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European University Professors of Ophthalmology

EUPO 2009
?jcZ&'"&(!'%%.6bhiZgYVb!I]ZCZi]ZgaVcYh

CORNEA, CONJUNCTIVA
and REFRACTIVE SURGERY
Course book

www.eupo.eu

European University Professors of Ophthalmology

EUPO 2009
?jcZ&'"&(!'%%.6bhiZgYVb!I]ZCZi]ZgaVcYh

CORNEA, CONJUNCTIVA
and REFRACTIVE SURGERY
Course book
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Degeneration : deterioration and decrease in function
Degenerations may be :

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

!! 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


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

WHITE LIMBAL GIRDLE OF VOGT

B.Secondary

!! 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

VOGTs LIMBAL GIRDLE TYPE 1

!! 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

!! Early calcific band keratopathy


!! Narrow lucent area from the limbus
!! White band contains holes (Swiss cheese)
!! Destruction and calcification of Bowman s layer

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

VOGTs LIMBAL GIRDLE TYPE 2

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)

!! Asymptomatic and incidental


!! Lesion is subepithelial
!! Elastotic degeneration and calcium
at the level of Bowmans layer

!! Hyperlipoproteinemia type 2 and3

SPHEROID DEGENERATION

IRON LINES

!! Climatic droplet keratopathy

!! 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
!! 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 Bowmans
membrane level and anterior stroma
!! Treatment:
PTK, lamellar KP, lamellar keratectomy

!! 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

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

!"#$%&'()*+%,--.%%/%#01+%Y2

BAND KERATOPATHY

BAND KERATOPATHY

Classification

Classification
Chronic ocular diseases
Systemic abnormalities

!! Uveitis (juvenile chronic arthritis)


!! Glaucoma
!! Corneal edema
!! Interstitial keratitis
!! Phthisis

!! Hypercalcemia
!! Hyperphosphatemia

Heredity
!! Norries disease
!! Autosomal recessive band keratopathy

Ocular trauma
!! Climatic exposure
!! Mercurial containing preservatives

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

!! 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

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

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!! 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

>

SALZMANNS NODULAR DEGENERATION

SALZMANNS NODULAR DEGENERATION


Etiology

!! First reported in 1925

Late sequelae of previous corneal inflammation

!! Rare, noninflammatory, slowly progressive

!! 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

!! 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

SALZMANNS NODULAR DEGENERATION

SALZMANNS NODULAR DEGENERATION

!! Clear area between the nodules


!! A fibrillar, hyaline degeneration of collagen
cellular debris.

!!Thinning of the overlying epithelium


!! Basal epithelial cell degeneration

!! The number of fibrocytes in the affected areas


can vary (numerous cells that are active to scarce
degenerating cells)

!! Replacement of Bowman s layer


by (eosinophilic) material

SALZMANNS NODULAR DEGENERATION


Treatment Modalities

!! Manual removal
!! PTK with or without MMC
!! Lamellar/penetrating keratoplasty
!! All Salzmann cases are individual in
their appearance and experience is
needed to reach optimal surgical
technique

Manual removal
Laser ablation

Schematic drawing of the surgical procedure


!! Tissue removal with a surgical knife
!! Laser ablation to smooth the surface
!! Masking fluid employed several times

Bowers Jr PJ et al. J Cataract Refract Surg 2003


Marcon AS, Rapuano CJ Cornea 2002

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

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

SALZMANNS NODULAR DEGENERATION

SALZMANNS NODULAR DEGENERATION


Please keep in mind
!! 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

After Treatment

Before Treatment

PTK appears to be an effective and


safe procedure for treatment of
Salzmann's nodular degeneration

!! Interface haze is a problem in lamellar keratoplasty


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

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

TERRIENS MARGINAL DEGENERATION

TERRIENS MARGINAL DEGENERATION


Deposition of refractile yellowish-white opacities
(superiorly peripheral anterior stroma)

!! Slowly progressive thinning of peripheral cornea


!! Most common in men (3:1)
!! Patient age: 10-70 years
!! Most cases are bilateral (+ asymmetry)

Development of gutter
(parallel to the limbus)

Superior or more extensive


corneal thinning

!! Early stages generally asymtomatic


!! Sometimes mild irritation in early stages
!! Induced against- the -rule astigmatism (late stages)
!! Spontaneous or traumatic corneal rupture (rare)

TERRIENS MARGINAL DEGENERATION

TERRIENS MARGINAL DEGENERATION

1
2

!! 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)

!! 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

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

>

TERRIENS MARGINAL DEGENERATION

TERRIENS MARGINAL DEGENERATION

Pathology

Differential Diagnosis
!! Arcus senilis (early)
A. Limbal side

!! Moorens ulcer

B.Central

!! Furrow degeneration

!! 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)

!! Marginal pellucid degeneration


!! Inflammatory peripheral keratitis
!! Peripheral corneal melting (autoimmune)

MOOREN S ULCER

MOOREN S ULCER

!! Inappropriate immunologic responses


!! 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

TERRIENS MARGINAL DEGENERATION

!! 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

RIGHT EYE

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

Cheng CL et al. Ophthalmology 2005

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

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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. 1. The normal
cornea, the transparent windscreen of the eye, is devoid of both blood and lymphatic vessels
<B+%03?%'C%6B3*%)+I3+A%6B+)+C')+%3*%6'%E0F%B31B;31B6%6B+%3?@')6056%8'56)3N(63'5*%6'%
efore is an ideal model system to study the mechanisms of hemangiogenesis and lymphangiogenesis (A). There
p transition '/@.+@"/"8.8&-"8"'-(6&U'$"&B7&O,$'6&W+#EU'/&'/$&(+P?+-E"-8%&,8./@&56&(81$9
from physiologically vascularized conjunctiva to avascular cornea (arrowhead in A and arrows in B
*&"(".("*(%*()%)1(210&'(.7.5&2G%ENF%6'%'(6;35+%6B+%@)'1)+**%35%;9?@B0513'1+5+*3*%
neal flatmount
stained with CD31 (Ref. 1. Reproduced with permission. 2006, National Academy of Sciences).

)+*+0)8B%6B06%B0*%N++5%?04+G%01035%(*351%56&(81$*&"(".("*(%*()%)1(210&'G%054%E8F%
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ecent years, not only in oncology, but also, for example, sight-threatening neovascular diseases, using, for example
r
56$&"5&*%*3(*&1)".8/'"$(0%.&".&.%&,8./@%&>+-&"]'U)#"%&R"0'(.A,U'B&_D0'8*./
phthalmology. Drugs such as Bevacizumab (Avastin), vacizumab (Avastin) eye drops. In F%+9+%
our opinion, this
), and Pegaptanib (Macugen) are
4)'@*K%>5%'()%'@353'5G%6B3*%3*%0%@+)C+86%+Z0?@;+%C')%0%*(88+**C(;%6)05*;063'50;%)+D
ibizumab (Lucentis
perfect example for a successful translational research s
w mainstay for8"'-(6&8*+-7%&8*'-*"$&B7&O,$'6&W+#EU'/&U+-"&*6'/&NL&7"'-8&'@+%&*6'*&/+?&8#+?#7&
treatment of age-related maculopathy, the started by Judah Folkman more than 30 years ago, that
t common form
of adult blindness in industrialized slowly comes back from bench to bedside to treat pat
8'?+*%N08M%C)'?%N+58B%6'%N+4*34+%6'%6)+06%@063+56*%A36B%*31B6D6B)+06+5351%8')5+0;%
2ntries.
REGENFUSS an
ET
with sight-threatening corneal neovascularization
/"+0'8(,#'-.A'*.+/&'/$&*+&)-+U+*"&(+-/"'#&*-'/8)#'/*&8,-0.0'#1

