Embryology / Pathology

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3 Embryology / Pathology

EMBRYOLOGY
PATHOLOGY

Microbial studies
Tissue stains
Tissue fixation
Hypersensitivity reactions
Immunoglobulins
HLA system
Inflammation
Eyelid epithelial changes
Aging changes
Wounds
Ocular injuries

Embryology

Formation of eye

embryonic plate → neural plate → optic pits → optic vesicles → optic cups

Embryonic plate (Figure 3.1)

1 Ectoderm (forms eye and brain): neural ectoderm, surface ectoderm, and neural crest
2 Mesoderm
3 Endoderm
image

Figure 3-1 Neural tube formation.

Optic pit

forms at day 23 of gestation

Optic vesicle

anterolateral outpouching of primitive brain stem; evaginates on day 25 and becomes the globe

Optic vesicle induces the lens placode at day 27
Abnormalities of evagination: may result in anophthalmia, cyclopia (synophthalmia), congenital cystic eye, congenital nonattachment of the retina. Apical forebrain lesions such as synophthalmia are associated with arrhinencephaly, proboscis, ethmocephaly, trisomy 13

Optic cup (Figure 3.2)

develops embryologically as an anterolateral evagination of the forebrain

Inner layer becomes the retina
Outer layer becomes the retinal pigment epithelium
Potential space between the two becomes the subretinal space (which was the cavity of the neural tube and optic vesicle)
Cells at anterior margin of optic cup form the posterior pigment epithelium of the iris
Cells between the future iris and the future retina form the ciliary body
image

Figure 3-2 Optic cup formation.

Embryonic fissure

on undersurface of optic cups; closes on day 33 allowing pressurization of globe

Closure occurs first in midzone / equator, then extends posteriorly and anteriorly
Serves as portal for mesoderm to enter eye (i.e. hyaloid artery)
Coloboma: failure of closure of embryonic fissure; sporadic or autosomal dominant (AD); typical (located in inferonasal quadrant) or atypical (located elsewhere)

May involve retina and choroid (associated with basal encephalocele, cleft palate, and CHARGE syndrome), iris, and / or optic nerve
An eyelid coloboma is not related to closure of embryonic fissure

Microphthalmos with cyst: small, abnormal eye with cystic expansion extending posteriorly into orbit

Arises in area of and external to a choroidal coloboma; cyst usually contains dysplastic neuroectodermal tissue and may not directly connect with the eye

Optic pit: considered an atypical coloboma; associated with basal encephalocele

Hyaloid artery (Figure 3-3)

enters through embryonic fissure and forms vasa hyaloidea propria (blood supply to primary vitreous)

Intravitreal portion regresses by image months; intraneural portion becomes central retinal artery
Posterior tunica vasculosa lentis supplies the posterior lens
Retinal vascular development begins during 16th week: mesenchymal cells next to hyaloid artery form capillary network, then form arteries and veins; vessels grow centrifugally from optic disc, reach nasal ora serrata during 8th month and temporal ora 1–2 months later
3% of normal neonates have a patent hyaloid artery
Remnants of hyaloid vasculature system:

BERGMEISTER’S PAPILLAE: at optic nerve head; glial sheath of Bergmeister envelops posterior third of hyaloid artery and begins to atrophy during 7th month; epipapillary veil results if it does not fully regress
PERIPAPILLARY LOOP: vascular loop extending from optic nerve head; risk of artery obstruction or vitreous hemorrhage
MITTENDORF’S DOT: small opacity on posterior lens capsule at which hyaloid artery is attached to posterior tunica vasculosa lentis
PERSISTENT PUPILLARY MEMBRANE: thin iris strands bridging pupil; may attach to anterior lens capsule; remnants of anterior tunica vasculosa lentis

image

Figure 3-3 Hyaloid vasculature and primary vitreous during embryologic ocular development.

(From Dass AB, Trese MT: Persistent hyperplastic primary vitreous. In: Yanoff M, Duker JS (eds): Ophthalmology. London, Mosby, 1999.)

Primitive epithelial papillae

cells from inner layer of optic cup at superior end of embryonic fissure, which becomes the optic disc

Ganglion cell axons grow through
Myelination starts centrally, reaching the chiasm at image months and lamina cribrosa at birth; complete approximately 1 month after birth
Inner limiting membrane of Elschnig: covers ON, contiguous with ILM
ON may show deceptively exaggerated cupping because nerve fibers posterior to lamina cribrosa are incompletely myelinated at birth
ON hypoplasia is associated with DeMorsier’s syndrome; 13% have pituitary abnormalities

Vitreous

produced by lens, retina, and walls of hyaloid artery; contains mesenchymal cells

Primary vitreous: formed by hyaloid vascular system (vasa hyaloidea propria, which includes hyaloid canal, hyaloid vessels, and posterior portions of tunica vasculosa lentis); eventually replaced by secondary vitreous; failure to regress causes persistent hyperplastic primary vitreous (PHPV) (Figure 3-4)
Secondary vitreous: formed by retina
Area of Martegiani: extends from disc into vitreous to become Cloquet’s canal
Cloquet’s canal: junction of primary and secondary vitreous
Tertiary vitreous: zonule fibers formed from ciliary processes and lens capsule
Berger’s space: retrolental space
image

Figure 3-4 Posterior segment development.

