Cornea and Sclera Development

Question 1

Inductive mechanisms of cornea development

Answer 1

• pax6 gene locus is transcription factor for the various
• developing lens necessary to act as inucer for ectoderm to transform into cornea
• morphogenesis requires coordinated cellular events: migration, proliferation, and differentiation

Question 2

Overview of cornea development

Answer 2

Surface ectoderm => presumptive corneal epithelium

Mesenchyme => neural crest mesenchyme => corneal endothelium and stroma

Question 3

Surface Ectoderm (5-6th week) => presumptive corneal epithelium

Answer 3

ECM-tissue interactions

initiated when lens vesicle separates from surface ectoderm

surface ectoderm: presumptive corneal epithelium (2 layers):

Question 4

Primary Stroma

Answer 4

produced by primitive corneal epithelial cells

acellular matrix: collagen fibrils, hyaluronic acid and GAGs

hydration of hyaluronic acid causes swelling to create space for cellular migration

directional membrae to guide the migration of neural crest cells

Question 5

1st wave Mesenchymal components produces what (7th wk)

Answer 5

the 1st wave of neural crest mesenchyme produces the corneal endothelium

1st wave mesenchyme: neural crest mesenchyme at anterior tip of optic cup

• migrates to form single layer in front of lens
• presumptive corneal endothelium

Question 6

2nd wave mesenchymal components produces what (8th wk)

Answer 6

2nd wave of neural crest mesenchyme produces secondary cornea stroma.

2nd wave of neural crest mesenchyme invades primary stroma at margin of optic cup
-do not invade anterior 10 um primary stroma => becomes bowman’s layer

Question 7

cornea stroma production

Answer 7

neural crest cells proliferate and differentiate into keratoblasts:

• synthesize type 1 collagen fibrils and GAGs
• layers fill in from posterior to anterior stroma

Question 8

corneal stroma differentiation

Answer 8

process begins in posterior stroma and progresses anteriorly
-collagen lamellae: 1st organized in posterior stroma

keratoblasts differentiate into keratocytes

collagen and lamellae create most of stroma, but initally started by these keratoblasts

Question 9

Descemet’s membrane development

Answer 9

endothelial cells produce basement membrane

DM seen 8wks and matures at 4 months

Question 10

innervation development

Answer 10

tissue of origin of innervation: neural crest cells

3-5 month: first seen
6-9 month: nerve inc. in number and form network

supplied by CN5 V1

Question 11

Fusion of eyelids and development

Answer 11

Eyelids fuse at 9th wk

in 24 weeks, eyelid open: cornea epithelium increase thickness and differentiates to basal, wing, squamous cells

Question 12

factors affecting corneal size, curvature, transparency

Answer 12

Eyelid fusion: transparency gradually achieved due to maturation of stromal lamellae, metabolic activity of endothelium dehydration of cornea

Question 13

cornea at birth and postnatally

Answer 13

newborn diameter: 9.5-10mm
diameter reaches adult size at 2 years of age

newborn radius of curvature: 47.00 (STEEEP)
-flattens with age

at birth: cornea may be thicker than adult (caused by increased water content caused by underdeveloped endothelial ion transport)

cornea translucent during fetal period

Question 14

Sclera development tissue origin

Answer 14

neural crest: 95% of sclera

mesoderm: small portion from paraxial mesoderm

Question 15

scleral development inductive mechanisms

Answer 15

• RPE influences scleral development (neural crest differentiation)
• IOP and vitreous formation: determines scleral shell size (expansion from IOP, increased vitreous volume)

Question 16

Scleral development timeline

Answer 16

7th week - scleral condensation– limbus

8th week - equator

3rd month - optic nerve

5th month - lamina cribosa

develops anterior to posterior

Question 17

scleral condensation

Answer 17

anterior to posterior development

neural crest cells differentiate to fibroblasts

fibroblasts: collagen, elastic fibers, and GAGs

neuro crest cells meet myoblasts of EOMs

neural crest cells form sheaths for muscle fibers near equator of globe

Question 18

Fibroblasts synthesize what

Answer 18

collagen fibrils - initially small diameter that steadily increases

elastic fibrils

proteoglycans and GAGs (13 wk)

Question 19

postnatal scleral development

Answer 19

birth: sclera thin, highly distensible, translucent
postnatal: collagen synthesis most active in posterior eye

diameter of fibers and rigidity change: outer scleral layers (larger diameter) collagen fibrils compared to inner layers (smaller)

• response to circumferential streses on scleral by IOP
• regional differences in fibril diameter likely contribute to scleral resistance to IOP

sclera increases diameter and thickness in relatively rapid manner, loses distensibility during first 3 years

growth continues at a slow pace after 3 years:
anterior sclera adult size by age 2
posterior sclera develops until age 13-16

Question 20

differences between cornea and sclera development

Answer 20

cornea development:

• derived from surface ectoderm and neural crest mesenchyme
• induced by lens
• formed by 1st and 2nd waves of neural crest mesenchyme that migrates anteriorly with a guiding matrix of primary stroma with a resulting regular lamellar arrange ment

sclera development:

• derived from neural crest mesenchyme and some mesodermal mesenchyme
• induced by RPE
• formed from scleral condensation that migrates posteriorly with a resulting irregular interweaving arrangement

