Download Peter R. Andrews, MD Eye Care Center of Northern Colorado

Peter R. Andrews, MD
Eye Care Center of Northern Colorado
Longmont, Lafayette
Greeley, Boulder
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Keratoconus Review
Evaluation Tools for Keratoconus
Existing Technologies for Keratoconus Treatment
History of Crosslinking
Present approaches and Protocols
Our protocol
• 1748 Burchard Mauchart (German) - early case description called
“staphyloma diaphanum”.
• 1854 John Nottingham (British physician) - described keratoconus "conical
cornea“ with classic features
• polyopia, corneal weakness, and difficulty matching corrective lenses
• 1859 William Bowman (British surgeon) used von Helmholtz’ new
ophthalmascope to diagnose keratoconus
• Surgical correction by pulling the iris to make the pupil a vertical slit
• 1869 Johann Horner (Swiss ophthalmologist) - thesis entitled On the
treatment of keratoconus
• ~ 1870 Albrecht von Graefe (German Ophthalmologist) - attempts to
reshape the cornea by chemical cauterization with silver nitrate, a miosiscausing agent, and a pressure dressing
• 1888 Eugène Kalt (French physician) - first practical applications of the new
contact lens
• 1936 Ramon Castroviejo (Spanish Ophthalmologist) - First successful cornea
transplant to treat keratoconus
• Statistics:
• Estimates on number of people with this disorder vary from
50 to 170 per 100,000 population1
• 142,000 - 484,000 patients affected in U.S.
• One of the most common causes of cornea transplantation in
Western developed countries
• 2011: 8,071 of 46,196 Transplants in U.S.
• An estimated $125 Million spent annually on healthcare in
U.S. for keratoconus2
• Over 10% of keratoconus patients have a loss of productivity
due to this disorder3
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Duke-Elder S, Leigh AG. Keratoconus. In Systems of Ophthalmology, Vol. 8 (1965); Hofsteller HW. A Keratoscope Survey of
13,395 eyes. Am. J. Optom. Arch Am. Acad. Optom. (1959)
2Company Estimate
3 Investigative Ophthalmology and Visual Science, Dec. 1998, Vol. 39, No. 13
• 8-year, multi-center, natural history study: 1209 KCN patients
• 7-year decrease in BCVa: 2.03 letters (4.06 in low contrast)
• 19% decrease 10+ letters (high-contrast) & 31% decrease 10+ letters (low-contrast) BCVA
• 8-year increase in corneal curvature of 1.60D in the flatter
corneal meridian
• 24% demonstrating increases of 3.00D or more.
• 8-year incidence of corneal scarring was 20%
• Risk factors for corneal scarring
• younger age, corneal staining, steeper baseline corneal curvature, contact lens wear, and poorer lowcontrast visual acuity
• Visual Function Questionnaire: KCN Q.O.L. < AREDS 3
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FLEISCHER RING abrupt change in curvature 50%
VOGT’S STRIAE 1st Sign 65%
STROMAL THINNING
STROMAL SCARS
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CLEK study showed
Steeper K 28% more scars
43% of flat fits had scars
26% of steep fits had scars
• SWIRL-LIKE PATTERN
• ENLARGED CORNEAL NERVES
• ACUTE HYDROPS 5%
SCLAFANI
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Few or No corneal signs!
Irregularly keratometry
corneal steepening (80% inferior, 15% central)
diagnostic rigid CL base curve equal to the flat K’s, can see
KCN pattern
• Is it or Isn’t it??
• ..LASIK Surgeon’s twitch
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Enlarged corneal nerves
40% develop Vogt striae
50% Fleischer ring.
20% develop corneal scarring. (fibular,
nebular, or nodular).
• Paraxial (usually inferior) stromal
thinning may be appreciated.
• Keratometry values increase - 45-52D
• "scissoring" on retinoscopy or the oil
drop sign on direct ophthalmoscopy.
