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Keratoconus – New Discoveries,

New Controversies

Jan Bergmanson, OD, PhD, PhD h.c., DSc Texas Eye Research and Technology Center University of Houston College of Optometry

Full Financial Disclosure

No Personal Financial Interest in any of the products mentioned in this presentation.

TERTC has received grants from the following

companies over the last 12 months:

Alcon AMO

Bausch & Lomb CooperVision

Contamac TruForm

Funding Ø  Internal Funding Ø NEI Core Grant P30 EY007551

TERTC Keratoconus (Kc)Team

Ø Jessica Mathew, OD, PhD Ø John Goosey, MD Ø Rune Brautaset, PhD Ø Maria Nilsson, PhD Ø William Miller, OD, PhD Ø Norman Leach, OD, MS Ø Jan Bergmanson, OD, PhD

Making the Diagnosis

Ø Patient history and symptoms l  Gradual development of reduced and/or

distorted vision l  Monocular or binocular diplopia or polyopia

•  Reported as ghost images or shadows l  Mild to severe photophobia or glare l  Headaches, asthenopia, and itching associated

with vigorous eye rubbing

Making the Diagnosis

Ø One eye is generally more advanced than the other l  Unilateral Kc (?)

•  CLEK study (2,379 eyes, 1,579 pts): 13% •  Other studies: 3.5 – 20% •  (Zadnik, Barr et al. Cornea. 1996)

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Making the Diagnosis

Ø Objective Clinical Signs l  Marked changes in

refraction l  Keratometry and/or

keratoscopy mire irregularities

Making the Diagnosis

Ø Objective Clinical Signs l  Corneal topography inferior steepening

•  5 - 7 % refractive surgery candidates have subclinical keratoconus

Making the Diagnosis

Ø Objective Clinical Signs l  Ophthalmoscopic fundus reflex

Making the Diagnosis

Ø Objective Clinical Signs l  Munson's sign

Making the Diagnosis

Biomicroscopy Ø Vogt’s striae

•  May disappear with digital pressure

Making the Diagnosis

Ø Fleischer's ring (50 - 90 %)

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Making the Diagnosis

Ø Apical thinning

Making the Diagnosis

Ø Corneal scarring Ø Try to grade density

Making the Diagnosis

Ø Ruptures in posterior limiting lamina (and endothelium)

Corneal Hydrops

Controversy 1: Ø  Is the pathology of Kc restricted to the confines

of the Fleischer Ring? OR

Ø  Is it a pancorneal pathology?

Why do we need to know? If peripheral cornea is involved in Kc – Ø  Clinical management may need to be modified. Ø  Surgical approach – may need to be re-assessed. Ø  Our counsel to the Kc Pt should reflect this consideration.

So far… Have we been over-concerned with the cone, ignoring the rest

of the cornea?

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George Waring: (on corneal dystrophies)

Post-transplant recurrence is

explained by existance of disease in peripheral host

cornea (1998)

Presence of Kc in peripheral cornea could explain post-transplant

recurrence

Past reports of Kc recurrence: Ø  Abelson, Collin, Gillette, Dohlman. BJO. 1980. (16 yrs –

1 case) Ø  Nirankari et al. BJO. 1983. (22 yrs – 1 case) Ø  Bechrakis et al. Cornea. 1994. (10 & 19 yrs - 2 cases ) Ø  Patel et al. BJO. 2009. (avg: 20 yrs – 25 cases)

TERTC Research Undertaking:

Clinical in vivo measurements and histopathological research can establish

the presence or the absence of the disease in the peripheral cornea.

Phase I: Histopathology of Kc

Ø  Mathew JH, Goosey JD, Bergmanson JPG. Quantified Histopathology of the Keratoconic Cornea. Optometry and Vision Science. 88(8):988-997, 2011.

Pathology of Epithelium in Kc

Ø  Epithelial thickness variations l  Central cone

•  Avg=42.2µm (13.5 – 91.6µm) l  Peripheral button

•  Avg=54.5µm (29.8 – 90.9µm)

Ø  Not always explained by the number of layers of cells

Ø  Not always correlated to the absence of ALL

Normal KC KC

~ 0.225µm

Pathology of Epithelium Central Cone & Peripheral Cornea •  Abnormal BM synthesis •  Pathological cytoplasm/shape •  Variable thickness •  Independent of stromal events

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Pathology of ALL in KC (eponymous name is Bowman’s layer)

Thinned or Lost over large areas

Pathology of ALL

Ø  Central cone l  PKP

•  72% was affected •  20% was completely missing

l  LKP •  36% was affected •  0% was completely missing

Ø  Peripheral button l  PKP

•  19% was affected •  5% was completely missing

l  LKP •  11% was affected •  0% was completely missing

Pathology of ALL

Ø  “Breaks, interruptions, fragmentations, dehiscences, ruptures” of ALL

•  Duke-Elder, 1961 •  Grayson’s, 1997 •  Krachmer, 1997 •  Liebowitz & Waring, 1998 •  Kauffman, et al., 1998 •  Eagle, 1999 •  Krachmer & Palay, 2006

Ø  No one suggested extreme areas of loss

Ø  No one suggested periphery to be involved!