Retina

neuroectoderm; vascularization begins at 4 months; temporal periphery is last portion to become vascularized

Development of fovea is not complete until 4 or more weeks after birth
Retinal dysplasia: abnormal proliferation of developing retina produces tubular structures with a rosette-like appearance; represents nonspecific response to disorganizing influence during development; associated with maternal LSD ingestion, Patau’s syndrome (trisomy 13), microphthalmos, congenital glaucoma, Peter’s anomaly, uveal and optic nerve colobomas, cyclopia, and synophthalmia

Choroid

requires RPE for development

Stroma is from neural crest cells
Vascular endothelium is from mesoderm
Vessel walls are from neural crest cells

Sclera

neural crest cells and mesoderm (temporal aspect)

Blue hue at birth due to thinness (see underlying uveal pigment)

Cornea

neural crest cells (2 waves)

1st wave grows between epithelium and lens, forming double layer of corneal endothelium
2nd wave grows between epithelium and endothelium; this zone is rich in hyaluronic acid and collagen fibrils
At 4 months, Descemet’s membrane develops
At 5 months, Bowman’s membrane develops

Angle

neural crest cells from peripheral cornea differentiate into chamber angle during 7th week

In 4th month, Schlemm’s canal forms
In 7th month, angle moves posteriorly
In 8th month, formation is complete; trabecular meshwork appears just before birth

Lens

at 27 days, surface ectoderm adjacent to optic vesicle enlarges to form lens placode (lens plate)

Circular indentation then occurs on lens plate, forming lens pit, which invaginates the wall of the optic vesicle until it closes to form a sphere
Basement membrane of the surface ectoderm forms the surface of the sphere (the lens vesicle) and subsequently becomes the lens capsule
Lens epithelial cells on posterior aspect of this sphere elongate and migrate first (primary lens fibers); these cells fill the core of the lens vesicle at approximately 40 days (embryonal nucleus)
At 7 weeks, anterior cells migrate toward equator and proliferate to form secondary lens fibers that encase the embryonal nucleus and form the Y sutures; Y sutures represent the meeting of embryonal and fetal nuclei (upright anteriorly, inverted posteriorly)
After 3 months, zonules of Zinn (zonular fibers) develop (Figure 3-5)
image

Figure 3-5 Lens development.

Summary

3 weeks lens placode from surface ectoderm
6 weeks lens vesicle; further development requires normal neuroretina
12 weeks tunica vasculosa lentis
28–38 weeks degeneration of tunica vasculosa lentis

Lens of a newborn is more spherical than that of an adult; therefore, anterior chamber appears shallow

Iris

rim of optic cup grows around lens and forms iris

Epithelial layers (iris pigment epithelium [IPE]; anterior pigmented and posterior nonpigmented) are from inner and outer layers of the optic cup (neuroectoderm); forms part of the blood–aqueous barrier
In 7th week, stroma forms from neural crest cells, and tunica vasculosa lentis forms
In 6th month, sphincter and dilator muscles form from neuroectoderm
In 7th month, blood vessels enter iris
In 9th month, tunica vasculosa lentis disappears
Newborn iris is usually gray-blue; development of iris color takes weeks to months, as stromal chromatophores (dendritic melanocytes from neural crest) complete their migration into uvea shortly after birth
Iris dilator muscle is immature, causing relative miosis in infancy
Retinal pigment epithelium (RPE) and posterior pigment epithelium of the iris form from the outer layer of the optic cup (have mature coloration because pigment granules develop very early in gestation)

Ciliary body (CB)

formation begins in 3rd month; fold in optic cup becomes epithelial layers of ciliary processes

In 4th month, filaments from surface cells form zonules; the major arterial circle of the iris (located in CB), the longitudinal ciliary muscle, and the ciliary processes develop
In 5th month, pars plana develops, and ciliary body stroma and ciliary muscle develop from neural crest cells adjacent to cornea
In 7th month, circular fibers of ciliary muscle differentiate
Patient’s age can be determined by analysis of CB cellularity

Nasolacrimal system

at 6 weeks, surface ectoderm is buried in mesoderm, between maxillary and lateral nasal processes

During 3rd month, the cord canalizes
Defects: may result in imperforate valve of Hasner; rarely, absent puncta or canaliculi