• Marked thinning
• Dense anterior stromal scar
• ? Prior hydrops
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Munson’s sign
Hydrops
K’s of 52 and up
Severe irregular astigmatism
Munson’s sign with
Apical Scarring
• History of trauma that causes
weakness
• Recurrent trauma due to
rubbing from
• Blepharitis, CL/lids, 53% have
atopic dx
• Lieber’s- rubbing produces
scotopsias
• Pressure on corneal nerves is
pleasing (right handed)
• Inflammatory component !!!
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Decrease proteinase inhibitors
Increase collagenase
Premature keratocytic apoptosis
Increase cytokine binding
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Vernal KC
Atopic Dermatitis
Down’s Syndrome
Floppy Eyelid Syndrome
Mitral Valve Prolapse
Ehlers-Danlos Syndrome
Osteogenesis Imperfecta
Lawrence-Moon-Biedl
Syndrome
• Neurofibromatosis
• Psuedoxanthoma Elasticum
SCLAFANI
• KCN is unlikely a single gene defect
• Chromosome 5, 21
• Multiple genes in a common pathway
• KCN natural – or only if exposed to oxidative stressors ?
• CL over-wear, UV light, allergy, or refractive surgery
• TX: Anti-inflammatory, Anti-oxidant?
• KCN have suppressed Aquaporin 5 (AQP5)
• AQP5 is the water transport gene that is responsible for cell migration
and wound healing.
• Quantitative PCR testing (epithelial cells) could diagnose this
• Yaron Rabinowitz et. Al, IOVS, 2006
SCLAFANI
• Retinoscopy
• Cheap & Portable
• Works well for regular
astigmatism
• Gross evaluation of
corneal regularity
• Scissoring reflex
• Keratometry
• Mires reflect corneal (&
tear film!) surface
• Measures central 3mm
• changes with K power
• Assumes regular
astigmatism
• But user can detect
irregular astigmatism
Topography History
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1880 Portuguese ophthalmologist Antonio Placido
used a painted disk (Placido's disk) of black and white
rings to view its reflection in the cornea.
1896, Gullstrand added rings to an ophthalmoscope
& manually computed curves from pictures of the
ring reflections.
1950s the Wesley-Jessen company added the curved
bowl to reduce the field defects.
1990’s the Corneal Modeling System (CMS-1) was
developed by Computed Anatomy, Inc. (CAI) as the
first completely automatic system
Placido Disk Mires
Indices from Topography
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SimK – Mires 7, 8, & 9 of topographer  3mm of
a keratometer
ACP Average Corneal Power
SAI - Surface Asymmetry Index – Weighted sum
of points 180o apart on mires
SRI - Surface Regularity Index – data from inner
10 rings
Keratoconus Cases Are
NOT All The Same
Cones Sensative Indices
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DSI/OSI – Differential Sector Index & Opposite Sector
Index
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Analysis of 8 pie-wedge 45o sectors
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I-S Ratio – Inferior-Superior ratio
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(Inferior 5 points 30o apart) – (Superior 5 points) = I-S ratio
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Central K Power > 48.7 & I-S > 1.9 = Keratoconus
K Power < 48.7 but > 47.2 & I-S > 1.4 to 1.9 = “Keratoconus Suspect”
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DSI – greatest power diff. of 2 sectors (High in Reg. Astig)
OSI – greatest power diff of opposite sectors. (Low in Reg. Astig)
CSI – Central Surround Index
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Difference in K power of central 3mm and surrounding 3 to 6mm area
Sensative to central cones
AXIAL (Sagittal) – usual maps
Distance to reference
point, not curves
More global:excludes extremes
Used for RGP fits: like K’s
Sphere biased
TANGENTIAL
Local or true curvature
Best for shape analysis: disease
Peripheral curve biased
More detailed
AKA: Instantaneous=True=Local
SCLAFANI
Predicts the relative
elevation or depression
of the cornea (in mm)
using a computer
generated BEST FIT
SPHERE as a reference
and fit at the steepest
point
SCLAFANI
• Wavefront scanners reveal
HOA’s
• Coma-like HOA’s higher in
Keratoconus
• Can be used in screening LASIK
• Intacs have been shown to
decrease HOA’s
• Up to 60% of vision loss may
be due to shape/Coma, not just
high cylinder
• COMA – Zernicke Z31
• 60% reduction in VA is due to
curvature, not just high cylinder
• Leads to reduced low contrast VA
• Off axis peripheral rays cause a
comet-shaped image deformity to
non-axial portions of the image.
