• Fundamentals
• Congenital abnormalities
• Conjunctiva
• Cornea
• Eyelids
• Intraocular Tumors
• Lens
• Optic Nerve
• Orbit
• Phacomatoses
• Retina and Vitreous
• Trauma

• Changes with Aging
• Pathologic changes
• Deposits
• Inflammatory Cells
• Immunologic Responses
• Granulomatous Inflammation
• Chronic inflammation and Phithisis

• Cornea
• Sclera
• Lens
• Ciliary Body
• Retina
• Optic nerve

• Thickening of Decemet’s layer
• Hassal-Henle warts= guttata in aging cornea

• senile calcified plaques over recti muscles
• calcification of Bruch’s membrane under macula
• calcification of internal elastic lamina

• thickening

• decreased cellularity of ciliary muscles
• processes become blunt and less vascular

• Lange’s folds- artifact folding of retina in infant eyes
• lag in vascularization of temporal retina after birth
• perepherial cystoid degeneration

• decreased arachnoid cellularity with age

• Metaplasia- replacement of one adult cell type for another

• osseous metaplasia of pigment epithelium
• anterior subcapsular cataract

• Displasia- disorderly maturation

• retinal dysplasia in Trisomy 13
• conjunctival dysplasia

• Neoplasia

• benign- well differentiated, enlarge by expansion, capsule, compression
• malignant- variably differentiated, infiltrative, metastasis (discontinuous spread)

• eyelid, conjunctiva- lymphatic spread
• intraocular-hematogenous (no lymphatics)
• uveal melanomas-bypass lymph nodes-go to liver
• intraocular tumor with local spread to conjunctiva-lymphatic spread possible
• retinoblastoma-growth into optic nerve-spread to brain

• Other types of pathologic growth

• Hamartomas – focal growth of tissue normally found in that location
• dissemated hamartomas = phakomatoses
• astrocytic hamartomas of optic nerve or retina: tuberous sclerosis
• neurofibromas = schwann cells, fibroblasts and axons (normal perepherial nerve elements)
• Choristomas = tissue not found in given location (heterotopic)
• limbal dermoid

• Hyaline
• Amyloid
• Acid mucopolysaccharide
• Urate
• Calcium oxalate
• Copper
• Iron

• eosinophilic & glassy by light microsope
• granular corneal dystrophy

• stain with congo red and dichromism with polarization
• lattice corneal dystrophy

• macular corneal dystrophy

• corneal deposits in gout

• lens of morganian cataract
• chronic retinal detachment
• necrotic uveal melanomas
• methoxflurane anesthesia
• oxalosis

• Kayser-Fleischer ring in Decemet's membrane or lens epithelium in Wilson Disease

Iron

• corneal "blood staining"
• Fleischer ring- corneal epithelial iron in keratoconus

• PMN’s (Neutrophils)

• usually first to respond-except in viral and some inflammations like Bechet’s disease
• form abscess, nuclear fragments= nuclear dust
• in cornea appear flattened- look at nuclei to differentiate from fibroblasts

• Eosinophils

• attracted to immediate hypersensitvity reactions, immune complex deposition and parasites (toxocara, trichinosis)
• bilobed nucleus

• Mast cells

• same as basophils but in tissue
• round central nucleus in blue cytoplasm
• immediate hypersensitivity reactions

• Lymphocytes

• small,round, little cytoplasm
• t-cells
• b-cells
• plasma cells
• eccentric, clock face nuclei
• produce antibodies
• Russell bodies, Dutcher bodies = cytoplasmic collections of immunoglobulin

• Macrophage, Monocyte, Histiocyte

• abundant cytoplasm, eccentiric bean shaped nucleus
• seen in AC in phacolytic glaucoma
• form epitheloid cells when full of stuff they can’t digest
• congregation of macrophages (often in epitheloid form) = a granuloma
• Giant cells
• fusion of epitheloid cells
• Langhans type- horseshoe of nuclei
• Tuton type- "two-tone" cytoplasm, ring of nuclei
• Foreign Body type – central, random nuclei

• Langerhans cell

• in epithelium, branching processes
• Birbeck or Langerhans granule= organelle in cytoplasm
• involved in corneal graft rejection
• Langerhans cell histiocytosis (Histiocytosis X) eosinophilic granuloma
• Hand-Schuller-Christian Disease
• Letterer-Siwe disease

• Type I: immediate (anaphylactic) hypersensistivity

• mast cell degranulation in response to antigen also eosinophils and plasma cells involved
• example: vernal conjunctivitis

