table 2.94–116 In general, di" culties associated with intra operative fl aps arise because of issues related to micro keratome function—eg, malfunctions of the micro keratome assembly (loss of suction, poor blade oscillation, or inter-rup tion of keratome movement) or abnormally steep (button-hole formation) or fl at (free-cap) patient cornea. The femtosecond laser has fewer problems in terms of creating irregular cuts, and managing irregular cuts created with the laser is less di" cult. However, femtosecond laser has the potential to induce di! use lamellar keratitis. Use of topical corticosteroids keeps the incidence and severity of di! use lamellar keratitis to a manageable level. Depending on the severity and type of complication associated with fl ap creation, a surgeon can either ablate the cornea as planned or abort the proce dure with the possibility of a future surface ablation.

For surface ablation, intraoperative complications are rare, and complications that do arise are usually not serious. If a LASEK epithelial sheet is torn or deranged, the procedure can revert to photorefractive keratectomy.

Postoperative complicationsDry eye is the most frequent complication after refractive surgery, particularly in LASIK surgery, in which the

corneal nerves are severed during the creation of the fl ap. Re-innervation in the subepithelial and anterior stroma is reduced by almost half, even 3 years after LASIK.117 The condition is often transient and tends to improve over weeks to months. For symptomatic patients, topical treatments—such as artifi cial tears—are used and punctal occlusion, a procedure whereby a plug is inserted in the lacrimal punctum to reduce tear outfl ow from the ocular surface to the nose via the lacrimal drainage system, is done for more severe cases.

The LASIK fl ap re-adheres initially as a result of deturgescence of the cornea, but actual collagen deposition and wound healing is quite slow (this, in part, allows the cornea to remain free from scarring). As such, the fl ap might be displaced in the days, weeks, or even months after the procedure. The risk of fl ap slippage is greatest in the immediate postoperative period, and can be caused by eye rubbing or lid squeezing. After several months, a substantial shearing force with a vector tangential to the ocular surface is usually needed to displace a fl ap. Displaced fl aps should be lifted and irrigated, and striae should be ironed out.

Epithelial ingrowth into the lamellar interface might occur if the fl ap edge is not well opposed. The ingrowth has the potential to reduce visual acuity and cause melting of the stroma as a result of enzymes secreted from the epithelial cells. If epithelial ingrowth occurs in the visual axis, or signs of stroma melting are noticed, irrigation and scraping of the fl ap interface should be done.

Postoperative scarring and haze is more common after surface ablation than LASIK, particularly in deeper ablations for higher degrees of myopia. Often a fi ne reticular haze can be seen at the slit lamp, but there are no visual consequences. Visually pronounced haze might occur in 1–2% of patients with high myopia. This haze

FDA trials* Non-FDA studies†

Epithelial defect94–98 0·50% 5·0–22·6%

Lamellar keratitis99–105 0·99% 0·2–3·2%

Haze99,106,107 0·57% 1·8–6·2%

Flap folds99,100 1·00% 0·2–1·1%

Thin fl ap99,100,108 0·42% 0·08–0·75%

Free-cap99,100,108 3·40% 0·08–1·00%

Irregular fl ap99,100 n/a 0·09–0·2%

Buttonholed fl ap99,100,108 n/a 0·13–0·56%

Incomplete fl ap99,100,108 n/a 0·23–0·75%

Dislodged fl ap99,100 0·22% 1·1–2·0%

Epithelial ingrowth99,100,109–111 0·14% 0·33–9·1%

Debris106,112,113 3·31% 1·9–100%

Infectious keratitis100,107,114,116 0·0% 0–0·2%

Ectasia116 0·0% 0·2%

n/a=not available. *Include studies of wavefront-guided LASIK for myopia, LASIK for myopia, and LASIK for hyperopia. †Include complications reported in studies of 1000 people or more and in reports focusing on specifi c complications. Data are proportion of patients a! ected.