• RGP corrects cylinder however some
HOA’s can remain
• May consider reverse geometry CLS,
scleral lenses, etc.
SCLAFANI
image courtesy of Prof. G. Baikoff
INTACS History
Concept for Corneal Reshaping
Brief History
1978 INTACS conceived by A.E. Gene Reynolds, O.D.
1984 First concept designed
1991 First Human Corneas implanted
1990’s Develop nomogram for myopia
1997 First Keratoconus Cases Treated with
INTACS Corneal Implants
• Develop Nomogram for KCN
2004 FDA approval for Keratoconus as HDE
• Refine Nomogram for Keratoconus
Colin J, Cochener B, Savary G, et al.INTACS inserts for treating keratoconus: one-year results. Ophthalmology
(United States), Aug 2001, 108(8) p1409-14
Colin J, Velou S Implantation of Intacs and a refractive intraocular lens to correct keratoconus. J Cataract
Refract Surg (United States), Apr 2003, 29(4) p832-4
Name and Address
• In 1995 design was modified
for two 150° segments
• Present INTACS
• Arc length 150°
• Hexagonal (cross section)
• Outer diameter (8.10 mm)
• Different thickness yield
different results
• Reduce corneal coning
• Restore functional vision
• More comfortably achieved with contact
lenses
• Sometimes with soft contacts, glasses, or
without any additional correction
• Defer or eliminate the need
for transplant
(high probability of success)
Courtesy Dr. Mark Swanson
Old Treatment Continuum
Successful
CL Fits
Contact Lens
Intolerance
Contact
Lenses
In the Past:
• Patient told they have Keratoconus or are Suspect
• Fit with Glasses or Contact Lenses
• Fit with Gas Perm or Specialty Contact Lenses
• Re-Fit with Specialty Contact Lenses
• Becomes Contact Lens Intolerant or scaring occurs
• Educated about Corneal Transplants
Corneal
Transplant
New Treatment Continuum
Successful
CL Fits
Contact
Lenses
Today:
Intacs
Corneal Implants
Contact Lens
Intolerance
Corneal
Transplant
• Patient told they have Keratoconus or are Suspect
• Patient Educated on Current and Future Options to Treat their
Condition (Including Intacs)
• Fit with Glasses or Contact Lenses
• Fit with Gas Perm or Specialty Contact Lenses and told about
Intacs
• Re-Fit with Specialty Contact Lenses
• Becomes Contact Lens Intolerant
• Get Intacs
• Potentially Defers a Corneal Transplant
• Usually:
• Uncorrectable to 20/40 in spectacles
• Intolerant of Contact Lenses regardless of BCVA
• Must have tried RGP’s at least once
• Have clear central corneas.
• Have a corneal thickness of 450 microns or greater at the
proposed incision site.
• Sometimes:
• Have corneal transplantation as the only remaining
option to improve their functional vision.
• K’s up to 60*
Mean
Preop BCVA
20/50
Postop BCVA
20/32
Mean Chg
+1.7 lines
P value
p < 0.01
Mean
Preop UCVA
20/160
Postop UCVA
20/50
Mean Chg
+2.5 Lines
P value
p < 0.01
Brian Boxer Wachler et al
Mean
Preop BSCVA Postop BSCVA Mean Chg
20/50+
20/32-2
+2 Lines
P value
p = 0.0003
Mean
Preop UCVA
20/250+2
P value
p < 0.0001
Postop UCVA
20/100-1
Mean Chg
+4 Lines
Does INTACS Correct Astigmatism?