here are no licensed antiangiogenic drugs available for promote corneal transplant survival.
against human corneal neovascularization yet, so to fiy close the circle from the cornea as an in vivo model to the
The Cornea as the In Vivo Model System to Study
nea as a place of angiogenic diseases, we can at least use
the Mechanisms of Angiogenesis
el antiangiogenic drugs off-label in patients with sightJudah Folkman established the basis for research into
atening corneal angiogenesis. We can now also try to
mote corneal graft survival by novel antihem- and espe- giogenesis, not only for tumor angiogenesis, but by usin
cornea as a model system also for corneal angiogenesi
y antilymphangiogenic drugs.1719
he aim of this review therefore is to (a) highlight the im- ready in the early 1970s. Since then, the corneal angiog
ant contributions to angiogenesis research made by Ju- sis assay has been one of the best in vivo assays for the
Folkman and co-workers, using the cornea as an in vivo uation of factors influencing angiogenesis.20 One reason
el system, (b) to outline the progress in lymphangiogen- makes the cornea an ideal object for observing neovasc
research that has been made, again using the cornea as ization is its normal lack of vascularity, maintained
n vivo model, and (c) finally closing the loop to discuss different molecular mechanisms (Fig. 1). New vessels
w this progressPSU6+W6(V6&(*1$2"'(81$*&"4(56&(5$"*.-"$&*5(:?%*0.8$&&*;(1=(56&(&7&4(%.(0&)1%0(1=(#156(#'110("*0('72-6"5%8(
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analysis
programs
(Fig.
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-6"*3%13&*&.%.(HQLS(V6&$&(%.("(.6"$-(5$"*.%5%1*(=$12(-67.%1'13%8"''7()".8/'"$%@&0(81*,/*85%)"(51(")".8/'"$(
refore is an ideal
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rp transition 81$*&"(H"$$1?6&"0(%*(Q("*0("$$1?.(%*(!S(H!1)2,#*+"()3"$.,4*$)0$"%*+5)6%$-)2789):;+<=)9=);+>#,54'+5)6%$-)
from physiologically vascularized conjunctiva to avascular cornea (arrowhead in A and arrows in B
](T\\Y4(Q"5%1*"'(M8"0&27(1=(U8%&*8&.LS
-&$2%..%1*S(
neal flatmount
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ecent years, not only in oncology, but also, for example, sight-threatening neovascular diseases, using, for example
ophthalmology. Drugs such as Bevacizumab (Avastin), vacizumab (Avastin) eye drops. In our opinion, this
nibizumab (Lucentis), and Pegaptanib (Macugen) are perfect example for a successful translational research s
w mainstay for treatment of age-related maculopathy, the started by Judah Folkman more than 30 years ago, that
st common form of adult blindness in industrialized slowly comes back from bench to bedside to treat pa
ntries.
with sight-threatening corneal neovascularization an
There are no licensed antiangiogenic drugs available for promote corneal transplant survival.
against human corneal neovascularization yet, so to fiy close the circle from the cornea as an in vivo model to the
The Cornea as the In Vivo Model System to Study
nea as a place of angiogenic diseases, we can at least use
the Mechanisms of Angiogenesis
vel antiangiogenic
drugs
off-label
in patients
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. 2. Pathologic,
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Judah
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e
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giogenesis,
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corneal angiogenes
ly antilymphangiogenic
The aim of this review therefore is to (a) highlight the im- ready in the early 1970s. Since then, the corneal angio
tant contributions to angiogenesis research made by Ju- sis assay has been one of the best in vivo assays for the
!"#$%&'()*+%,--.%%/%#01+%U=
h Folkman and co-workers, using the cornea as
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del system, (b) to outline the progress in lymphangiogen- makes the cornea an ideal object for observing neovasc

RNEAL (LYMPH)ANGIOGENESIS

PSU6+\6)2,*'4##+*$)%*54'$%,*),<)%*3".."$,#B)-+."*C%,C+*+0%0):DE)/(,,5)?+00+(0F)0$"%*+5)%*)C#++*E)27891)

G. 3. Concurrent
induction of inflammatory hemangiogenesis (B: blood vessels; stained in green: CD31) and lympha
"*5)(B.>-"*C%,C+*+0%0):GE)(B.>-"$%')?+00+(0F)0$"%*+5)%*)#+5E)GHIJK91)%*)").4#%*+).,5+(),<)',#*+"()%*3".9
esis (L: lymphatic
vessels;
stained in red:
LYVE-1)
in +&-$10/8&0(
a murine model
of corneal]inflammatory
neovascularization
(AD)
( T\\Z4( M2&$%8"*(
U18%&57( =1$(
2"51$7(
*&1)".8/'"$%@"5%1*(
HQ]AL(
H+&=S( aaS(
?%56( -&$2%..%1*S
Reproduced with
permission. 2004, American Society for Clinical Investigations). Central, normally avascular corne
G'%*%8"'(<*)&.5%3"5%1*.LS(G&*5$"'4(*1$2"''7(")".8/'"$(81$*&"(%.("5(56&(51-4(-67.%1'13%8"''7()".8/'"$%@&0(81*9
top, physiologically
vascularized conjunctiva at the bottom of each picture (segment of murine corneal flatmount).
L4*'$%?")"$)$-+)/,$$,.),<)+"'-)>%'$4#+):0+C.+*$),<).4#%*+)',#*+"()3"$.,4*$1=

78)%(/5:)3%36%;8)%S(+^.21%2/4)1%6C6;)2%;/%6;-4C%;8)%
nea offers a good
possibility for studying corneal he2)(83:E626%/&%3:GE/G):)6E6
ngiogenesis and
recently also lymphangiogenesis in vivo.
ing the last 30 years, Folkman and others achieved many
ults by the help
of a corneal angiogenesis assay.
O,$'6&W+#EU'/&"8*'B#.86"$&*6"&B'8.8&>+-&-"8"'-(6&./*+&'/@.+@"/"8.8%&/+*&+/#7&>+-&
n 1971, Judah 6(?')%0513'1+5+*3*G%N(6%N9%(*351%6B+%8')5+0%0*%0%?'4+;%*9*6+?%0;*'%C')%8')5+0;%
Folkman published a paper in the New Ennd Journal of Medicine, where he proposed that, by im0513'1+5+*3*%0;)+049%35%6B+%+0);9%O.V-c*K%7358+%6B+5G%6B+%8')5+0;%0513'1+5+*3*%0*D
nting a tumor into the corneal stroma, tumor growth is
9 He hypothesized that a tumor
*09%B0*%N++5%'5+%'C%6B+%N+*6%%*()%)1&'88'78&>+-&*6"&"0'#,'*.+/&+>&>'(*+-8&./F,"/(./@&
ending on angiogenesis.
0513'1+5+*3*K
%$5+%)+0*'5%6B06%?0M+*%6B+%8')5+0%05%34+0;%'NH+86%C')%'N*+)I351%
only grow beyond
a certain,-size
if it gets connected to
blood system/"+0'8(,#'-.A'*.+/&.8&.*8&/+-U'#&#'(E&+>&0'8(,#'-.*7%&U'./*'./"$&B7&$.>>"-"/*&U+#"(D
by neovascularization.9 For this hypothehe had to face
a lot of skepticism at this time, but over
,#'-&U"(6'/.8U8&_W.@1&3`1&m"?&0"88"#8&('/&"'8.#7&B"&.$"/*.!"$&'/$&T,'/*.!"$&?.*6&
years Folkman and his co-workers supplied evidence for
*6"&6"#)&+>&(+U),*"-.A"$&.U'@"&'/'#78.8&)-+@-'U8&_W.@1&u`1&Y6"-">+-"%&*6"&(+-/"'&
theory that now is widely accepted.
'CC+)*%0%1''4%@'**3N3;369%C')%*6(49351%8')5+0;%B+?0513'1+5+*3*%054%)+8+56;9%0;*'%
n 1972, Michael
Gimbrone and Folkman presented new
#7U)6'/@.+@"/"8.8&./&0.0+1&C,-./@&*6"&#'8*&NL&7"'-8%&W+#EU'/&'/$&+*6"-8&'(6."0"$&
a collected with
the rabbit eye in vivo model to support
theory. They ?059%)+*(;6*%N9%6B+%B+;@%'C%0%8')5+0;%0513'1+5+*3*%0**09K%
demonstrated that small tumor fragments
lanted in the anterior chamber did not become vascuzed and remained
at a small size, whereas fragments, im2/&34q3%&O,$'6&W+#EU'/&),B#.86"$&'&)')"-&./&*6"&m"?&9/@#'/$&O+,-/'#&+>&J"$.D
nted directly on the surface of the iris, introduced neo835+G%AB+)+%B+%@)'@'*+4%6B06G%N9%3?@;056351%0%6(?')%356'%6B+%8')5+0;%*6)'?0G%6(D
cularization and tumor size increased exponentially.21
.& V"& 67)+*6"8.A"$& *6'*& '& *,U+-& ('/&
?')%they
1)'A6B%
3*% 4+@+54351%
'5% 0513'1+5+*3*K
ed on these data,
considered
the possibility
to con+/#7&@-+?&B"7+/$&'&("-*'./&8.A"&.>&.*&@"*8&(+//"(*"$&*+&*6"&B#++$&878*"U&B7&/"+D
tumor growth
by preventing tumor-induced angiogen.
n 1974, Gimbrone et al. reported a new experimental
del using the rabbit cornea, supporting again that tumor
!"#$%&'()*+%,--.%%/%#01+%UU
wth is angiogenesis dependent. After intrastromal
tumor
lantation in the avascular cornea, the tumor size pri-