Table !: LASIK complications

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7

Quality of Vision after Refractive Surgery

Dimitri T. Azar, MDB.A. Field Endowed Chair,

Professor and Head,Department of Ophthalmology

and Visual Sciences,Illinois Eye and Ear Infirmary,

University of Illinois at Chicago

Non-Custom LASIK

1. Measurement of spherocylindrical error2. Flap dissection with microkeratome & 3. photoablation with excimer laser

Number of LASIK Procedures in US1998 430,0001999 800,0002000-2007 (projected) 1.5-2 mil./yr

Complication rate 0.5% - 2%

Mechanical complications relate to the flap Optical complications relate to decentration, optical

zone size, positive asphericity, and uncorrected HOA

7

Quality of Vision after Refractive Surgery

Dimitri T. Azar, MDB.A. Field Endowed Chair,

Professor and Head,Department of Ophthalmology

and Visual Sciences,Illinois Eye and Ear Infirmary,

University of Illinois at Chicago

Non-Custom LASIK

1. Measurement of spherocylindrical error2. Flap dissection with microkeratome & 3. photoablation with excimer laser

Number of LASIK Procedures in US1998 430,0001999 800,0002000-2007 (projected) 1.5-2 mil./yr

Complication rate 0.5% - 2%

Mechanical complications relate to the flap Optical complications relate to decentration, optical

zone size, positive asphericity, and uncorrected HOA

5

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Tear FilmEpitheliumBowman’s

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Stroma

Endothelium

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Optical complications may be reduced with custom LASIK and newer technologies of laser delivery

LASIK Limitations

!Potential Flap­related Complications

!Custom corneal limitations

!Ectasia

P

Mechanical complications may be reduced with newer technologies

# )&'*.(/'('*-(-0(1*'/.*1(+=D<ER /=H?;=+%+?J<";#=%H>)A%V)<<)A%)H%@*"JJ%"DD*";"<?);%JL>H"#=%

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Optical complications may be reduced with custom LASIK and newer technologies of laser delivery

LASIK Limitations

!Potential Flap­related Complications

!Custom corneal limitations

!Ectasia

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8

Corneal Ectasia in Myopia

Preexisting KCDeep flap

High myopiaDeep laser ablation

(Ectasia is more likely to occur after LASIK)

Potential Complications in Patients with Coexistent Keratoconus and Fuchs’ Dystrophy

Case 1. Top, Orbscantopography showed advanced inferior steepening consistent with keratoconuschanges on the right eye (OD), despite a diffusely thick cornea. Slit-lamp photography showed corneal guttae. Specularmicroscopy was unable to provide an image of the eye due to corneal edema. Bottom, Orbscantopography showed inferior steepening consistent with keratoconus. Specularmicroscopy of the left eye (OS) captured multiple guttae, with inability to perform cell counts. N = nasal; T = temporal.

Jurkunas U, Azar DT. Ophthalmology. 2006 Dec;113(12):2187-97.

8

Corneal Ectasia in Myopia

Preexisting KCDeep flap

High myopiaDeep laser ablation

(Ectasia is more likely to occur after LASIK)

Potential Complications in Patients with Coexistent Keratoconus and Fuchs’ Dystrophy

Case 1. Top, Orbscantopography showed advanced inferior steepening consistent with keratoconuschanges on the right eye (OD), despite a diffusely thick cornea. Slit-lamp photography showed corneal guttae. Specularmicroscopy was unable to provide an image of the eye due to corneal edema. Bottom, Orbscantopography showed inferior steepening consistent with keratoconus. Specularmicroscopy of the left eye (OS) captured multiple guttae, with inability to perform cell counts. N = nasal; T = temporal.

Jurkunas U, Azar DT. Ophthalmology. 2006 Dec;113(12):2187-97.

@?