• TypeII: antibody-dependant, cytotoxic hypersensitivity

• antibody targets tissue enciting inflammation
• example: pemphigoid

• Type III: immune-complex mediated hypersensitivity

• antibody-antigen complex deposit in tissue enciting compliment response
• example: phacoantigenic(phacoanaphylactic) endophthalmitis possibly related to P.acnes

• Type IV: cell-mediated hypersensitivity

• macrophages present antigen to senstitized t-lymphocytes, create lymphokines
• example: sympathetic ophthalmia

• Type V: Antibody stimulation or supression

• antibody stimulation via receptors. eg.Graves Disease
• antibody supression via receptors. eg. Myasthenia Gravis

Granulomatous inflammation

• Sympathetic Ophthalmia
  • Bilateral, spares choriocapillaris
  • Dalen-Fuchs’ nodules- granulomas between Bruch’s membrane and RPE
  • HLA A-11 association
  • If inflammation occurs in sympathazing eye will occur in one year in 90%
• Phacoanaphylactic Endophthalmitis-zonal abscess
• Voght-Koyanagi-Harada’s Disease
  • vitiligo, poliosis, dysacusis, tinnitis, CSF pleocytosis
  • involves choriocapillaris and leaves chorioretinal scars
• Sarcoid
  • Busacca nodule: perepherial iris granuloma
  • Koeppe nodule: iris margin granuloma
  • PAS, CPS, cataract
  • phlebitis-vein occlusion
  • Dalen-Fuchs’-like nodules
  • Optic nerve granuloma=possible CNS
  • biopsy visible lesions in conjunctiva
• Tuberculosis
• Toxoplasmosis- acquired or congenital retinitis

Results of chronic inflammation and phthisis

• band keratopathy
• cataract
• chronic retinal detachment, suprachoroidal hemorrhage
• RPE hyperplasia, osseous metaplasia of RPE
• cholesterol deposition following hemorrhage

• Surgical
• Non-Surgical:
  • Blunt Trauma
  • Penetrating Trauma
• Acid Burns
• Alkali Burns
• Electrical Injury
• Intraocular Foreign Bodies
• Tear Gas
• Thermal Injury
• Radiation
• Signs of Non-Ocular Trauma in the Eyes

Surgical Trauma

• Cataract Surgery
• Retinal Laser Scars
• Penetrating Keratoplasty

• Iris stroma doesn’t heal, iris pigment epithelium can close small holes
• Lens epithelium can seal small rents in lens capsule
• Sclera doesn’t heal either, episcleral tissue grows down into wound or uveal fibrous tissue grows up into wound

Cataract Surgery

• epithelial downgrowth
• implantation cyst- epithelium implanted in AC
• stromal fibrous ingrowth
• vitreous wick
• sputtering hyphema-vessels in wound
• Sommering’s ring cataract-after ECCE
• Elschnig pearls-lens epithelium along posterior capsule
• CME- swelling in outer plexiform layer

Retinal Laser Scars- surrounding pigment-RPE hypertropy or hyperplasia

Penetrating Keratoplasy

• primary graft failure- first post-operative day #1 graft unclear-endothelial cell loss; poor graft, improper handling of tissue
• secondary graft failure-loss of endothelium, membrane formation
• endothelial rejection
  • vascularization, rejection line, inflammation
• epithelial rejection
  • epithelium repopulated by host cells
  • supepithelial infiltrates, rejection line, Langerhan’s cells play a role

Blunt Non-Surgical Trauma

• Anterior Chamber: cell & flare
• Corneal abrasion
• Corneal edema
• Lens Subluxation or Dislocation
• Other Lens Changes
• Iris Injury
• Angle Injury
• Hyphema
• Posterior Segment Injury
• Late Sequelae
  • atrophy- soft eye with deep anterior chamber
  • phthisis bulbi- atrophy with disorganization

Corneal abrasion

• recurrent erosions from faulty reconnection of hemi-desmosomes to basement membrane
• if Bowman’s layer compromised, facette results

Corneal edema with Descemet’s folds

• if Decemet’s ruptures- corneal hydrops, renewal of endothelial barrier resolves edema
• forcep’s injury-usually unilateral, vertical or diagonal striae
• Haab’s striae (congenital glaucoma) are usually bilateral and horizontal
• healing of Decemet’s occurs in scrolls- clinically lines

Lens subluxation or dislocation

• subluxation-partial zonular dehiscence, lens partially out of position
• dislocation (luxation)- complete zonular dehiscence-lens in AC or vitreous
• refractive error, PAS, pupillary block with lens in AC
• Other causes of lens malposition

Other lens alterations from Blunt Trauma

• Vossius ring-imprint of iris pigment on anterior capsule
• Cataract- petaloid pattern