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

mangiogenesis (B: blood vessels; stained in green: CD31) and lymphangio) in a murine model of corneal inflammatory neovascularization (AD) (Ref.
Society for Clinical Investigations). Central, normally avascular cornea is at
the bottom of each picture (segment of murine corneal flatmount).

rneal heis in vivo.


ved many
y.
New Enat, by imgrowth is
t a tumor
nected to
hypothebut over
dence for

nted new
o support
ragments
me vascuments, imuced neoentially.21
ty to conangiogen-

erimental
hat tumor
mal tumor
size prir got vassing this
scapular
found to
d vessels,
could be
, or cortito rabbit
rnea.23

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:*1%.&;(HQ]ULS

FIG.
4. Using the cornea to analyze pharmacologic effects
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of antiangiogenic and antilymphangiogenic drugs is enabled
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by
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lar
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with
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noise
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RNEAL (LYMPH)ANGIOGENESIS

. 5. Inhibition
of hemangiogenesis and lymphangiogenesis promotes graft survival after low-risk corneal transp
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lymphangiogenesis (red: LYVE-1) using a VEGF-A cytokine trap significantly promotes graft surviv
urine model $,R%*+)$#">)0%C*%&'"*$(B)>#,.,$+0)C#"<$)04#?%?"()%*)").4#%*+).,5+(),<)',#*+"()$#"*0>("*$"$%,*=):QL(G1*5$1'S(
of corneal transplantation. (A) Control. (B) VEGF trap. (C) Survival proportions.
H!L(`O!K(5$"-S(HGL(U/$)%)"'(-$1-1$5%1*.S

ic and topical application of Bevacizumab significantly in- corneal angiogenesis, and very recently also cor
ted the outgrowth of blood and lymphatic vessels.17 Al- lymphangiogenesis. In parallel, great efforts have
ugh the binding affinity for murine VEGF is very low, sig- made to translate the discoveries in angiogenesis rese
cant binding could be detected by Western blot analysis, into clinical medicine, primarily in the field of oncol
!"#$%&'()*+%,--.%%/%#01+%VO
SA, and a surface plasmon resonance assay.17 Based on but also in ophthalmology. VEGF inhibitors such
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the inner and outer borders of the cornea. These include inhibitors such as angiostatin, endostatin, thrombopondins, and PEDF, and there are certainly more inhibitors to be identified.59,60

but also by secondary changes caused by immature co


blood vessels, that is, lipid deposition in the cornea (
keratopathy, Fig. 2), corneal edema and bleeding int
cornea.19 Furthermore, pathologic blood, and especially

PSU6+X6)J'$,>%'"((B)+S>#+00+5)IJOP)#+'+>$,#)8)%*)$-+)',#*+"()+>%$-+(%4.):QL(H"$$1?.L("85.(".("(*"5/$"'(.%*B(

. 6. Ectopically
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ptors on vascular
endothelium in the adjacent conjunctiva
(B) (Ref. 1. Reproduced and modified with permission.
2%..%1*(=$12(A&5&$(b"''&*4(U86&-&*.(O7&(+&.&"$86(<*.5%5/5&4(X1.51*LS
ional Academy
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FIG. 7. Avastin (Bevacizumab) eye drops potently stop pro<B+%353630;%8;35380;%+Z@+)3+58+%'C%(*351%TI0*635%+9+%4)'@*%')%*(N8'5H(5863I0;%35H+8D


gressive
corneal angiogenesis, lead to partial regression of
immature
blood vessels and reduced perfusion of mature
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blood
vessels (Ref. 10. ReproducedOPGVOoV2
with %$()%353630;%@063+56*%N+351%6)+06+4%A36B%TI0*635%
permission. 2007,
/"+0'8(,#'-.A'*.+/&./&*6"&(#./.(1
Springer Verlag). (A) prior to and (B) 4 weeks after addi"7"&$-+)8&+>>P#'B"#&>+-&)'*6+#+@.(&(+-/"'#&/"+0'8(,#'-.A'*.+/&,/-"8)+/8.0"&*+&(+/D
tional
therapy with Avastin eye drops five times a day in a
0"/*.+/'#&*6"-')7&86+?"$&'&8.@/.!('/*%&B,*&'#8+&0"-7&0'-.'B#"%&-"8)+/8"&*+&'$$.*.+/D
patient
with progressive corneal neovascularization after
limbal
stem cell deficiency.
'#&D0'8*./&"7"&$-+)8&?6"/&/"+0'8(,#'-.A'*.+/&?'8&'/'#7A"$&U+-)6+U"*-.('##7&+/&

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such as anti-inflammatory steroids and cyclosporine A. The
only specific antiangiogenic treatment options available are:
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a. The off-label use of anti-VEGF agents such as Bevacizumab (Avastin), Ranibizumab (Lucentis), and Pe-

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mall case series support the concept of Avastin eye of the eye, several potential side effects come into
subconjunctival applications being relatively effec- pecially given the nonangiogenic effects of VEGF
ontrolled trials available yet) and relatively safe (no its neurotrophic effect, its role in wound healing
safety studies available yet).48,7174 Therefore, flammation:
ve randomized studies are necessary to define ina. Neurotrophic keratopathy: the cornea is on
, safety, and effectiveness of that approach in inmost densely innervated tissues of the hum
corneal neovascularization.
8')5+0;%0513'1+538%@)3I3;+1+G%?09%0;*'%B0I+%05%+CC+86%'5%+@36B+;30;%@)';3CD
and we know now that VEGF is a potent neur
e other two off-label available
anti-VEGF agents,
O
+)063'5K &2/&'$$.*.+/%&i9GW8a&E/+?/&">>"(*&+/&-"(-,.*U"/*&+>&./F'UU'*+-7&
growth factor.75 Physiologically, there ar
much less known about their effect on human corneal
8+;;*G%+*@+830;;9%?08)'@B01+*G%?09%0;6+)%8')5+0;%*6)'?0;%A'(54%B+0;351K==