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Potential Complications in Patients with Coexistent Keratoconus and Fuchs’ Endothelial Dystrophy

Case 2. Top, Orbscantopography showed inferior steepening of the right eye (OD) consistent with keratoconus. Slit-lamp photography showed multiple guttae. Specular microscopy was unable to provide an image. Bottom, Orbscantopography showed inferior steepening of the left eye (OS). Corneal guttae were noted on slit-lamp photography. Specular microscopy was unable to provide an image of the eye. N = nasal; T = temporal.

Jurkunas U, Azar DT. Ophthalmology. 2006 Dec;113(12):2187-97.

Ectatic Disorders Associated with a Claw-Shaped Pattern on Corneal Topography

Lee BW, Jurkunas UV, Harissi-Dagher M, Poothullil AM, Tobaigy FM, Azar DT. Am J Ophthalmol. 2007 Jul;144(1):154-156.

Y

Potential Complications in Patients with Coexistent Keratoconus and Fuchs’ Endothelial Dystrophy

Case 2. Top, Orbscantopography showed inferior steepening of the right eye (OD) consistent with keratoconus. Slit-lamp photography showed multiple guttae. Specular microscopy was unable to provide an image. Bottom, Orbscantopography showed inferior steepening of the left eye (OS). Corneal guttae were noted on slit-lamp photography. Specular microscopy was unable to provide an image of the eye. N = nasal; T = temporal.

Jurkunas U, Azar DT. Ophthalmology. 2006 Dec;113(12):2187-97.

Ectatic Disorders Associated with a Claw-Shaped Pattern on Corneal Topography

Lee BW, Jurkunas UV, Harissi-Dagher M, Poothullil AM, Tobaigy FM, Azar DT. Am J Ophthalmol. 2007 Jul;144(1):154-156.

Z

Surface Ablation?

!Potential Flap­related Complications

!Custom corneal limitations

!Ectasia

Surface Ablation, Combined with MMC, May Overcome Several Limitations of Phakic IOLs

!Shallow AC

!Low initial endothelial cell counts

!Progressive endothelial cell loss

!Cataract formation

!Serious Intraoperative/Postoperative Complications

Z

Surface Ablation?

!Potential Flap­related Complications

!Custom corneal limitations

!Ectasia

Surface Ablation, Combined with MMC, May Overcome Several Limitations of Phakic IOLs

!Shallow AC

!Low initial endothelial cell counts

!Progressive endothelial cell loss

!Cataract formation

!Serious Intraoperative/Postoperative Complications

:

# Retrospective, nonrandomized, control-matched study# The charts of 2257 eyes that underwent LASEK or LASIK

treatment were reviewed. # Inclusion criteria: patients who were 21 years of age or

older having between !0.75 and !6.00 diopters (D) of myopia with up to !2.25 D of astigmatism.

# One hundred twenty-two LASEK-treated eyes were matched with 122 LASIK-treated eyes having preoperative spheres, cylinders, and SE within ±0.50 D.

# Both groups had similar preoperative best spectacle-corrected visual acuity (BSCVA), laser platform, and follow-up durations.

Tobaigy FM, Ghanem RC, Sayegh RR, Hallak JA, Azar DT. Am J Ophthalmol. 2006; 142(6): 901-8

Control-Matched Comparison of LASEK and LASIK

Control-Matched Comparison of LASEK and LASIK

Line Loss/Gain of 122 LASEK Eyes Matched with 122 LASIK Eyes

9'9 9'Z9'9 9'Z

5W'P

8Y'5

W'Y:'9

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% o

f Eye

s

S301O S30BO

Postoperative results: Mean SE was !0.15 ± 0.40 D

for LASEK and !0.37 ±0.45 D for LASIK

Mean logMAR of BSCVA was !0.03 ± 0.06 (20/19) for LASEK and !0.02 ± 0.05 (20/19) for LASIK.

No eye lost 2 or more lines of BSCVA in both groups.

