Corneal morphology in Corneal morphology in Epithelial Basement Epithelial Basement

Membrane Dystrophy:Membrane Dystrophy:

A large cross-sectional study with in vivo A large cross-sectional study with in vivo confocal microscopyconfocal microscopy

Johan Germundsson M.D, Per Fagerholm M.D Ph.D, Johan Germundsson M.D, Per Fagerholm M.D Ph.D, Neil Lagali Ph.DNeil Lagali Ph.D

Department of Clinical and Experimental MedicineDepartment of Clinical and Experimental Medicine

Faculty of Health Sciences, LinkFaculty of Health Sciences, Linköping Universityöping University

Linköping, SwedenLinköping, Sweden

Authors have no financial interestAuthors have no financial interest

PurposePurpose To document corneal morphology in a To document corneal morphology in a

large group of patients with Epithelial large group of patients with Epithelial Basement Membrane Dystrophy Basement Membrane Dystrophy (EBMD), in both surgically-treated and (EBMD), in both surgically-treated and non-treated eyesnon-treated eyes

MethodsMethods We examined, under a 6 month period in 2009, We examined, under a 6 month period in 2009,

76 eyes of 39 EBMD patients treated with 76 eyes of 39 EBMD patients treated with phototherapeutic keratectomy (PTK) between phototherapeutic keratectomy (PTK) between the years 2001-2008. There were 52 operated the years 2001-2008. There were 52 operated and 24 fellow eyes.and 24 fellow eyes.

Slit lamp examinations and in vivo confocal Slit lamp examinations and in vivo confocal microscopy (IVCM) were performed microscopy (IVCM) were performed

By IVCM, we: By IVCM, we: Determine the presence of map, dot, or fingerprint Determine the presence of map, dot, or fingerprint

featuresfeatures Grade the severity with a numerical score in a Grade the severity with a numerical score in a

blinded fashionblinded fashion Quantify subbasal nerve density Quantify subbasal nerve density Assess stromal morphologyAssess stromal morphology

GradingGrading

1. Mild1. Mild Presence of isolated, cell-Presence of isolated, cell-

sized dot opacities and/or sized dot opacities and/or small (< 250small (< 250m) isolated m) isolated regions with folding of regions with folding of basement membranebasement membrane

2. Intermediate 2. Intermediate Larger dots or confluent dot Larger dots or confluent dot

features, map-like regions, features, map-like regions, and inhomogeneous and inhomogeneous epithelial cells epithelial cells

3. Severe 3. Severe Extensive basement Extensive basement

membrane folds, large map membrane folds, large map regions (with dimensions regions (with dimensions exceeding 1mm), and large, exceeding 1mm), and large, extensive dot opacities extensive dot opacities

Three-point grading scale was used to classify the Three-point grading scale was used to classify the severity of EBMD morphology as observed by IVCMseverity of EBMD morphology as observed by IVCM

Two observers independently graded 76 images in a Two observers independently graded 76 images in a blinded fashion.blinded fashion.Grading differed by 1 grade in 7 cases (p = 0.89, Grading differed by 1 grade in 7 cases (p = 0.89, Mann-Whitney Rank Sum TestMann-Whitney Rank Sum Test))

Results - EBMD Results - EBMD morphologymorphology

Recurrence of EBMD morphology was seen in Recurrence of EBMD morphology was seen in 33% of operated eyes by IVCM, with a mild to 33% of operated eyes by IVCM, with a mild to moderate grade (mean score 1.5) moderate grade (mean score 1.5)

EBMD morphology was noted in 78% of fellow EBMD morphology was noted in 78% of fellow eyes, with a grade of moderate to severe eyes, with a grade of moderate to severe (mean score 2.5) (mean score 2.5)

EBMD grade was significantly more severe in EBMD grade was significantly more severe in unoperated eyes (p<0.001, Mann-Whitney unoperated eyes (p<0.001, Mann-Whitney test)test)

Results - subbasal nerve Results - subbasal nerve densitydensity

Trend towards regeneration with postoperative timeTrend towards regeneration with postoperative time Similar density between eyes operated in 2001 and unoperated Similar density between eyes operated in 2001 and unoperated

eyeseyes Nerve density was measured by two independent observersNerve density was measured by two independent observers

95% LOA for difference in nerve density: -3260 to 3098 95% LOA for difference in nerve density: -3260 to 3098 m/mmm/mm22 (76 (76 measurements)measurements)

Average interobserver difference in nerve density was ± 9% Average interobserver difference in nerve density was ± 9%

Subbasal nerve density: EBMD Subbasal nerve density: EBMD vs Normalvs Normal

In EBMD eyes operated in 2001 (n=4, 60.8±20y)In EBMD eyes operated in 2001 (n=4, 60.8±20y) 17191±8598 µm/mm17191±8598 µm/mm2 2 (mean ± SD)(mean ± SD)

In unoperated EBMD eyes (n=24, age 57.5±14y)In unoperated EBMD eyes (n=24, age 57.5±14y) 14370±6931 µm/mm14370±6931 µm/mm22

In a normal population (n=20, age 60.7±7y)In a normal population (n=20, age 60.7±7y) 10552±6688 µm/mm10552±6688 µm/mm22

Patel DV et al., Cornea 2009; 28:735-40.Patel DV et al., Cornea 2009; 28:735-40. ~17000 µm/mm~17000 µm/mm22

Niederer RL et al., Br JOphthalmol 2007; 91:1165-69.Niederer RL et al., Br JOphthalmol 2007; 91:1165-69.

Large inter-patient variations in subbasal nerve Large inter-patient variations in subbasal nerve densitydensity

No clear differences between EBMD (unoperated No clear differences between EBMD (unoperated or 8y postop) and a normal age-matched populationor 8y postop) and a normal age-matched population

IVCM images from the stroma of 6 different patients with EBMD In 29% of all eyes examined, abnormal stromal nerve

morphology was observed with nerves exhibiting a tortuous path, being intimately associated with stromal cells

Abnormally tortuous stromal nerves, with multiple nerve-keratocyte linkages.

Seen in 9 operated and 14 unoperated eyes

Results - nerve Results - nerve morphologymorphology

ConclusionsConclusions EBMD grade was significantly reduced in EBMD grade was significantly reduced in

eyes operated by PTK (p<0.001)eyes operated by PTK (p<0.001) Subbasal nerves regenerate over time Subbasal nerves regenerate over time

after PTKafter PTK Subbasal nerve density in EBMD does not Subbasal nerve density in EBMD does not

appear to be pathologically lowappear to be pathologically low Examining corneas with EBMD using Examining corneas with EBMD using

IVCM may give new insight into the IVCM may give new insight into the disorder and the efficacy of PTK treatmentdisorder and the efficacy of PTK treatment

We believe this to be the first report of We believe this to be the first report of stromal abnormalities in EBMD stromal abnormalities in EBMD