PSU6+a6)J00+*$%"()#,(+),<)IJOPKQ)%*)%..4*+)".>(%&'"$%,*)"0)+?%5+*'+5)<#,.)%*3".."$,#B)',#*+"()*+,?"09

Essential role
of VEGF-A in immune amplification as evidenced
from inflammatory corneal neovascula
](T\\Z4(M2&$%8"*(U18%&57(=1$(G'%*%8"'(<*)&.5%9
8/'"$%@"5%1*(210&'.(H+&=S(aaS(+&-$10/8&0(?%56(-&$2%..%1*S(
Ref. 55. Reproduced
with
permission.
2004,,#)American
Society
for 0$,>0)
Clinical
Investigation). Early depleti
C"$%,*1=) J"#(B)
5+>(+$%,*)
,<) +%$-+#) IJOPKQ)
."'#,>-"C+0)
',.>(+$+(B)
$-+) %..4*+K".>(%&'"$%,*)
F-A or macrophages
completely stops the immune-amplification cascade, leading to inflammatory corne
'"0'"5+A)(+"5%*C)$,)%*3".."$,#B)',#*+"()-+."*5)(B.>-"*C%,C+*+0%0=)IJOPKQ)-"0)"*)%*5%#+'$)(B.>-"*C9
phangiogenesis.
VEGF-A has an indirect lymphangiogenic effect via macrophage recruitment.
%13&*%8(&==&85()%"(2"8$1-6"3&($&8$/%52&*5S
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!"#$%&'()*+%,--.%%/%#01+%OP2

Custom FDA studies


Non-custom FDA studies
Other studies (non-custom)

80
60
40
20
0

0 to 2 D

2 to 4 D

4 to 7 D

0 to 7 D

7 to 12 D

Percentage of eyes with UCVA20/40

UCVA20/40

100

100

Percentage of eyes with MRSE 10 D

Percentage of eyes with UCVA20/20

UCVA20/20

100

80
60
40
20
0

MRSE 05 D

Percentage of eyes with MRSE 05 D

view

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'*.0"&+,*(+U"8&>+-&*6"&)-+("$,-"81&<,-&-"8,#*8&'-"&86+?/&./&!@,-"8&3oN1&;,B#.86"$&
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6')9%C(5863'50;%I3*(0;%'(68'?+*%0C6+)%)+C)0863I+%*()1+)9K%R0*+)%)+C)0863I+%*()1+)9%805%
80(*+% B31B+)D')4+)% 0N+))063'5*G% *(8B% 0*% 1;0)+G% B0;'G% ')% 531B6DI3*3'5% 43*6()N058+G%
054%'6B+)%I0)30N;+*%*(8B%0*%8'56)0*6%*+5%*363I369G%054%*8'6'@38%054%?+*'@38%I3*3'5K%
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80
60
40
20
0 to 2 D

2 to 4 D

4 to 7 D

0 to 7 D

7 to 12 D

2 to 4 D

4 to 7 D

0 to 7 D

7 to 12 D

MRSE 10 D

100

0 to 2 D

2 to 4 D

4 to7 D

0 to 7 D

7 to 12 D

80
60
40
20
0

0 to 2 D

Figure 1: Visual outcomes of LASIK for myopia at 36 months after surgery


UCVA=uncorrected
visual accuity. MRSE=manifest refraction spherical equivalents. For every assessment, results for low myopia with error 0 to 7 D (individual
P.H+W<+ ^.3'$5+1'0)17#3+1;+&QKST+;1"+7D1F.$+$0+\]X+71(0*3+$;0#"+3'"H#"D
ranges and grouped) compared with high myopia with refractive error 7 D to 12 D.3745, 5061

(
NG`Me/*81$$&85&0( )%./"'( "88/%57S( b+UOe2"*%=&.5( $&=$"85%1*( .-6&$%8"'( &>/%)"'&*5.S( K1$( &)&$7((
(
"..&..2&*54($&./'5.(=1$('1?(271-%"((?%56(&$$1$(\(51(Pc(E(H%*0%)%0/"'($"*3&.("*0(3$1/-&0L(812-"$&0((
the Snellen chart was used to measure negative
We
compared
a combination of measures of refraction lines onYVo2=G%=-oUO
(
?%56((6%36(271-%"(?%56($&=$"85%)&(&$$1$(Pc(E(51(PDT(ES
and visual acuity. Fortunately, these variables are outcomes for the procedures. Our results are shown in
primary outcomes in almost all studies of laser vision figures 13. Published results were obtained by the
correction. Manifest refraction spherical equivalent is following criteria: (1) randomised prospective study
the amount of refractive error that remains after (n25, follow-up period 3 months), (2) controlled
ablation, and combines both the spherical and prospective study (n50, follow-up period 3 months),
astigmatic correction. Manifest refraction spherical and (3) case series (n100, follow-up period 6 months).
equivalent thus measures the ability of the laser However, it should be noted that even though the
refractive procedure to reach the target refraction. We Snellen chart-based visual acuity has been judged as
analysed postoperative manifest refractive
spherical the standard method of assessing the outcomes of
!"#$%&'()*+%,--.%%/%#01+%OP=
equivalents to determine the percentage of patients ophthalmic surgery, the variables mentioned above
whose residual refractive error fell within about 050 D might not be enough to assess the satisfactory functional

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Custom FDA studies


Non-custom FDA studies
Other studies (non-custom)
UCVA20/40
Percentage of eyes with UCVA20/40

Percentage of eyes with UCVA20/20

UCVA20/20
100
80
60
40
20
0

0 to +2 D

+2 to +4 D

+4 to +6 D

0 to +6 D

100
80
60
40
20
0

0 to +2 D

+2 to +4 D

+4 to +6 D

0 to +6 D

+2 to +4 D

+4 to +6 D

0 to +6 D

Percentage of eyes with MRSE 10 D

Percentage of eyes with MRSE05 D

MRSE 05 D
100
80
60
40
20
0

0 to +2 D

+2 to +4 D

+4 to +6 D

0 to +6 D

100

MRSE10 D

80
60
40
20
0

0 to +2 D

Figure 2: Visual outcomes of LASIK studies for hyperopia


UCVA=uncorrected
visual acuity. MRSE=manifest refraction spherical equivalents. Data analysed for different degrees of hyperopia and for all hyperopia.4649,6266
P.H+Z<+ ^.3'$5+1'0)17#3+1;+&QKST+30',.#3+;1"+*DF#"1F.$