YES
Pre Astigmatism
-7.50
-3.25
-6.00
-5.25
-7.00
-6.00
-9.50
-6.00
Post Astigmatism
-2.25
-1.50
-1.25
-2.00
-3.00
-2.75
-4.50
-3.00
Pre-Surgical Planning
Step #1
Determine Cone Location
 Posterior Float Anomaly Appearance
Centered
De-Centered
Verify Posterior
Float AND
Keratometric
Corneal
Topography
to best evaluate
corneal imbalance
Case Example 2 – Pre-Op
UCVA CF
BCVA: 20/50
MR: -4.75 + 5.00 @ 20
Max K: 55.78 @ 90
Custom RGP Intolerant
Case Example 2 – Post-Op
UCVA 20/40
BCVA: 20/25
MR: -2.00
Max K: 51.69 @ 89
RGP Tolerant
• Drops
• Antibiotics 7-10 days
• Steroid taper 3-4 weeks
• Frequent artificial tears
• Temporary vision
correction
• Bandage Soft Contact
• First 3+ weeks SCL for
Spherical Equivalent if desired
• Toric SCL’s for after 3-4 weeks
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Glasses & Custom CL Fitting
• Avoid custom CL fitting until
suture(s) removed for 2-3 weeks
• Cornea not ‘concrete’ for about 3
months
 Lamellar Keratoplasty
 Interface haze limits visual result
 DALKP – Deep Anterior Lamellar Keratoplasty
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Less haze, but technically difficult. Can become PKP
 Penetrating Keratoplasty
 Most frequent procedure
 2011: 8,071 of 46,196 Transplants in U.S.
 80% to 90% Successful
 Issues
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Graft Rejection rate as high as 20%
Continued Astigmatism
Endothelial Cell Loss (Limited graft longevity)
Recurrence of Keratoconus
 Phakic IOL
 Central cones with high myopia/low-astigmatism
 Toric Phakic IOL (Verisyse ACIOL available, Visian – not)
 .. But concern that cornea may still progress
• Deep Anterior Lameller KP (DALKP)
• For anterior corneal pathology
• Kerataconus
• Anterior K scars
• Advantages
• Lower rate of rejection: Aqueous does not contact graft
• Faster healing –vs- PKP
• Can ‘undersize’ graft to flatten severe myopia (useful for
Kerataconus grafts)
• Most PKP’s are ‘oversized’ to better “plug the hole”
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Do they die younger?
NO
Do they not visit doctor?
POSSIBLE
Have they CE/PKP
POSSIBLE
Getting lenses from 1-800
THEORY BY KRACHMER
• The eye becomes more rigid as the patient ages and
therefore the condition stabilizes
• 70% have reduction in max K by 2D (N=23)
• Increase in rigidity by 329%
• Increase in spacing (1nm) between the collagen
molecules leads to increase diameter with no effect on
transparency (150nm)
• Increased resistance to enzymatic digestion
• Has been shown to be effective for iatrogenic ectasia in
animals.
• Bed < 400 um, severe endothelial damage
• (before epi removal)
• The cross-linking in KCN
is abnormal
• Too elastic and the
biomechanical resistance
is 50% less
• Loss of Bowman’s
GOAL:
• Increase cross-linking
• Increase diameter
• 12% Anterior
• 5% Posterior
UVA 370nm
O2
O2
Riboflavin 0.1%
<Oxygen Free-Radicals>
O2
O2
Biomechanical
Stiffness
Corneal Collagen
Crosslinking
Stability
• Immediate evidence of increased x linking:
• Resistance to swelling and stretching - decreased
historesis of cornea (bounce)
• Reichert’s Ocular Response Analyzer (ORA) - measures area
of deformation.
• Increases anchoring and reduces bulge
• Cellular Process 24h-12 weeks
Leads to apoptosis of keratocytes with late migration
of keratoblasts that result in flattening
• 5 yrs, N = 60, BCVA >1.4 lines K flat 2.87 D
• Goal is to strengthen the cornea
• Still not FDA approved in U.S.