Epithelial Adhesion Apparatus

Ø  Hemidesmosomes Ø  Basement membrane

(type IV collagen) Ø  Type I collagen fibers Ø  Type VII collagen fibers Ø  Anchoring plaques Ø  Fibronectin Ø  Laminin

Phase II: Clinically measurements of the in vivo

Kc cornea.

Accepted for publication Cornea, 2012

Demographics of Subjects

Kc Patients Controls

# of subjects 26 26

# of eyes 48 52

Age (mean + SD) 38.7 + 13.2 36.9 + 13.8

Male/Female 13/13 11/15

Spherical equiv (D) -8.5 (+7.18) -2.9 (+3.68)

Visual Acuity (logMar) 0.33 (+0.31) 0.01 (+0.14)

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Kc grading and distribution of clinical findings

Eye Sim´s K-Value CLEK

Cyl (D) Axis (º) Max K (D) Min K (D) Category 1/2/3

OD -5.27 129.25 52.58 47.28 2/7/14

OS -4.77 60.65 51.18 49.80 4/12/9

Prominant nerve fibres Fleischer´s ring Vogt´s

striae Munson´s sign Anterior corneal scarring

Posterior corneal scarring

OD 20 7 23 3 5 9

OS 19 8 24 0 4 12

Scanning Slit Elevation Topography – Orbscan

Average Range (mm) Kc Controls Diff P

0-3 458.38 (±65.4)

546.1 (±46.0)

87.72 <0.0001

3-5 564.66 (±50.6)

620.36 (±31.0)

55.70 <0.0001

Doughty & Zaman 2000 •  Central Av: 535 um •  Range: 474-596 um •  Periph: 700 um

Optical Coherence Tomography (OCT) – Visante

Visante (OCT) Provided 4 Corneal Thickness Measurements

Ø Centrally Ø 2-5 mm peripherally Ø 5-7 mm peripherally Ø 7-10 mm peripherally

Corneal Thickness (um) in Central and Peripheral Cornea in Kc and Control

Range (mm) Kc Patients Controls p-value Change in Thickness

0-2 470.6 537.0 <0.001 66.4

2-5 501.7 558.5 <0.001 56.8

5-7 548.1 595.5 <0.001 47.4

7-10 605.5 647.4 0.0006 41.9

Kc cornea is thinner also in periphery

In-Vivo Clinical & Histopathological Research

has now Demonstrated Ø Kc appears to involve the entire cornea. Ø Disease manifestation is less pronounced in

the periphery.

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Controversy 2:

Can Kc recur or was your pt unlucky and had someone else’s

Kc transplanted?

Keratoconus Recurrence We can explain this now!

But, how does this happen? Ø Presence of disease in host cornea

l  In periphery l  Incomplete cone removal

Ø Presence of disease in donor cornea

Keratoconus Recurrence Case Example

Ø Music Professor & Professional Jazz Musician: l  Hx of Kc OU l  Bilateral PKP 22 yrs

ago (3 mos apart, 2 donors), Las Vegas

Musician’s Odds in Las Vegas

Ø Given Kc incidence of 1 in 2000 l  What is the chance that he would get unlucky with

both eyes? l  1 in 4000000 l  YES, One chance in 4 million!

You would not bet in Las Vegas on those odds!

Musician’s Odds in Las Vegas

Ø Most likely, his recurrent Kc came from his own (host) corneas

Ø BCVA 20/25 OD, OS Ø  Currently not a candidate for re-graft

Ø  Topo pic

Explanation of Kc Recurrence

Ø The disease is pan-corneal. Ø Typical keratoplasty will not eliminate all of

the diseased tissue. Ø Although it is theoretically possible to

transplant a cornea with subclinical Kc, it is a highly unlikely scenario because corneas are screened.

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Ünal et al., Cornea, 2006 (Turkey)

Ø Reported ‘recurrence’ of Kc in corneas of 2 separate individuals who got transplants from the same donor: l  One received PKP for FED, the other for

corneal scarring

The disease can travel in both directions!

Recurrent Kc Latency is Long

Average is 15 years

No immediate worry for patient and practitioner –

just regular monitoring…

Take Home Message Recurrence of Kc

Ø Has a long latency period: 1-2 decades Ø Will be first noticed topographically Ø May not require re-graft Ø Most likely will come from host cornea.