506&/78 9:;($<&+*=(>?;(@&8*7< >>;(A&%%&B(!3-3`"> /&'%3A%!%GDE<E"*A)*'%5998j%7P5^8_C%:97iZ

:

# Retrospective, nonrandomized, control-matched study# The charts of 2257 eyes that underwent LASEK or LASIK

treatment were reviewed. # Inclusion criteria: patients who were 21 years of age or

older having between !0.75 and !6.00 diopters (D) of myopia with up to !2.25 D of astigmatism.

# One hundred twenty-two LASEK-treated eyes were matched with 122 LASIK-treated eyes having preoperative spheres, cylinders, and SE within ±0.50 D.

# Both groups had similar preoperative best spectacle-corrected visual acuity (BSCVA), laser platform, and follow-up durations.

Tobaigy FM, Ghanem RC, Sayegh RR, Hallak JA, Azar DT. Am J Ophthalmol. 2006; 142(6): 901-8

Control-Matched Comparison of LASEK and LASIK

Control-Matched Comparison of LASEK and LASIK

Line Loss/Gain of 122 LASEK Eyes Matched with 122 LASIK Eyes

9'9 9'Z9'9 9'Z

5W'P

8Y'5

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% o

f Eye

s

S301O S30BO

Postoperative results: Mean SE was !0.15 ± 0.40 D

for LASEK and !0.37 ±0.45 D for LASIK

Mean logMAR of BSCVA was !0.03 ± 0.06 (20/19) for LASEK and !0.02 ± 0.05 (20/19) for LASIK.

No eye lost 2 or more lines of BSCVA in both groups.

506&/78 9:;($<&+*=(>?;(@&8*7< >>;(A&%%&B(!3-3`"> /&'%3A%!%GDE<E"*A)*'%5998j%7P5^8_C%:97iZ

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79

Conclusions:# Although there were some differences in the

visual and refractive results favoring LASEK, they were not clinically significant.

# Both procedures seemed safe, effective, and predictable for the treatment of low and moderate myopia.

# Nomogram adjustment may be necessary for LASIK surgeons adopting surface ablation.

Control-Matched Comparison of LASEK and LASIK for Low to Moderate Myopia

Attempted versus Achieved Spherical Equivalent Correction at the Final Visit

9

7

5

X

P

W

8

Y

Z

9 7 5 X P W 8 Y Z

Achieved (D)

Att

empt

ed (D

)

Epi-LASIK Attempted versus achieved spherical equivalent correction

79

Conclusions:# Although there were some differences in the

visual and refractive results favoring LASEK, they were not clinically significant.

# Both procedures seemed safe, effective, and predictable for the treatment of low and moderate myopia.

# Nomogram adjustment may be necessary for LASIK surgeons adopting surface ablation.

Control-Matched Comparison of LASEK and LASIK for Low to Moderate Myopia

Attempted versus Achieved Spherical Equivalent Correction at the Final Visit

9

7

5

X

P

W

8

Y

Z

9 7 5 X P W 8 Y Z

Achieved (D)

Att

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ed (D

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Epi-LASIK Attempted versus achieved spherical equivalent correction

77

Surface Ablation

<=><?!<@A;B# Surface ablation is a viable alternative to LASIK

especially in young patients with thin pachymetry, steep K, and/or corneal irregularities.

# Microkeratome and flap- related complications are avoided.

# Surface ablation is a reasonable alternative to phakic IOLs in patients with low endothelial cell counts, shallow AC, early lens opacities, and/or high astigmatism.

CD3D!<!D*?;B# The long-term risks of prophylactic MMC are

unknown.

Conclusions:# Despite a trend towards worse final BSCVA

and higher retreatment rates in older patients, a greater risk of visual loss after LASIK was not observed with increasing age.

# LASIK for myopia and hyperopia has reasonable safety, efficacy and predictability profiles in the presbyopic age group.

LASIK in the Presbyopic Age Group: Safety, Efficacy and Predictability in 40-69 Year Old Patients

Ghanem RC, de la Cruz J, Tobaigy FM, Ang LP, Azar DT. Ophthalmology. 2007 Jul;114(7):1303-10

77

Surface Ablation

<=><?!<@A;B# Surface ablation is a viable alternative to LASIK

especially in young patients with thin pachymetry, steep K, and/or corneal irregularities.