• Standard treatment in Europe
• Least invasive intervention
• Different types of treatments – evolving standards
• All involve riboflavin (Vitamin B2) eyedrops
• Reaction with specific Ultraviolet light
• Strength and timing of light vary
• Decreases Astigmatism 1 to 2 diopters
• Not great for KCN with -5.00 astigmatism
• May reverse or arrest KCN Development
• Slow change over months
• Multiple refraction changes
• Can be combined with Intacs
• Best use will likely be EARLY KCN or fellow eye of
significant KCN patient, or as combined treatment
• Dresden Protocol – Theo Seiler, MD et. al
• Epithelial removal
• 3mW/cm2 of U.V. light (365 nm) for 30 minutes
• Effective, but risks of infection, epithelial healing problems
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2005, 127 eye, F/U up to 60 months.
Progression of KCN stopped in all the eyes
81.7% - mean decrease of 2.87 D in Kmax.
Lasting Effect @ 3-5 years
• No progression of KCN in any eyes
• 51.2% (31/60) slight flattening of the Kmax.
• Australian study 50 eyes – observation –vs- CXL for
keratoconus.
• Maxi-K’s 3 & 6 mos s/p CXL decrease of -1.10D & 1.39D
• Control eyes Increased 0.70 D and 0.78 D @ 3 & 6 mos.
• Treatment group - mean 2.2-line improvement in BSCVA
• BSCVA in the control group worsened.
• Quicker worsening than in CLEK study
• Likely worse cases seeking care.
• Topical Anesthetic, then epithelium is scraped
• Acts as diffusion barrier, potential damage
• 0.1% Riboflavin drops q 5 min throughout
• Protects the endothelium, lens, retina
• Increases absorption into stroma
• 30 min. radiation 370 nm UVA –3mW/cm3
• Post-op F/U and pain relief
• Depth goes to 300 um therefore must have 400 um
pachymetry to protect endothelium (before epi off)
SCLAFANI
• Higher power of light, for shorter period of time
• Same total energy delivered to the cornea
• Epithelium debate
• Epithelium left on, or scraped off?
• Important that the stroma is loaded with riboflavin
• Don’t want reaction and U.V. light on endothelium
• An identical total dosage of 5.4 joules of radiant energy
applied per square centimeter of exposed tissue.
• Suggests using it early in the disease to freeze tissue
and prevent further ectasia
• Scrapes the epithelium prior to procedure.
• 12 eyes followed for 3months in 2004.
• All showed improved UCVA, BCVA, and reduced
steepness• One side effect was transient stromal edema
SCLAFANI
• Day of surgery – Loading Riboflavin into corneal stroma
• Epi on, Epi interruption, Epi-off
• Controlled U.V. Light Exposure
• Depends on strength of light and exposure time.
• Initial healing phase
• Epithelial healing if needed
• Early Transient corneal edema
• Month 1 – Vision usually worse
• Anterior corneal haze forms, similar to some PRK patients
• No haze – likely no effect from CXL
• Months 2-3 – Vision begins to improve
• Likely stabilized by month 3
• Suggest waiting for month 6 or more if further intervention desired
• ICL, ?PRK
SCLAFANI
• Avedro
• Epithelium-off, Classic Dresden Protocol (3mW x 30min)
• Upcoming trials?
• High energy / short time
• Wave-front or Topography guided UV light
• Orphan Drug status on certain Riboflavin
• Cross-Linking USA (Topcon)
• Epi-on trial
• Shorter exposure time
• Allows prior intacs
• Turkish Trials
• CXL 4 mos s/p Intacs
• Intacs results: 1.9 Snellen lines UCVA & 1.7 BCVA.
• CXL ~4 mos later:
• Gained Additional 1.2 Snellen lines UCVA & 0.36 lines BCVA
• Later trial of Riboflavin injection into Intacs channels – similar results.
• Yaron Rabinowitz, MD, California, in progress
• Cross-linking < PTK LASER+CXL < Intacs < Intacs+CXL
• Physician-sponsored, Multi-center randomized treatment trial
• POCKET: “Pulsed Or Continuous Keratoconus and post-surgical Ectasia
Treatment” CXL Trial
• Randomized CXL treatment of Riboflavin and UV light of 18mW/cm2
– Pulsed 1min x 5 UV light -vs- 5min continuous UV light
• Does re-supplying oxygen increase Oxygen-radicals and therefore CXL ?