Iris changes from Blunt Trauma

• Iridodialysis- associated with hyphema
• Sphincter tear

Angle changes from Blunt Trauma

• Trabecular Meshwork
  • endothelium deposits glycosaminoglycans and additional collagen
  • endothelial cells engulf pigment and debris and can clog meshwork
  • corneal endothelial cells may grow over meshwork-a secondary ICE syndrome
• Angle Recession
  • tear through face of ciliary body, through longitudinal and meridional muscles
  • clinically; prominent ciliary body band
  • histologically; if line parallel to visual axis drawn through scleral spur is anterior to angle= recession
  • glaucoma in 6%
  • PAS can form
• Cyclodialysis
  • disinsertion of ciliary body from scleral spur
  • uvea attached to sclera at scleral spur, vortex veins and optic nerve
  • clinically see sclera posterior to scleral spur or enlargement of scleral spur

Posterior Segment Injury from Blunt Trauma

• Vitreous Hemorrhage
  • cholesterol bulbi-cholesterol crystals from degenerated RBC’s (contrast with asteroid hyalosis is usually bilateral although very asymmetric)
• Hemosiderosis bulbi-build up of hemosiderin leading to retinal damage
• Ghost cell glaucoma can occur if anteior hyloid face is defective. Ghost cells may appear khaki or white. Treat with AC washout or vitrectomy if meds ineffective
• Retinal Dialysis- separation of perepherial retina from ora
  • can occur after blunt or penetrating trauma, inflammation or even spontaneously
• Commotio Retinae
  • macular edema or photoreceptor disorganization,
  • complicated by macular cysts progressing to macular hole
  • pigment mottling
• Retinal Necrosis- posttraumatic pigmentary retinopathy "pseudoretinitis pigmentosa"
• Retinal/ subretinal hemorrhage
• Choroidal rupture
  • indirect injury (contre-coup) concentric to optic nerve
  • associated with tear of overlying retina
• Retinitis sclopeteria- overlying the area of impact
• Avulson of optic nerve
  • early- blood in optic nerve sheath
  • late-fibrous tissue replaces optic nerve, this may extend into globe for a short distance
• Globe rupture
  • globe weakest posterior to recti insertions, at limbus and around optic nerve.

Penetrating Trauma

• Definitions
• Intraocular Foreign Bodies

Penetrating Trauma- Definitions

• penetrate-enter structure
• perforate- through and through

Thermal injury

• blink provides some protection
• results in coagulative necrosis of cornea

Electrical injury

• perepherial anterior subcapsular lens vacuoles
• progression to anterior subcapsular cataract
• lightening- both anterior and posterior lens changes

Acid burns

• precipitation of tissue proteins creates barrier for further damage
• tears buffer
• coagulative necrosis of epithelium

Alkali burns

• denature proteins and saponify lipids therefore penetrate deeper
• extensive necrosis and damage to intraocular tissues
• chemical cautery cause focal blanching of vessels
• late corneal perforation maybe caused by collagenases released by neutrophiles
• late consequences
  • symblepharon with dry eye
  • entropion
  • corneal scar and vascularization
  • chronic non-granulomatous anterior uveitis
  • cataract
  • glaucoma
  • phthisis

Tear Gas

• fumes: epithelial defects that heal well
• powder: severe keratitis if direcly in contact with eye

Radiation

• Non-Ionizing
• Ionizing

Non-ionizing Radiation

• Radio, TV: no ocular effects
• Microwave: cataracts
• Infrared (770nm-12,000nm)
  • true exfoliation(spliting) of lens epithelium
  • longer the wavelength more cataractogenic
• Ultraviolet (180nm-390nm)
  • keratitis, conjunctivitis
  • skin erythema
  • solar elastosis
  • penguecula, pterygium, actinic keratoses
  • squamous and basal cell carcinomas
  • melanomas
  • retinal phototoxicity

Ionizing Radiation

• x-rays (artificially produced), gamma rays(naturally occuring)
  • electromagnetic
  • high tissue penetration (feet)
• alpha rays: ionized helium
  • very low penetration
• beta rays
  • charged electrons
  • used to prevent pterygium recurrence
  • low penetration
• protons
  • hydrogen nuclei
  • medium low penetration
  • theraputic modality eg. uveal melanomas
• effects
  • lid erythema ,chronic radiodermatitis, entropion, ectropion
  • conjunctival teleangectasis
  • corneal keratinization, vascularization, scarring, necrosis
  • cataract
  • obliteration of retinal vessels-endothelium very sensitive
  • pre-retinal membrane, tractional retinal detachment, retinal neovascularization
  • late optic atropy
  • post-radiation orbital sarcomas esp. in retinoblastoma patient