Question 21

differences between developed cornea and sclera

Answer 21

cornea - transparent

• regular lamellar arrangement
• uniform fibrils with uniform diameter
• regularly spaced with regular size
• less interweaving and regular directed bundles
• steeper curve – clear cap on front of eye
• lacks elastin components

sclera - opaque

• irregular lamellar arrangement
• more nonuniform in diameter
• more irregularly spaced, arranged in variously sized
• high interweaving, irregularly directed bundles
• flatter curve-opaque covering of eye
• elastin components

Question 22

Cryptophtalmos

Answer 22

absent cornea

• facial skin replaces eyelids, covers orbit, obliterating cornea
• bilateral
• associated with other congenital birth defects

Question 23

megalocornea

Answer 23

megaocornea newborn: 12 mm (normal 10 mm)

in adults: >13 mm (normal 12 mm)

-hereditary or secondary to congenital glaucoma

Question 24

megalocornea - hereditary

Answer 24

resulting from anomalies of differentiation of neural crest

greater than normal steepness (myopia)

defect in growth of optic cup

typically isolated but many ocular and systemic associations

Question 25

**megalocornea - 2nd to congenital glaucoma**

Answer 25

buphthalmos - ox eye - elevated IOP stretches cornea and sclera - ocular enlargement - descemet's may rupture or tear - -haab's stria: old, healed horizontal ruptures in descemet's - -curved lines or scars at endothelial level (tend to be horizontal) other findings with congenital glaucoma: tearing, photophobia, blepharospasm

Question 26

**microcornea**

Answer 26

horizontal diameter < 10mm nonprogressive, can be unilateral or bilateral flat cornea 2 proposed cause: 1) arrest in growth of cornea (after 5th gestational month) 2) overgrowth of anterior lips of optic cup

Question 27

**sclerocornea**

Answer 27

non-progressive cornea opaque and limbus indistinct corneal flat (< 43 D) cornea plana cornea curvature < scleral curvature occur alone or with other ocular defects usually bilateral, commonly asymmetric caused by abnormailty of 2nd wave of mesenchyme (severity variable) central cornea usually clearer than periphery (differnt than peter's anomaly)

Question 28

**posterior corneal defect (peters' anomaly)**

Answer 28

- rare, sporadic and frequently bilateral disorder - range of severity, from barely detectable focal indentation to total corneal scarring and ectasia - results from delay or failure of separation of lens vesicle from surface ectoderm - results in adhesion between cornea and lens --migration of mesenchyme is impeded by this adhesion, causing characteristic features of this anomaly

Question 29

peter's anomaly characteristic features

Answer 29

opacity of central cornea central concave defect in posterior corneal stroma corneal endothelium and descemet's membrane absent in posterior ulcer lens adheres to cornea iris adheres to cornea (iridocorneal adhesions) severe form: corneal staphyloma, scarring, ectasia

Question 30

**tears in endothelium and desecemet's membrane**

Answer 30

birth trauma: vertical or oblique lines in inner corneal layers congenital glaucoma: haab striae: horizontal breaks or circumferential breaks

Question 31

corneal dystrophy

Answer 31

occur early in life familial inheritances - AR or AD bilateral, central cornea involved - almost all autosomal dominant - not associated with any other systemic diseases - onset of dystrophy is by age 20 - bilateral - slowly progressive - primary involved in a single cornea layer (either epithelium, stroma, endothelium)

Question 32

anterior corneal dystrophies

Answer 32

corneal epithelium epithelial basement membrane bowman's layer

Question 33

**epithelial-basement membrane dystrophy (EBMD)**

Answer 33

most common anterior corneal dystrophy abnormal basement membrane synthesized onset 30-40 central 3 patterns: maps - gray epithelial patches: islands of anomalous basement membrane dots - multiple intraepithelial cysts + cellular debris; intraepithelial opacities fingerprints - gray or refractile fine lines; basement membrane separating sheets of duplicated epithelium

Question 34

**stromal dystrophies**

Answer 34

abnormal substances appear within keratocytes or among collagen fibrils - Granular (hyaline) - Lattice (amyloid) - Macular (GAGs/ MMP) mnemonic: Mickey Mouse Goes Home to LA

Question 35

**granular dystrophy (hyaline deposits) - stroma**

Answer 35

hyaline deposits in anterior stroma gray-white opacities do not extend to limbus visual loss relative late in life

Question 36

**macular dystrophy (GAGs deposits/MMP deposits) - stroma**

Answer 36

least common, most severe begins as central gray-white superficial stromal opacities clear corneas that cloud between age 3-9 autosomal recessive accumulation of GAGs

Question 37

**lattice dystrophy (amyloid deposit) - stroma**

Answer 37

most common stromal dystrophy localized amyloidosis glasslike branching lines in stroma, seen best with retroillumination autosomal dominant

Question 38

**Endothelial dystrophy: Fuch's endothelial dystrophy**

Answer 38

thickening of descemet's membrane (corneal guttata: droplets) compromise of endothelial fxn corneal edema rare symptomatic before 50 corneal decompensation marked stromal edema microcystic and bullous epithelial edema subepithelial fibrosis

Question 39

**anterior keratoconus - ectatic dystrophy**

Answer 39

- progressive thinning of central stroma - leads to conical configuration of cornea - present in teens - bilateral, central, and slowly progressive - munson's sign - pushes on lower lid when looking down - fleisher's ring (iron) in deep epithelium and BM at base of cone - vogt's lines (vertical striae/stress lines) - stromal thinning - acute hydrops (stromal edema - scissors reflex in ret