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largest proportion of the general population; also, 20/20 or better uncorrected. These other studies did,
(
&>/%)"'&*5.S(
E"5"(might
"*"'7.&0(
=1$( 0%==(
&$&*5( 0&3$&&.(
1=( rate
67-&$1-%"(
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have a higher
of best spectacle-corrected
patients
with
higher 2Uo2.GU,oUU
myopia
not qualify
as however,
(
67-&$1-%"S
candidates
for laser surgery. In view of the visual acuity loss totalling more than 23%. These
preponderance of low to moderate myopia, it is not overall excellent success rates explain the popularity of
surprising that the first FDA-approved use of the laser refractive surgery.
excimer laser for LASIK was for these patients.
Grouped data from the FDA-approved laser platforms High myopia (conventional laser ablation)
(LADAR Vision, Alcon, Fort Worth, TX, USA; EC5000, With the larger degree of refractive error and the
NIDEK, Gamagori, Japan; S2 & S3, VISX, Santa Clara, concomitant need to remove more tissue in higher
CA,
USA; Technolas 217a, Bausch & Lomb, Rochester, myopia, this group of patients is often analysed
g+?&*+&U+$"-'*"&U7+).'&_(+/0"/*.+/'#&#'8"-&'B#'*.+/`&Y6+8"&?.*6&#+?&_ou&C&+-&#"88`&
NY, USA; Allegretto Wave, WaveLight, Sterling, VA, separately when measuring outcomes of refractive
+-&U+$"-'*"&_ou&C&*+&oq&C`&U7+).'&-")-"8"/*&*6"&#'-@"8*&)+),#'*.+/&+>&)'*."/*8&,/D
USA)3742 for low to moderate myopia showed manifest surgery. In the high myopia group, FDA data showed
refraction
spherical equivalent within about 100 D of manifest refraction spherical equivalent within about
4+)1'351%;0*+)%)+C)0863I+%*()1+)9K%<B+9%)+@)+*+56%6B+%;0)1+*6%@)'@')63'5%'C%6B+%1+5+)0;%
96% and within about 050 D of 81%. Similarly, 100 D of 80% and within about 050 D of 61%.
)+),#'*.+/l&'#8+%&)'*."/*8&?.*6&6.@6"-&U7+).'&U.@6*&/+*&T,'#.>7&'8&('/$.$'*"8&>+-&#'8"-&
uncorrected visual acuities better than 20/40 were Although 89% of patients were 20/40 or better, less than
measured
in 96%, although 72% of patients had vision half (48%) achieved 20/20 or better. A loss of best
*()1+)9K%>5%I3+A%'C%6B+%@)+@'54+)058+%'C%;'A%6'%?'4+)06+%?9'@30G%36%3*%5'6%*()@)3*351%
equal to or better than 20/20. A loss of best spectacle- spectacle-corrected visual acuity of greater than two
*6'*&*6"&!-8*&WCDP'))-+0"$&,8"&+>&*6"&"](.U"-&#'8"-&>+-&gDS2X&?'8&>+-&*6"8"&)'*."/*81
corrected visual acuity of more than two lines was noted lines was recorded in only 1% of patients.
Similarly, combined data from the non-FDA dataset
in just under 10% of patients.
showed
manifest refraction
Comparison $'*'&
of the>-+U&
FDA *6"&
data WCDP'))-+0"$&
with other studies#'8"-&
G-+,)"$&
)#'*>+-U8&
_gDCDH&spherical
i.8.+/%&equivalent
D#(+/%& within
W+-*&
revealed similar outcomes with respect to ecacy. about 100 D of 79% and within about 050 D of 59%.
n+-*6%&YZ%&:SDl&9=pLLL%&m2C9X%&G'U'@+-.%&O')'/l&SK&Q&SN%&i2SZ%&S'/*'&=#'-'%&=D%&
Combined data from the non-FDA dataset show 94% of patients were 20/40 or better; 64% were 20/20 or
manifest
refraction spherical equivalent within about better. Compared with FDA data, a loss of best spectacle:SDl&Y"(6/+#'8&K3q'%&R',8(6&Q&g+UB%&H+(6"8*"-%&mt%&:SDl&D##"@-"**+&n'0"%&n'0"D
100 D of 94% and within about YVo2,
050 D of 79%. About corrected visual acuity of more than two lines was noted
R31B6G%76+);351G%WTG%"7TF
95% of patients were 20/40 or better%C')%;'A%6'%?'4+)06+%?9'@30%*B'A+4%?053C+*6%)+C)0863'5%
and 67% were in a higher rate of 2% of patients.

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www.thelancet.com Vol 367 April 29, 2006

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

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WCD&$'*'%&'&#+88&+>&B"8*&8)"(*'(#"(+--"(*"$&0.8,'#&'(,.*7&+>&U+-"&*6'/&*?+&#./"8&
A0*%5'6+4%35%0%B31B+)%)06+%'C%,j%'C%@063+56*K

Percentage of eyes losing


2 lines of BSCVA

Myopia
6
4

Custom FDA studies


Non-custom FDA studies
Other studies (non-custom)

2
0

0 to 2 D

2 to 4 D

4 to 7 D

0 to 7 D

Hyperopia

Percentage of eyes losing


2 lines of BSCVA

view

qKe&+>&)'*."/*8&6'$&0.8.+/&"T,'#&*+&+-&B"**"-&*6'/&KL^KL1&D&#+88&+>&B"8*&8)"(*'(#"(+-D
)+86+4%I3*(0;%08(369%'C%?')+%6B05%6A'%;35+*%A0*%5'6+4%35%H(*6%(54+)%Oz-j%'C%@063+56*K

7 to 12 D

The rate of best spectacle-corrected visual acuity loss


was essentially the same for all myopic groups. This
finding 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


P.H+\<+ K$;#0D+1;+&QKST+;1"+0"#$07#(0+1;+7D1F.$++
myopia

Wavefront
aberrometers represent a major advance in
+
1"+*DF#"1F.$
our ability to measure subtle, yet visually substantial,
(
XUG`Me#&.5(.-&85"8'&981$$&85&0()%./"'((
optical
defects.
The
outcomes for wavefront-guided
YVo2.G=OG=,G==oUU
(
"8/%57Shave
LASIK
in myopia
been investigated by the FDA for
three separate laser platforms. In view of the fewer
numbers of non-FDA studies, the diering outcome
Figure 3: Safety of LASIK for treatment of myopia or hyperopia
BSCVA=best spectacle-corrected visual acuity.
measurements, and follow-up for these studies, only
the FDA data are presented here.
Grouped data from the FDA-approved wavefrontComparison of low to moderate versus high myopia
In general, we might expect less accuracy and larger guided laser platforms (LADAR Vision; Technolas 217z;
wound-healing eects with the deeper ablations. !"#$%&'()*+%,--.%%/%#01+%OPV
As the and Star S4 and Wavescan Wavefront System, VISX,
depth decreases, the cornea might also be destabilised, and Santa Clara, CA, USA, and Bausch & Lomb Technolas
this instability can further retard the ability to reach a target 217z)4345 for low to moderate myopia showed manifest
refraction. With the FDA data, a comparison of manifest refraction spherical equivalent within about 100 D in
2

0 to +2 D

+2 to +4 D

+4 to +6 D

0 to +6 D

3749,51,52,5566

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6'%C'8(*%'I+)%0%N)'04%+5'(1B%)051+%6'%0;;'A%C')%N'6B%C(5863'50;%5+0)%054%43*6058+%
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!"#$%&'()*+%,--.%%/%#01+%O.,

Outcomes of LASIK for presbyopia

Presbyopia is an age-related refractive condition in which Outcomes of surface ablations (photorefractive