Ocular manifiestations of non-ocular trauma

• Terson's Syndrome
• Retinal fat emboli
  • chest, pelvis and long bone fracture
  • retinal hemorrhage, exudate, edema
• Shake injury
  • Blood in optic nerve subdural space
  • Blood in multiple layers: subrential, intraretinal and preretinal
  • See: Shaken Baby Impact syndrome

Terson’s syndrome

• Retinal hemorrhage over optic nerve-associated with subdural hemorrhage,
• Increased cerebral spinal fluid pressure causes compromise of venous flow around optic nerve and rupture of vessels around the surface of the disk and peripapillary retina
• Blood may collect under internal limiting membrane

• Anatomy and Pathologic responses: Epithelium, Bowman's layer, Stroma, Decemet's membrane, Endothelium
• Disease that change corneal shape
• Dystrophies
• Infections
• Limbal pathology
• Neoplasia

Epithelium: Anatomy and Pathologic Responses

• PAS stain highlights epithelium basement membrane
• reduplication of basement membrane seen in bullous keratopathy or Map-Dot-Fingerprint dystrophy
• hydropic degeration= epithelial edema, bullous detachement
• Depositions
  • Immunoglobulins- in macroglobulinemia
  • Iron
    • Fleisher ring- surrounds cone in Keratoconus
    • Ferry line- near filtering bleb
    • Stocker line- at the advancing edge of a pterygium
    • Hudson-Stahli line- horizonal
  • Urate in gout
  • Cystinosis- refractive crystals in epithelium
  • Amiodarone-vortex pattern
  • Thioridazine (mellaril)
  • Chloroquine
  • Cysts in Meesman’s dystrophy
• Degenerative pannus
  • avascular tissue
  • non-specific response to corneal inflammation and edema
  • deposition of connective tissue in supepithelal space
  • possible sources
    • limbus
    • stroma through holes in Bowman’s that normally transmit nerves
    • fibrous metaplasia of epithelial cells
• Inflammatory pannus
  • vascular tissue from limbus
  • inflammatory cells present
  • often destroys Bowman’s

Bowman’s layer: Anatomy and Pathologic responses

• condensation of anterior layers of stroma
• no keratocytes, doesn’t regenerate
• focal defects filled in by epithelium= facette
• PAS doesn’t stain it
• Band Keratopathy
  • calcification of Bowman’s layer in interpalpebral fissure
  • Calcific: calcium salts in Bowman’s layer
• Actinic= Labrador keratopathy= Droplet Keratopathy= Spheroidal Degeneration
  • solar elastosis of Bowman’s and anterior stoma
  • altered collagen from UV damage stains more blue on H&E
  • appears more like elastic tissue but isn’t digested with elastase
• Fracturing/Fragmenting: diagnostic of keratoconus

Corneal Stroma: Anatomy and Pathologic Responses

• fibroblasts (keratocytes) populate and lay down collagen fibers into lamellae
• artifact of parafin embedding causes clefts in lamellae, corneal edema causes fewer clefts
• collagen misalignment leads to stromal whitening = scarring
• excessive scarring= keloid
• Congenital white cornea DDx: (see glaucoma notes)
  • Sclerocornea: congenital misalignment of corneal collagen
  • Congenital Glaucoma
  • Peter’s Anomaly: absence of Decemet’s membrane centrally, =/- adhesions of iris or lens to cornea
  • Mucopolysaccharidoses: accumulation of intra- and extra-cellular mucopolysaccharides
• Corneal ulcer: involves stromal loss, inflammation, edema, necrosis
  • necrosis
  • keratocytes absent
  • inflammatory cells unless aseptic necrosis (eg. radiation)
  • loss of collagen fibril structures
  • seen in:
    • inflammation/infection
    • radiation
    • chemical injury
    • anterior segment ischemia
  • healing involves, scarring, vascularization
• Deposits
  • Hylaine: stains red with Trichrome stain
    • Granular dystrophy (chromosome 5q)
  • Amyloid: stains red with Congo Red
    • Lattice dystrophy (chromosome 5q)
    • Polymorphic amyloid degeration
  • Mucopolysaccharide:
  •  
    • Macular dystrophy: Alcian blue stain (acid mucopolysaccharide)
    • Mucopolysaccharidoses
    • Fleck dystrophy: lipid and mucopolysaccharide deposits
  • Hemoglobin:
    • corneal blood staining-hemoglobin in stroma
    • iron found in keratocytes not in collagen in late blood staining
  • Iron: late corneal blood staining can find iron in the form of hemosiderin in keratocytes
  • Lipid: Oil-red-O stain
    • deposited in triangles with base towards Bowman’s or Decemet’s and apeces in center of stroma
    • corneal arcus= lipid
  • Cholesterol
    • Schnyder’s crystalline dystrophy
  • Immunoglobulins: macroglobulinemia