# Microkeratome and flap- related complications are avoided.

# Surface ablation is a reasonable alternative to phakic IOLs in patients with low endothelial cell counts, shallow AC, early lens opacities, and/or high astigmatism.

CD3D!<!D*?;B# The long-term risks of prophylactic MMC are

unknown.

Conclusions:# Despite a trend towards worse final BSCVA

and higher retreatment rates in older patients, a greater risk of visual loss after LASIK was not observed with increasing age.

# LASIK for myopia and hyperopia has reasonable safety, efficacy and predictability profiles in the presbyopic age group.

LASIK in the Presbyopic Age Group: Safety, Efficacy and Predictability in 40-69 Year Old Patients

Ghanem RC, de la Cruz J, Tobaigy FM, Ang LP, Azar DT. Ophthalmology. 2007 Jul;114(7):1303-10

75

Corneal Topography/Wavefront Analyzer

Custom Ablation

AFFERENT ARM EFFERENT ARM

Scanning Laser+=

+

What are the Optical Limits to Corneal Refractive Surgery?

75

Corneal Topography/Wavefront Analyzer

Custom Ablation

AFFERENT ARM EFFERENT ARM

Scanning Laser+=

+

What are the Optical Limits to Corneal Refractive Surgery?

@?

!"#$%&'()*+%,--.%%/%#01+%,O-

7X

Comparison of Outcomes of Custom and Non-custom LASIK# FDA trials of LVC# Subgroups: 0 to -2D, -2 to -4D, -4 to -7D,

0 to +2D, +2 to +4, & +4 to +6D# Pooled data of approved lasers (3 custom and

5 non-custom) rather than head-to-head comparisons of individual lasers

# Literature Search (past 10 years); data pooled# Outcomes: % > 20/20; % > 20/40; % + 0.50D;

%+ 1D; % loss of > 2 Snellen lines

Sakimoto T, Rosenblatt MI, Azar DT - - Lancet 4/2006

7X

Comparison of Outcomes of Custom and Non-custom LASIK# FDA trials of LVC# Subgroups: 0 to -2D, -2 to -4D, -4 to -7D,

0 to +2D, +2 to +4, & +4 to +6D# Pooled data of approved lasers (3 custom and

5 non-custom) rather than head-to-head comparisons of individual lasers

# Literature Search (past 10 years); data pooled# Outcomes: % > 20/20; % > 20/40; % + 0.50D;

%+ 1D; % loss of > 2 Snellen lines

Sakimoto T, Rosenblatt MI, Azar DT - - Lancet 4/2006

7P

7P

7W

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R[=D="<%A="JL>=A=;<J%#)AD">=+%H)>%#);J?J<=;#,'

Avoidance of Eye drift during surgery

# Tracking of cornea in 3 dimentions: x, y, and rotational

# Differentiation of rotational vs. translational movement (eye mvt vshead mvt)

Scanning and Tracking Laser Technology Limitations

7W

S?A?<"<?);J%?;%k"]=H>);< 3;"*,J?JC%.="JL>=A=;<%0<=DJ

# C&4*D.0+-' .*E0+'-.3E-*1F&+&%8G*1RE?@E=>%)>+=>%Q=>;?$=%D)*,;)A?"*%)>%2)L>?=>%>=D>=J=;<"<?);%)H%T"]=H>);<@=;=>"<=+'

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Avoidance of Eye drift during surgery

# Tracking of cornea in 3 dimentions: x, y, and rotational

# Differentiation of rotational vs. translational movement (eye mvt vshead mvt)

Scanning and Tracking Laser Technology Limitations

!"#$%&'()*+%,--.%%/%#01+%,OO

78

3++?<?);"*%S?A?<"<?);J%)H%k"]=H>);<i@L?+=+%1M#?A=> S"J=>%3V*"<?);J

The refractive outcomes may be altered by surgically-induced HOA:

# Wound healing # Biomechanical changes after surgery

(collagen relaxation, ectasia)

78

3++?<?);"*%S?A?<"<?);J%)H%k"]=H>);<i@L?+=+%1M#?A=> S"J=>%3V*"<?);J

The refractive outcomes may be altered by surgically-induced HOA:

# Wound healing # Biomechanical changes after surgery

(collagen relaxation, ectasia)

7Y

Corneal AsphericitySpherical surface (Shape factor: Q = 0); or Oblate surface (Shape factor: Q > 0) :Peripheral rays are bent more than the para­axial rays

Q > 0

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Corneal AsphericitySpherical surface (Shape factor: Q = 0); or Oblate surface (Shape factor: Q > 0) :Peripheral rays are bent more than the para­axial rays

Q > 0

7Z

Myopic LASIK:

Central area flatter than Peripheral untreated zone

Is the treatment zone oblate?

0

R1

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X1(y)X2(y)=X1(y)+t(y)

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Preoperative Corneal Asphericity

Gatinel and Azar Invest. Ophthalmol Vis Sci

Original curvature: Prolate; low spherical aberrations

Spherically­based treatment

7Z

Myopic LASIK:

Central area flatter than Peripheral untreated zone

Is the treatment zone oblate?

0

R1

R2

X1(y) X1(y)t(y)

X2(y)

R1

X1(y)X2(y)=X1(y)+t(y)

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x

y

Preoperative Corneal Asphericity

Gatinel and Azar Invest. Ophthalmol Vis Sci

Original curvature: Prolate; low spherical aberrations

Spherically­based treatment

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Outcome of Asphericity R1=7.8

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Outcome of Asphericity R1=7.8

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Gatinel, Malet, H­Xuan, Azar, Invest. Ophthalmol Vis Sci, April 2004

55

Gatinel, Malet, H­Xuan, Azar, Invest. Ophthalmol Vis Sci, April 2004

5X

CONCLUSIONS# Recent improvements in LVC include improved

technology, patient selection, surface ablation (Epi-LASIK), monovision, and customized wavefront-guided LASIK.

# Despite improved outcomes of custom LVC, biomechanical changes and WH interfere with the ability to eliminate optical aberrations

# Other limitations include inability to measure and render all HOA at all wavelengths, inability to predict the surgically-induced aberrations, and inability to perfectly position Rx on the corneal plane.

&E";$ ,)L H)>%,)L> "<<=;<?);

Dimitri T. AZAR, M.D.

5X

CONCLUSIONS# Recent improvements in LVC include improved

technology, patient selection, surface ablation (Epi-LASIK), monovision, and customized wavefront-guided LASIK.

# Despite improved outcomes of custom LVC, biomechanical changes and WH interfere with the ability to eliminate optical aberrations

# Other limitations include inability to measure and render all HOA at all wavelengths, inability to predict the surgically-induced aberrations, and inability to perfectly position Rx on the corneal plane.

&E";$ ,)L H)>%,)L> "<<=;<?);

Dimitri T. AZAR, M.D.

A.7.0".+N6+Q9$"@+4A!6Q6+P.#5,+O(,1J#,+G*$."@B"1;#331"+$(,+E#$,@A#F$"07#(0+1;+RF*0*$57151HD+$(,+^.3'$5+K).#()#3@+=11*,.*/$:#+$%,9$:%8$=,582%8#BC(.2#"3.0D+1;+S55.(1.3@+G*.)$H1,$9$"8'.)6#,'

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ANNUAL CONGRESS

ANNUUAL CONGRESS

ANNUAL CO

AL CONGRESSANNUA

ANNUAL CONGRESS

CONGRESS

ANNUAL CONGRESS

ANNUAL CON

UAL CONGRESS

JOIN EVER in Portoroz ­ Slovenia

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