the eye is no longer able to focus over a broad enough keratectomy and LASEK)
range to allow for both functional near and distance Surface ablation (photorefractive keratectomy) was the
vision. Laser vision correction is unable to correct this first ablative refractive surgical technique approved by
condition per se, but can be harnessed to create corneal the FDA. Although photorefractive keratectomy came
multifocality and pseudoaccommodation. Attempts to into some disfavour during the late 1990s, surface
create multifocal corneas using new ablation profiles ablation has seen a partial resurgence for the treatment
during
LASIK surgery are under investigation in France of refractive error in patients with thinner corneas and
36*%0**'8306+4%)3*M*K%<B+%3?@)'I+?+56*%35%6B+%;0*+)%*9*6+?*%805%0;*'%3?@)'I+%'(6D
and South America,72,73 and hold promise as future low to moderate myopia, as a result of the avoidance of
(+U"8&'(6."0"$&B7&8,->'("&'B#'*.+/1&Y6"&gDS9X&)-+("$,-"&-")-"8"/*8&'&U+$.!D
lamellar flap creation and its associated risks. The
techniques
to treat presbyopia.
LASIK surgery can, however, treat the symptoms of improvements in the laser systems can also improve
8063'5%'C%6B+%')31350;%@B'6')+C)0863I+%M+)06+86'?9%@)'8+4()+%35%AB38B%6B+%@063+56c*%
presbyopia through the use of a technique termed outcomes achieved by surface ablation. The LASEK
7476
").*6"#.,U&.8&-"*'./"$&_B7&U'E./@&'/&").*6"#.'#&F')`&./8*"'$&+>&-"U+0"$1
monovision.
In monovision, the distance refraction for procedure represents a modification of the original
one eye is emmetropic and the distance correction for the photorefractive keratectomy procedure in which the
second eye is myopic; one eye is set for distance vision and patients epithelium is retained (by making an epithelial
Y6"&
+-.@./'#&
)6+*+-">-'(*.0"&
E"-'*"(*+U7&
of removed. ?"-"& ,/$"-*'E"/& ./&
the
other
for nearerWCD&
vision.8*,$."8&
In phakic >+-&
patients
who still flap) instead
VV%054%(*+4%;0*+)%*9*6+?*%6B06%434%5'6%B0I+%80@0N3;363+*%'C%;0*+)*%6'409s+1G%
The original FDA studies for photorefractive keratectomy
have
some
degree of accommodation, albeit insucient
O..=G
for their needs, the near eye need not be corrected (or left were undertaken in 1995,77 and used laser systems that did
'$0'/("$&8+>*?'-"%&'((,-'*"&"7"P*-'(E./@%&'/$&#'-@"-&'B#'*.+/&A+/"81&2/&0."?&+>&
untreated)
at a level of myopia for near alone (about not have capabilities of lasers todayeg, advanced soft275
D), but instead can be only mildly near-sighted. The ware, accurate eye-tracking, and larger ablation zones. In
*6"&#.U.*'*.+/8&+>&*6"&#'8"-8&,8"$&./&*6"8"&8*,$."8%&'/'#78.8&+>&*6"&WCD&$'*'&'#+/"&
outcomes for monovision treatment are dependent not view of the limitations of the lasers used in these studies,
C')%@B'6')+C)0863I+%M+)06+86'?9%3*%5'6%;3M+;9%6'%93+;4%(*+C(;%)+*(;6*%C')%6'409c*%@0D
only on the ability of the laser to accurately reach the target analysis of the FDA data alone for photorefractive
*."/*81&m+&WCD&*-.'#&>+-&*6"&gDS9X&)-+("$,-"&6'8&B""/&$+/"1
refraction,
but also on the patients ability to adjust to keratectomy is not likely to yield useful results for todays
anisometropia and the slight decrement in visual acuity patients. No FDA trial for the LASEK procedure has been
and depth perception that arises from the dierent focal done.
<B+%0I03;0N;+%4060%*(11+*6%6B06%*()C08+%0N;063'5%08B3+I+*%)+*(;6*%*3?3;0)%6'%RT7>_K%
points
in each eye. Therefore, the preoperative use of
The available data suggest that surface ablation achieves
monovision
lenses 8(?(;063I+%
might be useful. 4060% C')% @B'6')+C)0863I+%
results similar to LASIK.
Table 1 provides
<0N;+% O% contact
@)'I34+*%
M+)06+86'?9%
054% cumulative
RT7!_%
There are no FDA trials for the use of LASIK for data for photorefractive keratectomy and LASEK
Y-G=-o=,G=UG=VGVPo.O
30,5052,56,57,7891
*"(6/.T,"81
%
&'?N35351%
0;;%
?9'@30G%
@B'6')+C)0863I+%
M+)06+86'?9%
monovision. Non-FDA data suggest that about 80% of techniques.
Combining all myopia, photopatients
will make the adjustment to monovision, and refractive keratectomy achieves best spectacle-corrected
08B3+I+*%N+*6%*@+8608;+D8'))+86+4%I3*(0;%08(369%'C%,-g,-%')%?')+%35%UOj%'C%@0D
that most patients will adapt to monovision within visual acuity of 20/20 or more in 61% of patients and of
63+56*%054%'C%,-g2-%')%?')+%35%.2jG%054%RT7!_%08B3+I+*%N+*6%*@+8608;+8'))+86+4%
34
weeks. Perhaps the most important factor for 20/40 or more in 94%, and LASEK achieves best spectacleobtaining
good outcomes with this technique is proper corrected visual acuity of 20/20 or more in 74% of patients
I3*(0;%08(369%'C%,-g,-%')%?')+%35%V2j%'C%@063+56*%054%'C%,-g2-%')%?')+%35%.2jK%
selection of patients and adequate counselling before the and of 20/40 or more in 94%. For manifest refraction
W+-&
U'/.>"8*&
8)6"-.('#&
"T,.0'#"/*%&
)6+*+-">-'(*.0"&
E"-'*"(*+U7&
6'8&
procedure. Patients-">-'(*.+/&
must understand
that improved
spherical
equivalent, photorefractive
keratectomy
has'&
a
functional
vision, if it does arise, will come only after the postoperative value of about 050 D in 71% of cases and
)+8*+)"-'*.0"&0'#,"&+>&'B+,*&LpL&C&./&q3e&+>&('8"8&'/$&gDS9X&./&que&+>&('8"81&
adaptation period, and that it comes at some price to both LASEK in 74% of cases. From a refractive standpoint, the
W-+U&'&-">-'(*.0"&8*'/$)+./*%&*6"&*"(6/.T,"8&8""U&0"-7&8.U.#'-1
near and distance acuity. When the patient is unhappy, techniques seem very similar.
Myopia

Hyperopia

PRK5052,56,57,7885

LASEK78,79,8588

PRK30,8991

LASEK89

Visual range

1 to 130 D

1 to 125 D

+1 to +5 D

+2 to +5 D

UCVA =20/20

2559/4184 (611%)

471/637 (739%)

474/630 (752%)

79/108 (731%)

UCVA =20/40

3877/4112 (943%)

361/382 (945%)

594/682 (871%)

98/108 (907%)

Within about 05 D of MRSE

2965/4158 (713%)

451/610 (739%)

481/682 (705%)

82/108 (759%)

Within about 10 D of MRSE

3748/4158 (901%)

482/538 (896%)

581/682 (852%)

99/108 (917)

Loss of =two lines of BCVA

3/517 (06%)

13/610 (21%)

14/682 (21%)

0/108 (00%)

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 1: Cumulated outcomes of photorefractive keratectomy (PRK) and LASEK for myopia and hyperopia

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g the LASIK
ive complicain table 2.94116
perative flaps
icrokeratome
icrokeratome
tion, or interrmally steep
atient cornea.
s in terms of
rregular cuts
lt. However,
duce diuse
ids keeps the
keratitis to a
y and type of
surgeon can
he procedure
on.
plications are
usually not
or deranged,
eratectomy.

fter refractive
n which the

Postoperative scarring and haze is more common after


surface ablation than LASIK, particularly in deeper
ablations for higher degrees of myopia. Often a fine
reticular haze can be seen at the slit lamp, but there are
no visual consequences. Visually pronounced haze might
occur in 12% of patients with high myopia. This haze
FDA trials*

Non-FDA studies

Epithelial defect9498

050%

50226%

Lamellar keratitis99105

099%

0232%

Haze99,106,107

057%

1862%

Flap folds

100%

0211%

Thin flap99,100,108

042%

008075%

Free-cap99,100,108

340%

008100%

Irregular flap99,100

n/a

00902%

Buttonholed flap99,100,108

n/a

013056%

Incomplete flap99,100,108

n/a

023075%

Dislodged flap99,100

022%

1120%

Epithelial ingrowth99,100,109111

014%

03391%

Debris106,112,113

331%

19100%

Infectious keratitis100,107,114,116

00%

002%

Ectasia

00%

02%

99,100

116

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 specific complications. Data are
proportion of patients affected.

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Table 2: LASIK complications

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

@?

Quality of Vision after Refractive


Surgery
Dimitri T. Azar, MD
B.A. Field Endowed Chair,
Professor and Head,
Department of Ophthalmology
and Visual Sciences,
Illinois Eye and Ear Infirmary,
University of Illinois at Chicago

c-31E;C%/&%RE6E/:%3&;)5%5)&53(;ER)%6-5G)5C
d%ME2E;5E%UT35=%":E;)4%N;3;)6%d

Quality of Vision after Refractive


Surgery
Dimitri T. Azar, MD
B.A. Field Endowed Chair,
Professor and Head,
Department of Ophthalmology
and Visual Sciences,
Illinois Eye and Ear Infirmary,
University of Illinois at Chicago

1.
2.
3.

fB0h%S"J=>%&=#E;)*)@,%
Non-Custom LASIK
3+]";#=A=;<J

Measurement of spherocylindrical error


Flap dissection with microkeratome &
photoablation with excimer laser

B>?J%[=@?J<>"<?);
.L*<?H)#"*%3V*"<?);J

Number of LASIK Procedures in US


1998
430,000
1999
800,000
2000-2007
(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

3**=@>=<<)%S"J=>%&=#E;)*)@,%
3+]";#=A=;<J

1.
2.
3.