Decemet’s membrane: Anatomy and Pathologic Responses

• endothelial basement membrane
• Two layers
  • anterior banded: deposited in utero
  • posterior non-banded: deposited after birth: thickens throughout life
• Guttata or Hassal-Henle warts
  • focal thickening of Decemet’s
  • Fuch’s endothelial dystrophy: guttata plus loss of endothelial cells plus corneal edema
  • can have pigment settle on them-pigmented guttata
  • strings of guttata or large scrolls of Decemet’s seen in congenital syphillis
• Decemetocele-herniation of Decemet’s through ulcer. Tensile strengh prevents Decemet’s rupture in ulcer
• Hydrops in keratoconus, forceps injury, congenital glaucoma (Haab’s striae), trisomy 21
• Peter’s Anomly: central absence of Decemet’s this causes scarring of stroma. Possible adhesion of iris or lens to cornea
• Detachment- a result of surgery or trauma
• Granulomatous inflammation: inflammation in HSV infection
• Deposits
  • Copper: chalosis-retained intraocular copper foreign body
  • Kayser-Fleischer ring in Wilson disease

Corneal Endothelium: Anatomy and Pathologic Responses

• derived from neural crest cells
• maintains stromal dehydration
• regenerates poorly
• halts downgrowth of epithelium
• Endothelium can grow over angle (forming "neo-Decemet’s") in response to:
  • trauma
  • Iridocorneal endothelial (ICE) syndromes
    • Cogan-Reese syndrome (iris-nevus)
    • Chandler’s syndrome
    • Essential iris atrophy
  • Posterior polymorphous membrane dystrophy (PPMD): endothelium acqures characteristics of epithelium
  • Chronic intraocular inflammation
  • With rubeosis irides
• Fibrous retrocorneal membrane can cover endothelium
  • from iris after PAS
  • from corneal stroma through gap in Decemet’s
  • fibrous metaplasia of endothelium-deposition of posterior collagenous layer of Decemet’s membrane
• Pigment deposition
  • pigment can deposit on endothelium. eg. pigmented guttata
  • endothelium can take up pigment. eg. Krukenburg spindle in pigment dispersion syndrome

Corneal Changes in size and shape

• Megalocornea
  • X-linked non-progressive enlargement of cornea
  • 13-18 mm in diameter
• Microcornea
  • less than 10 mm in diameter
  • may be complicated by glaucoma
• Keratoconus
  • bilateral ectasia, often asymmetric, leads to irregular corneal curvature
  • thinning to a conical or irregular shape
  • Vogt striae- stress lines in cornea that disappear with pressure on cornea
  • fracturing or fragmentation of Bowman’s layer
  • rupture of Decemet’s= hydrops
• Keratoglobus
  • bilateral ectasia leading to uniform corneal thinning
• Staphyloma
  • a bulging lined by uveal tissue
  • corneal staphyloma is lined by iris

Selected Corneal Infections

• Fungi
  • Decemet’s doesn’t offer a barrier to fungi
  • seen on GMS (silver) stain
• Herpes Simplex
  • Dendrites
  • Geographic ulcers
  • Disciform keratitis
  • stromal inflammation and superficial scarring
  • fragmented Bowman’s layer
  • granulomatous reaction to Decemet’s membrane
• Acanthamoeba
  • resembles herpetic disciform keratitis
  • ring infiltrates, spoke infiltrates along nerves
  • Calcoflour white with flourescence highlights cysts
  • Trophozoite seen on routine stains as well
  • Corneal scraping or biopsy

Corneal Dystrophies

• Epithelium
  • Meesman's Dystrophy
  • Map-Dot-Fingerprint Dystrophy
• Bowman’s Layer
  • Reis-Bückler’s dystrophy
• Stroma
  • Granular dystrophy
  • Lattice dystrophy
  • Macular dystrophy
  • Schnyder’s crystalline dystrophy
• Endothelium
  • Fuchs’ Dystrophy