• Epithelium-on treatment
• Possible Anterior Stromal Micropuncture, or injection into Intacs channels
• Multiple Arms of Study:
• Keratoconus – with or without Intacs
• Post-LASIK/PRK ectasia.
• RK/AK with daily fluctuation
• Will enroll patients 12 years old and up
• One or both eyes – meet two of the following :
• Having a clinical diagnosis of progressive keratoconus consistent
with:
• An increase of ≥ 1.00 D in the steepest keratometry value
• An increase of ≥ 1.00 D in astigmatism manifest refraction
• A myopic shift (decrease in the spherical equivalent) of ≥ 0.50 D on
subjective manifest refraction
• Axial topography consistent with keratoconus
• Steepest keratometry (Kmax) value ≥ 47.00 D
• Contact lens removal prior to evaluation and treatment
• History of having undergone a keratorefractive
procedure and:
• Steepening by topography (Pentacam, Orbscan, or
Humphrey)
• Thinning of cornea
• Shift in the position of thinnest portion of cornea
• Change in refraction with increasing myopia
• Development of myopic astigmatism or irregular astigmatism
• Loss of BSCVA
• History of having undergone radial keratotomy (RK)
and or astigmatic keratotomy (AK) surgery.
• Complaints of difficulties due to vision changing during
the course of the same day.
• A difference in MRx ≥ 0.75D measured on the same
day, at least 6 hours apart.
• Intacs surgery will not be considered in patients with RK/AK
for this study.
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Pre-operative requirements
Follow-up visits
1 day, 1 week, 1 month, 3 months, 6 months, 1 year
Your participation
• Patient will have frequently fluctuating vision
• Will need on-going support of changing cornea/Rx
• Optimize other eye
• Topography-guided PRK combined with CXL
• The “Athens Protocol”
• Topo-guided PRK not available in U.S. (Alcon Wavelight LASER)
• LASIK eXtra
• Abbreviated CXL immediately following LASIK
• Goal is to decrease regression and need of enhancements
• Consider with thinner corneas and myopic treatment
• Could do PRK?
• However: Results for Hyperopic LASIK eXtra have been impressive
• Post CK or Post Ortho-K to enforce result
• Early studies not promising
SCLAFANI
1. Colin J, Simonpoli-Velou S. The Management of Keratoconus with Intrastomal Corneal Rings.
International Ophthalmology Clinics. 43(3):65-80, Summer 2003.
2. Kaiser P, Friedman N, et. al. The Massachusetts Eye and Ear Infirmary Illustrated Manual of
Ophthalmology. Ed. 2. 2004.
3. Kunimoto D, Kanitkar K, et al. The Wills Eye Manual. Fourth Edition. Lippincott Williams &
Wilkins 2004.
4. Roque M, Limbonsiong R, et. al. Myopia, Intracorneal Rings. August 14, 2002.
www.emedicine.com/oph/topic665.htm
5. Wachler B, Chandra N, et. al. Intacs for Keratoconus. American Academy of Ophthalmology.
2003. 1031-1039.
6. Weissman B, Yeung K, et al. Keratoconus. Jan 29, 2005 www.emedicine.com/oph/topic104.htm
7. Kılıç A, Kamburoglu G, Akıncı A., J Cataract Refract Surg. 2012 May;38(5):87883. doi: 10.1016/j.jcrs.2011.11.041. Epub 2012 Mar 15
8. Wollensak G. Cross-linking treatment of progressive keratoconus: new hope. Curr
Opin Ophthalmol. 2006; 17(4):356-60.
9. Kohlhaas M, Spoerl E, SpeckA, SchildeT. SandnerD, Pillunat LE. A new treatment
of keratectasia after LASIK by using collagen with riboflavin/UVA light crosslinking. Klin Monatsbl Augenheilkd. 2005; 222(5):430-6.
10.Snibson, G. (Principal Investigator). A prospective, randomised, clinical trial of
corneal collagen cross-linking in progressive keratoconus. Data on File; 2007.
SCLAFANI