Non-Custom LASIK
fB0h%S"J=>%&=#E;)*)@,%
3+]";#=A=;<J
Measurement of
spherocylindrical error
Flap dissection with microkeratome &
photoablation with excimer laser

B>?J%[=@?J<>"<?);
.L*<?H)#"*%3V*"<?);J

Number of LASIK Procedures in US


1998
430,000
1999
800,000
2000-2007
(projected)
1.5-2 mil./yr
Complication rate

KFS%S"J=>%&=#E;)*)@,%
3+]";#=A=;<J
.?M=+%3J<?@A"<?JA%3DD>)]"*
B;J<";<";=)LJ%%I"#E,A=<>?#
A);?<)>?;@
.L*<?H)#"*%3V*"<?);J

0.5% - 2%

Mechanical complications relate to the flap


Optical complications relate to decentration, optical
zone size, positive asphericity, and uncorrected
HOA

2=A<)J=#);+ GD<?#"*%/=*?]=>,%0,J<=A

3**=@>=<<)%S"J=>%&=#E;)*)@,%
3+]";#=A=;<J
KFS%S"J=>%&=#E;)*)@,%
.?M=+%3J<?@A"<?JA%3DD>)]"*
3+]";#=A=;<J
B;J<";<";=)LJ%%I"#E,A=<>?#
A);?<)>?;@
.L*<?H)#"*%3V*"<?);J

# $%&''()*+'(&,,%&+&-*'(
#)>;="%<)%H*"<<=;%=,=%F%
A"?;<"?;%D>=#?J=%
7
+?J<";#=%H>)A%*"J=>%
E="+%<)%H)#"*%D)?;<%

Tear Film
Epithelium
Bowmans
Stroma
Descemets
Endothelium

2=A<)J=#);+ GD<?#"*%/=*?]=>,%0,J<=A
# $%&''()*+'(&,,%&+&-*'(
#)>;="%<)%H*"<<=;%=,=%F%

5
!"#$%&'()*+%,--.%%/%#01+%,-U

Optical complications may be reduced with custom


LASIK and newer technologies of laser delivery

Mechanical complications may be reduced


with newer technologies

LASIK Limitations

# )&'*.(/'('*-(-0(1*'/.*1(
+=D<E

1D?<E=*?"*%4,J<J

R /=H?;=+%+?J<";#=%H>)A%V)<<)A%
)H%@*"JJ%"DD*";"<?);%JL>H"#=%

!PotentialFlaprelatedComplications

# 23%'*'(1*%/4*.*1(/+(&(
D>=J#>?V=+%D"<<=>;%#>="<?;@%"%
E)>?`);<"*%)>%]=><?#"*%#*="]"@=%
D*";=%?;%<E=%#)>;="

!Customcorneallimitations
!Ectasia

Optical complications may be reduced with custom


LASIK and newer technologies of laser delivery

LASIK Limitations

1D?<E=*?"*%4,J<J

0<>?"=

!PotentialFlaprelatedComplications
!Customcorneallimitations

Corneal Ectasia in Myopia

!Ectasia

Preexisting KC
Deep flap
High myopia
Deep laser ablation
(Ectasia is more likely to occur after LASIK)

0<>?"=
Potential Complications in Patients with Coexistent
Keratoconus and Fuchs Dystrophy

Corneal Ectasia in Myopia


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

Preexisting KC
Deep flap
High myopia
Deep laser ablation
(Ectasia is more likely to occur after LASIK)

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

Potential Complications in Patients with Coexistent


Keratoconus and Fuchs Dystrophy

!"#$%&'()*+%,--.%%/%#01+%,-V
Case 1. Top, Orbscan
topography showed
advanced inferior
steepening consistent

@?

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

Potential Complications in Patients with Coexistent


Keratoconus and Fuchs Endothelial Dystrophy

Case 2. Top, Orbscan


topography showed
inferior steepening of the
right eye (OD) consistent
with keratoconus. Slitlamp photography
showed multiple guttae.
Specular microscopy was
unable to provide an
image. Bottom, Orbscan
topography showed
inferior steepening of the
left eye (OS). Corneal
guttae were noted on slitlamp photography.
Specular microscopy was
unable to provide an
image of the eye. N =
nasal; T = temporal.

Ectatic Disorders Associated with a Claw-Shaped


Pattern on Corneal Topography

Surface Ablation?

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

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

Ectatic Disorders Associated with a Claw-Shaped


Pattern on Corneal Topography

Surface Ablation?

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

Surface Ablation, Combined with MMC, May


Overcome Several Limitations of Phakic IOLs
Control-Matched Comparison of
LASEK and LASIK
!ShallowAC

# Retrospective, nonrandomized, control-matched study


# The charts of 2257 eyes that underwent LASEK or LASIK
!Lowinitialendothelialcellcounts
treatment were reviewed.
# Inclusion criteria: patients who were 21 years of age or
!Progressiveendothelialcellloss
older having between !0.75 and !6.00 diopters (D) of
myopia with up to !2.25 D of astigmatism.
!Cataractformation
# One hundred twenty-two LASEK-treated eyes were
matched with 122 LASIK-treated eyes having preoperative
!SeriousIntraoperative/Postoperative
spheres,
cylinders, and SE within 0.50 D.
Complications
# Both groups
had similar preoperative best spectaclecorrected visual acuity (BSCVA), laser platform, and followup durations.

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

!ShallowAC
# Retrospective,
nonrandomized, control-matched study
# The charts of 2257 eyes that underwent LASEK or LASIK
!Lowinitialendothelialcellcounts
treatment
were reviewed.
# Inclusion criteria: patients who were 21 years of age or
!Progressiveendothelialcellloss
older having
between !0.75 and !6.00 diopters (D) of
myopia with up to !2.25 D of astigmatism.
!Cataractformation
# One hundred twenty-two LASEK-treated eyes were
matched with 122 LASIK-treated eyes having preoperative
spheres,
cylinders, and SE within 0.50 D.
!SeriousIntraoperative/Postoperative
# Both groups
had similar preoperative best spectacleComplications
corrected visual acuity (BSCVA), laser platform, and followup durations.

Control-Matched Comparison of
LASEK and LASIK

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.

Line Loss/Gain of 122 LASEK Eyes


Matched with 122 LASIK Eyes
Z9
8Y'5

Y9

85'X

89

% of Eyes

Surface Ablation, Combined with MMC, May


Overcome Several Limitations of Phakic IOLs
Control-Matched Comparison of
LASEK and LASIK

W9
P9
5Z'Y

X9

5W'P

59
79

W'Y

:'9

i5%S?;=J

i7%S?;=

S301O

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

9'Z

9'9 9'9

9'9

9'Z 9'9

9
N)%S)JJ

g7%S?;=

g5%S?;=J

g%X%S?;=J

S30BO

506&/78 9:;($<&+*=(>?;(@&8*7< >>;(A&%%&B(


!3-3`"> /&'%3A%!%GDE<E"*A)*'%5998j%
7P5^8_C%:97iZ

Control-Matched Comparison of
LASEK and LASIK

!"#$%&'()*+%,--.%%/%#01+%,-P
Postoperative results:
Mean SE was !0.15 0.40 D
for LASEK and !0.37

Line Loss/Gain of 122 LASEK Eyes


Matched with 122 LASIK Eyes

# Nomogram adjustment may be necessary for


LASIK surgeons adopting surface ablation.