Perepherial Cornea and Limbus Pathology

• Limbal Dermoid: a choristoma- heterotropic rest of tissue
  • Goldenhar’s syndrome
  • contrast with dermoid cyst which occurs in eyelid and has dermal elements
• Degenerations
  • Pelucid Marginal Degeneration: perepherial, usually inferior ectasia
  • Terrian’s Marginal Degeneration
    • thinning of perepherial cornea
    • perepherial corneal staphylomas
    • astigmatism
    • risk of rupture with blunt trauma
• Inflammations
  • Staphlyococcal marginal infiltrate: hypersensitivity to staphylococcal exotoxins
  • Phlyctenular keratoconjunctivitis: hypersensitivity to systemic staphylococcus or turberculosis at limbus or in conjunctiva
  • Limbal vernal keratoconjunctivitis: papillary reaction, Horner-Trantas dots- degenerative products of eosinophiles
  • Superior Limbic keratoconjunctivitis: injection and superior conjunctival thickening

Corneal Neoplasia: conjuctival tumors tend to arise at the limbus (see conjunctiva section)

• Anatomy
• Pathologic responses
• Deposits
• Choristomas
• Color Changes
• Epithelial Lesions/ Squamous Cell Carcinoma
• Inflammation
• Lymphoid Lesions
• Nevi
• Melanosis-Congenital
• Melanosis-Acquired
• Melanoma
• Biopsy

Conjunctival Anatomy

• Bulbar
  • non-keratinizing stratified squamous epithelium
  • goblet cells not usually near surface
  • substantia propria (aka stroma)
  • sclera under substantial propria
• Fornix
  • pseudostratified columnar epithelium with goblet cells
  • substantia propria (aka stroma)
• Palpebral
  • pseudostratified columnar epithelium with goblet cells
  • substantia propria (aka stroma)
  • Tarsus
    • Meibomian glands
  • dermis
  • epidermis
  • Accessory lacrimal tissue
    • Krause and Wolfring glands: produces aqueous layer of tear film
• Lymphoid tissue
  • lymphocytes and plasma cells
  • part of Mucosa Associted Lymphoid Tissue (MALT)
  • form IgA
  • Forms lymphoid follicles in: follicular conjunctivitis, lymphoid hyperplasia
  • Diffusely infiltrates substantia propria in lymphoma

Conjunctival Pathologic Responses

• loss of goblet cells (keratitis sicca, vitamin A deficency)
• conjunctival scarring (alkali burns, pemphigoid)
• increase in goblet cells (ocular irritations: pterygium)
• keratin production
  • Bitot spot in vitamin A deficency,
  • diptheroids produce gas in keratin and give bubbly appearance,
  • Dry eye
  • Exposure
• squamous metaplasia
  • replacement of pseudostratified columnar epithelium in fornix or palpebral conjuctiva with squamous epithelium
• epidermidalization
  • formation of rete ridges
  • seen often with keratinization
• follicles- formation of germinal centers by lymphoid tissues
• papillae- substantia propria is loosly organized causing redundancy and folding, usually increase in goblet cells
• cysts- chronic conjunctivitis, compound nevi, rarely seen in melanomas that arise from compound nevi
• bullae
  • pemphigus: intraepithelial bullae, antibodies directed to intercellular substance
    • acantholysis-epithelial cells separate from each other
    • bullae can rupture and become infected
  • pemphigoid: subepithelial bullae, antibodies against epithelial basement membrane
  • rupture of bullae leads to scarring, symblepharon, obliteration of orifices of lacrimal glands and accessory lacramal gland- tear deficency
  • loss of goblet cells- decreased corneal wettablility
• Solar elastosis
  • marker of damage by UV light
  • sub-epithelial elastoic collagen- stains blue on H&E but doesn’t digest with elastase
  • seen in penguecula, pterygium, (recurrent pterygium is granulation tissue and scarring not solar elastosis)

Conjunctival Deposits

• urate in gout
• cystinosis- refractive crystals in epithelium
• immunoglobulins
• drugs
  • epinepherine
  • silver
  • tetracycline
• amyloid: reflects local disease
• pseudoexfoliation material

Conjunctival Choristomas

• limbal dermoid
• lipodermoid
  • superior temporal quadrant
  • adipose tissue with elements of solid dermoid tumor
  • carilage and secretory glands can be present
• osseous choristoma: usually involves epislera in superior temoral quadrant

Conjunctival Color Changes

• Red: vascular injection or blood
  • conjunctivitis
  • episcleritis (more violet color)
  • scleritis (more dusky red)
  • polycythemia
  • blood
    • subconjunctival hemorrhage
    • trauma
    • Kaposi’s sarcoma
      • appears as chronic non resolving hemorrhage in skin or eyelid
      • histologically-slit like spaces between spindle shaped cells and RBC’s confined to these spaces
• Blue
  • hemosiderin
  • melanin in episclera or sclera
    • congenital ocular melanosis
    • Nevus of Ota- accompanying blue pigmentation of periocular skin
• Brown or black
  • melanin
  • nevi
  • primary acquired melanosis
  • secondary acquired melanosis
  • melanoma
• yellow
  • lipid of sebacious carcinoma
  • solar elastosis
  • "scleral" icterus is really bilirubin deposits in conjunctiva not sclera
• gray or white
  • conjuntival keratosis
  • Bitot spot in vitamin A deficency
  • chronic exposure
  • squamous cell carcinoma