Eyelids

at 8 weeks, upper lids form by fusion of medial and lateral frontonasal processes; lower lids by fusion of maxillary processes and medial nasal processes

At 12 weeks, lid folds fuse
At 24 weeks, separation begins from nasal side

Embryologic tissues and their components

Neural ectoderm: sensory retina, RPE, nonpigmented ciliary body epithelium, pigmented CB epithelium (extension of RPE), IPE, iris sphincter and dilator muscle, optic nerve (neural and glial elements), sympathetic ganglion, lateral geniculate body, ocular pigment granules (RPE, CB, IPE), peripheral nerves related to eye function, erector pili muscle associated with hair follicles of the skin
Surface ectoderm: crystalline lens, corneal and conjunctival epithelium, lid epithelium, lacrimal gland, nasolacrimal system
Surface and neural ectoderm: vitreous, zonules
Neural crest cells: corneal stroma and endothelium, iris stroma, TM, chamber angle, Schlemm’s canal, sclera (except temporal portion), sheaths and tendons of extraocular muscles, ciliary muscle (nonpigmented layer of ciliary body), choroidal stroma, melanocytes, meningeal sheaths, orbital bones, connective tissue of orbit, muscular and connective tissue layers of blood vessels

S-100 STAIN: specific for neural crest–derived structures
3 WAVES OF NEURAL CREST CELL MIGRATION (during 7th week): corneal and TM endothelium, keratocytes (corneal stroma), iris stroma
ANTERIOR SEGMENT DISORDERS DUE TO NEURAL CREST ABNORMALITIES:

ABNORMAL MIGRATION: congenital glaucoma, posterior embryotoxin, Axenfeld-Rieger syndrome, Peter’s anomaly, sclerocornea
ABNORMAL PROLIFERATION: iridocorneal endothelial (ICE) syndromes
ABNORMAL TERMINAL INDUCTION: corneal endothelial dystrophies

Mesoderm: blood vessel endothelium, anterior chamber angle outflow apparatus, sclera (small area temporally), EOM, Schlemm’s canal, portion of vitreous
Mesenchyme: primitive connective tissue; originates from neural crest cells and mesoderm (Figure 3-6)
image

Figure 3-6 Time line of ocular embryogenesis.

(From Azar NJ, Davis EA: Embryology in the eye. In: Yanoff M, Duker JS (eds): Ophthalmology, 2nd edn. St. Louis, Mosby, 2004.)

Pathology

Microbial studies

Stains

Gram

bacteria, fungi

Giemsa

Acanthamoeba, fungi, and cytology; best for intranuclear inclusion bodies

Acid fast (Ziehl-Neelsen)

Mycobacterium, Nocardia

Periodic acid-Schiff (PAS)

fungi

Gomori’s methenamine silver

fungi

Calcofluor white

fungi and Acanthamoeba (binds to cell wall, visible with fluorescent microscopy)

KOH

fungi

Culture Media

Blood agar

most bacteria; very good for atypical Mycobacterium

Blood agar in 5–10% carbon dioxide

Moraxella

Chocolate (contains hemin and nicotinamide adenine dinucleotide [NAD])

Haemophilus, Neisseria

Thioglycolate

anaerobes

Sabouraud’s

fungi

Löwenstein-Jensen

Mycobacterium tuberculosis, Nocardia

Loeffler’s

Corynebacteria

Non-nutrient agar with E. coli overgrowth

Acanthamoeba

Cytology

Intracytoplasmic basophilic inclusions (Giemsa stain)

Chlamydia

Intranuclear eosinophilic inclusions (Papanicolaou stain)

herpes (Tzanck smear)

Tissue stains

Hematoxylin and eosin (H&E)

hematoxylin is specific for nucleic acids within nuclei and stains blue (basophilic); eosin is specific for most cytoplasmic organelles (such as mitochondria) and stains pink (eosinophilic)

Periodic acid-Schiff (PAS)

stains basement membrane material magenta (Descemet’s, lens capsule, Bruch’s membrane, ILM [internal limiting membrane], gutattae, drusen); also stains glycogen, fungi, conjunctival goblet cells (useful for differentiation of corneal from conjunctival epithelium)

Masson trichrome

stains collagen blue and hyaline red; used for granular dystrophy

Congo red

stains amyloid orange; used for lattice dystrophy

Crystal violet

stains amyloid red-purple; used for lattice dystrophy

Alcian blue

stains acid mucopolysaccharide blue; used for macular dystrophy

Colloidal iron

stains acid mucopolysaccharide blue; used for macular dystrophy

Oil red O

stains neutral lipids red-orange in frozen section; must be used on fresh tissue because formalin leaches out lipid

Sudan black

stains phospholipids; myelin in ON

Luxol fast blue

stains myelin blue; demyelinated plaques lose affinity for stain

Bodian

stains nerve fibers black

Mucicarmine

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