Control-Matched Comparison of LASEK


and LASIK for Low to Moderate Myopia

Epi-LASIK Attempted versus achieved spherical equivalent correction

Surface Ablation

Attempted versus Achieved Spherical Equivalent


Correction at the Final Visit

Conclusions:

<=><?!<@A;B
Y
# Surface
ablation is a viable alternative to LASIK
8
especially in young patients with thin
W
pachymetry,
steep K, and/or corneal
P
irregularities.
# Microkeratome
and flap- related complications
X
are
avoided.
5
# Surface
ablation is a reasonable alternative to
7
phakic IOLs in patients with low endothelial cell
9
counts,
shallow
AC,
early
lens
opacities,
and/or
9
7
5
X
P
W
8
Y
Z
high
astigmatism.
Achieved (D)
Attempted (D)

# 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.

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

79
Epi-LASIK Attempted versus achieved spherical equivalent correction

Surface Ablation

Attempted versus Achieved Spherical Equivalent


Correction at the Final Visit

LASIK in the Presbyopic Age Group: Safety, Efficacy


and Predictability in 40-69 Year Old Patients

Attempted (D)

<=><?!<@A;B
Y
# Surface
ablation is a viable alternative to LASIK
8
especially in young patients with thin
W
pachymetry,
steep K, and/or corneal
irregularities.
P
# Microkeratome
and flap- related complications
X
are 5avoided.
# Surface
ablation
is a reasonable alternative to
7
phakic IOLs in patients with low endothelial cell
9
counts,
shallow
AC,X early
lens
opacities,
and/or
9
7
5
P
W
8
Y
Z
high astigmatism. Achieved (D)
CD3D!<!D*?;B
# The long-term risks of prophylactic MMC are
unknown.

Conclusions:
AFFERENTARM
EFFERENTARM
# 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.
Corneal Topography/
Wavefront Analyzer

+ ScanningLaser
=
CustomAblation

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

79

77

LASIK in the Presbyopic Age Group: Safety, Efficacy


and Predictability in 40-69 Year Old Patients
Conclusions:
AFFERENTARM
# Despite
a trend towards EFFERENTARM
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.

What are the Optical Limits to


Corneal Refractive Surgery?

Corneal Topography/
Wavefront Analyzer

+ ScanningLaser
=
CustomAblation

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

77

What are the Optical Limits to


Corneal Refractive Surgery?

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

@?

75

# Outcomes: % > 20/20; % > 20/40; % + 0.50D;


%+ 1D; % loss of > 2 Snellen lines
Sakimoto T, Rosenblatt MI, Azar DT - - Lancet 4/2006

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

S?A?<"<?);J%?;%k"]=H>);< 3;"*,J?JC%
.="JL>=A=;<%0<=DJ
# C&4*D.0+-' .*E0+'-.3E-*1F&+&%8G*1
R E?@E=>%)>+=>%Q=>;?$=%D)*,;)A?"*%)>%
2)L>?=>%>=D>=J=;<"<?);%)H%T"]=H>);<
@=;=>"<=+'
R 1HH=#<?]=%#*?;?#"*%D>=J#>?D<?);%@=;=>"<=+%
";+%#)AD">=+%<)%DE)>)D<=>'
R [=D="<%A="JL>=A=;<J%#)AD">=+%H)>%
#);J?J<=;#,'
7X

7P

S?A?<"<?);J%?;%k"]=H>);< 3;"*,J?JC%
.="JL>=A=;<%0<=DJ
# C&4*D.0+-' .*E0+'-.3E-*1F&+&%8G*1
R E?@E=>%)>+=>%Q=>;?$=%D)*,;)A?"*%)>%
2)L>?=>%>=D>=J=;<"<?);%)H%T"]=H>);<
@=;=>"<=+'
R 1HH=#<?]=%#*?;?#"*%D>=J#>?D<?);%@=;=>"<=+%
";+%#)AD">=+%<)%DE)>)D<=>'
R [=D="<%A="JL>=A=;<J%#)AD">=+%H)>%
#);J?J<=;#,'

Scanning and Tracking Laser


Technology Limitations
Avoidance of Eye drift
during surgery
# Tracking of cornea in
3 dimentions: x, y, and
rotational
# Differentiation of
rotational vs.
translational
movement (eye mvt vs
head mvt)

7P

7W

Scanning and Tracking Laser


Technology Limitations
!"#$%&'()*+%,--.%%/%#01+%,OAvoidance of Eye drift

(collagen relaxation, ectasia)

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

CornealAsphericity
Sphericalsurface(Shapefactor:Q=0)
orOblatesurface(Shape factor: Q > 0) :
Peripheralraysarebentmorethantheparaaxialrays

Myopic LASIK:

Central area flatter than


Peripheral untreated zone
Is the treatment zone oblate?

Q>0

78

7Y

CornealAsphericity
Sphericalsurface(Shapefactor:Q=0)
orOblatesurface(Shape factor: Q > 0) :
Peripheralraysarebentmorethantheparaaxialrays

PreoperativeCornealAsphericity
Originalcurvature:Prolate
lowsphericalaberrations

y
Myopic LASIK:

S/2

R2
t(y)

X1(y)

Central area flatter than


Peripheral untreated zone

X1(y)
X2(y)

R1

Is the treatment zone oblate?

Sphericallybasedtreatment x

Q>0
X1(y)
X2(y)=X1(y)+t(y)

Gatinel andAzarInvest.Ophthalmol VisSci

7Y

PreoperativeCornealAsphericity
y
S/2

Originalcurvature:Prolate
lowsphericalaberrations

R2

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

7Z

@?

X1(y)
X2(y)
C(y):conicsectionwithapicalradiusR

2andshapefactor

pc

C(y)
S/2

R2

R1
X1(y)

t(y)

X2(y)

X1(y)
X2(y)
C(y):conicsectionwithapicalradiusR

2andshapefactor

pc

7:

Prolate andOblateOutcomes
Outcome of Asphericity R1=7.8
Magnitude of treatment (D)
9

79

77

75

7X

5-W

prolate
D7l7'P
5

7-W

sphere

D7l7'X

7
P

D7l7
9-W

oblate
D7l9'YW

i9-W
D7l9'P

i7

7:

59

Prolate andOblateOutcomes
Outcome of Asphericity R1=7.8
Magnitude of treatment (D)
9

79

77

75

7X

5-W

prolate
D7l7'P
5

7-W

sphere

D7l7'X

7
P

D7l7
9-W

oblate
9

D7l9'YW

i9-W
D7l9'P

dZ "

i7

S 2 D ( 3S 2 %( S 2 D % (& 3Q1 S 2 %#( ! S 2 D % (& dQS 4 %#


&
) &&
2 #&
3 #
##&&
## ) &
## ) &
3
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59

57

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

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.

Gatinel,Malet,HXuan,Azar,Invest.Ophthalmol VisSci,April2004

55

CONCLUSIONS

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

# 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

DimitriT.AZAR,M.D.

# Other limitations include inability to measure

and render all HOA at all wavelengths,


inability
Gatinel,Malet,HXuan,Azar,Invest.Ophthalmol
VisSci,April2004
to predict the surgically-induced aberrations,
and inability to perfectly position Rx on the
corneal plane.

55

5X

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ANNUAL CO

ANNUAL CONGRESS

ANNU

UAL CONGRESS

AL CONGRESS
ANNUAL CONGRESS

CONGRESS

ANNUA

ANNUAL CONGRESS

ANNUAL CON
UAL CONGRESS

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EVER 2009

JOIN EVER in Portoroz Slovenia


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21 CME CREDITS

www.ever.be
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October 1-3, 2010 - Athens, Greece

RETINA

EUPO COURSE 2010

EUROPEAN PROFESSORS OF OPHTHALMOLOGY

www.eupo.eu

European University Professors of Ophthalmology


8DGC:6!8DC?JC8I>K6VcYG:;G68I>K:HJG<:GN
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