Conjuncitval Epithelial and Supepithelial Lesions (Neoplastic and other)

• epithelium: abrupt elevations and irregular surfaces characterize lesions arising from epithelium
  • Squamous Papilloma
    • papillary fronds
    • core of fibrovascular tissue surrounded by hyperplastic epithelium
    • dysplasia
  • carcinoma in situ: thickening of epithelium appears gelatinous and translucent
• supepithelial compartment: tend to elevate and streach normal epithelium
• pinguecula
• lymphoid lesions- "salmon patch"
• cysts
  • chronic conjunctivitis
  • compound nevus
• lymphatics
  • lymphangiectasia
  • lymphangioma

Conjunctival Inflammation

• Actinic granuloma: Granulomatous inflammation
  • inflammed penguecula clinically
  • granulomatous response to elastoic collagen
• Sardoid
• Cat Scratch
  • follicular conjunctivitis with or with out a granulomatous mass
  • granulomas with central abscess characteristic
  • excision of the granulomatous mass may hasten recovery
  • if enlarged lymph nodes- cat scratch fever
  • one of Parinaud’s Oculoglandular Fever
  • DDx: tularemia, syphilis, sporotrichosis, tuberculosis, other rare infections

Conjunctival Lymphoid lesions

• Features:
  • Typically unilateral, 60’s-70’s
  • can be subepithelial and space occupying "salmon patch"
  • can involve orbit
  • tend to be hyperplastic, benign
  • bilaterality doesn’t mean malignancy
• Classification
  • benign reactive lymphoid hyperplasia
  • atypical lymphoid hyperplasia
  • malignant lymphoma
  • lymphoasmacytic proliferations
• Management
  • systemic workup by oncologist
  • CBC
  • serum electrophoresis
  • bone marrow aspirate and biopsy
  • liver & spleen scan
  • thoracic and abdominal CT
  • radiation with shielding of eye
  • lesions respond poorly to steroids

Conjunctival Squamous Cell Carcinoma

• Definitions
  • acanthosis- epithelium thickened (hyperplastic)
  • hyperkeratosis- any keratin in conjunctiva
  • dyskeratosis- individual cell keratinization within epithelium
  • dysplasia- abnormal maturation of partial thickness epithelium
    • cytoplasmic atypia
    • abnormal mitosis
    • loss of polarity
  • carcinoma in situ- full thickness dysplasia
    • no invasion into stroma (substantia propria)
• Heriditary benign intraepithelial dyskeratosis (HBID)
  • autosomal dominant
  • Haliwa indians-from Halifax and Washington
  • triracal families- white, african-american and american indian
• Conjunctival intraepithelia neoplasia (CIN)- dysplasia & carcinoma in situ
  • Clinical features
    • may have solid elevated appearance
    • may have papillary appearance
    • may resemble a pterygium
    • may look like a thin hazy membrane creaping across corneal epithelium
    • commonly at limbus but can occur elseware
  • Histologic features
    • exophytic (out growth) as in papillary squamous cell carcinoma (scleral invasion absent in this type)
    • invasion into substantia propria and sclera
    • intraocular invasion rare
    • metastisis rare

Conjunctival Nevi

• Features
  • pigmented or nonpigmented
  • affect bulbar conjunctiva, fornix or caruncle rarely palpebral conjunctiva
  • circumscribed
  • often contain small cysts in compound nevus
• Types
  • Junctional
    • children or adolescents
    • proliferation of nevus cells at juction of epithelium and stroma
    • nesting may be prominent
    • may be indistinguishable from primary acquired melanosis with atypia
  • Compound
    • contain cysts usually
    • lie in the epithelium and subepithelial substantia propria
  • Subepithelial
    • may have nests and cysts
    • confined to substantia propria

Conjunctival Melanosis: Congenital - more blue in color, scleral or episcleral melanin

• Congenital ocular melanosis
• Nevus of Ota
  • accompanying blue pigmentation of periocular skin
  • clinical differentiation of congenital ocular melanosis and conjunctival melanin
  • conjunctival melanin will move with movement of conjuctiva