New Explanations to Ectasia Controversy 3: Lamellar Splitting vs Slipping

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Dawson et al. Ophthalmol. 2008;115(12):2181-2191 –

“…believe that interlamellar slippage is

most likely caused by the fracture of collagen type VI bridging filament

networks that frequently join adjacent lamellae together throughout the entire

corneal stroma…”

Dawson et al. Ophthalmol. 2008;115(12):2181-2191 –

“…keratocytes, which reside in the

interlamellar space, may accelerate this first phase of the biomechanical failure

process, particularly if interlamellar shear (e.g., eye rubbing) or fracture results in

keratocyte cellular damage…”

Lamellar Count Results

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50

100

150

200

250

300

350

400

450

1 2 3 4 5 6 Normal

# of

lam

ella

e

Cornea

Number of Lamellae in Kc Corneas

Total Lamellae

Anterior Lamellae

Posterior Lamellae

Healthy vs. Kc Cornea

Ø  Healthy Cornea: 242 (Bergmanson, Horne et al., 2005)

Ø  Kc Cornea: 357

Despite anterior stromal lamellar dropout, we counted more lamellae!

Normal Fragmented

0 50

100 150 200 250 300 350 400 450

1 2 3 4 5 6 Normal

# of

lam

ella

e

Cornea

Number of Lamellae in Kc Corneas

Total Lamellae

Anterior Lamellae

Posterior Lamellae

Dawson and colleagues (including Stulting and Edelhauser). Ophthalmol. 2008;115(12):2181-2191.

Corneal Ectasia After Excimer LaserKeratorefractive Surgery: Histopathology,Ultrastructure, and Pathophysiology

Daniel G. Dawson, MD, 1,2 J. Bradley Randleman, MD,1 Hans E. Grossniklaus, MD, 1Terrence P. O’Brien, MD, 2 Sander R. Dubovy, MD,2 Ingo Schmack, MD,1,3 R. Doyle Stulting, MD, PhD,1Henry F. Edelhauser, PhD1

Purpose: To evaluate the histopathology and ultrastructure of corneas developing ectasia after LASIK orphotorefractive keratectomy (PRK).

Design: Retrospective case series.Participants: Thirteen specimens from 12 patients undergoing corneal transplantation for progressive

ectasia after LASIK (12 specimens) or PRK (1 specimen) were obtained for histopathologic and ultrastructuralevaluation.

Methods: All 13 ectatic corneas were submitted in formalin for light microscopy. Nine specimens werebisected, and the second half was placed in 2.5% glutaraldehyde for transmission electron microscopy (TEM).

Main Outcome Measures: Corneal histopathology, ultrastructure, and pathophysiology.Results: Light microscopy of the post-LASIK specimens showed corneal epithelial hypoplasia and occa-

sional foci of epithelial hyperplasia, Bowman’s layer breaks, a normal stromal thickness of the LASIK !ap, anormal thickness of the hypocellular primitive stromal scar, a thinned residual stromal bed (RSB), and larger thannormal artifacteous interlamellar clefts in the RSB of the ectatic region. The post-PRK specimen showed similar"ndings with the addition of a thinned hypercellular "brotic stromal scar. TEM showed thinning of the collagenlamellae and loss o! amellar number in the RSB of post-LASIK ectasia corneas or throughout the entire cornealstromal bed in the post-PRK ectasia cornea, with the posterior aspect of the corneal stroma being most a#ected.

Conclusions: Histopathologic and ultrastructural studies suggest that interlamellar and inter"brillar biome-chanical slippage occurs when the cornea becomes ectatic after LASIK or PRK in the postoperative stress-bearing regions of the corneal stroma. This 2-phase chronic biomechanical failure process is similar to that seenin keratoconus. Composite sciences classify this chronic biomechanical failure process as inter"ber fracture.

Financial Disclosure(s): The authors have no proprietary or commercial interest in any materials discussedin this article. Ophthalmology 2008;115:2181–2191 © 2008 by the American Academy of Ophthalmology.

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Post Refractive Surgery Ectasia vs Kc

Post PRK Ectasia Dawson et al.

Kc TERTC, Houston, Tx

Kc TERTC, Houston, Tx

Post LASIK Ectasia Dawson et al.

Post Refractive Surgery Ectasia vs Kc

Proposed Ectasia Etiology:

Post-Refractive Sx = Kc

Conclusion

Lamellar fragmentation (predominantly)

+ Anterior stromal tissue loss

(secondarily) =

Corneal ectasia

New Hypothesis: Lamellar Fragmentation Ectasia

1um

Normal Fragmented