Conjunctival Melanosis: Acquired

• Primary (PAM)
  • Features
    • unilateral, flat, in light complected individuals
    • discontinuous foci of pigmentation
    • can involve, bulbar, palpebral, fornix epithelium
    • can also involve caruncle and corneal epithelium
    • may wax and wane, spread, or disappear
  • PAM without atypia
    • hyperpigmentation without hyperplasia or
    • hyperplasia without cytologic atypia
    • little risk of progression to melanoma
  • PAM with atypia
    • atypical melanocytes confined to epithelium
    • risk of developing melanomal approches 50%
    • features linked to progression to melanoma
    • any growth pattern other than basilar hyperplasia
    • epitheloid cells present
  • Management
    • biopsy all patients with PAM
    • if atypia present, lesion should be extirpated by excision, cryotherapy, laser or topical chemotherapy
• Secondary
  • no predilection for melanoma
  • conjunctival pigmentation in african-americans
  • Addison’s disease
  • drugs such as epinepherine, silver, tetracycline

Conjunctival Melanoma

• Features
  • 25% overall mortality rate
  • spreads to regional lymph nodes (in contrast to uveal melanoma which first spreads to liver)
  • most develop from PAM
• PAM with upward invasion into conjunctival epithelium (Pagetoid spread) has worse prognosis
• tumors thicker than 0.85 mm have worse prognosis
• tumors of caruncle have worse prognosis

Conjunctival Biopsy

• spread tissue on flat absorbant surface such as paper wrapping for gloves, the file-card envelope for sutures or filter paper
• allow tissue to become adherent to mount
• float in formalin, sample will sink to bottom in proper orientation

• Epidermis pathology
• Dermis pathology
• Sub-cutaneous fat pathology
• Definition of terms
• Clinical clues to underlying pathology
• Specific Conditions:

Epidermis- by layers

• keratin layer
  • normally acellular
  • parakeratosis- nuclei in keratin layer, sign of rapid epithelial turnover
  • hyperkeratosis- excessive keratin
• granular layer
  • basophilic keratohylain granules in cytoplasm
  • eventually nucleus is lost
• prickle cell layer
  • spines represent sites of desmosomal attachment
  • acanthosis- thickening of this layer
• germative layer
  • only layer with mitotic figures
  • sits on basement membrane
• other cells
  • melanocytes
    • derived from neural crest
    • reside in basal layer
    • inject melanin into overlying prickle cells by way of dendritic processes
  • Langerhans cells
    • capture antigens, process them and present them to dendritic reticulum cells or lymphocytes in the dermis

Dermis

• hair tumors
  • pilar cyst
  • trichoepithelioma
  • trichofolliculoma
  • tricholemmoma
  • pilomatrixoma
• glands
  • eccrine glands
    • hidrocystomas
    • syringoma
  • apocrine glands (glands of Mol)
    • hidrocystomas
    • sebaceous glands
    • sebacious hyperplasia
    • adenoma
    • carcinoma
• vessels
  • capillary hemangioma
  • nevus flammeus
  • artrio-venous hemangioma
  • Kaposi’s sarcoma
• nerves
  • schwannoma (neurolemmoma)
  • neurofibroma

Sub-cutaneous fat

• absent in eyelid
• dermis rests on obicularis
• fat on eyelid biopsy represents orbital fat

Terminology-Skin

• Acanthosis
  • epidermal thickening by hyperplasia
  • prickle cell hyperplasia
  • acanth= "spines"
  • element of seborrheic keratosis
• Hyperkeratosis
  • increased amount of keratin
  • clinically grey or white scale
  • abundant amounts appear waxy and yellowish. generic term for this is "cutaneous horn"
  • causes
    • actinic keratosis
    • squamous cell carcinoma
    • inverted follicular keratosis
    • sebacious carcinoma
  • removal of lesion involves removal of epidermis under lesion
• Parakeratosis
  • a type of keratosis with retention of nuclei in keratin layer
  • granular layer is thin or absent
  • sign of shortented epidermal turnover time
• Dyskeratosis
  • individual cell keritinization occurs within epidermis rather than at the surface
• Dysplasia
  • abnormal maturation of an epithelium
  • cells lose polarity
  • atypical cytologically
  • partial thickness
• Carcinoma-in-situ
  • full thickness dysplasia of epithelium (epidermis)
  • does not invade dermis
• Squamous cell carcinoma
  • dysplasia with evasion through basement membrane
  • invasive component may have:
    • dyskeratosis
    • keratin pearls- aggregates of keratin
    • atypical mitotic figures
    • nuclear atypia
    • infiltrative borders
• Elastosis
  • assoicated with actinic keratosis, squamous cell carcinoma, basal cell carcinoma, melanoma
• Keratosis
  • non specific term meaning a lesion in the epidermis
  • examples:
    • seborrheic keratosis
    • actinic keratosis
• Actinic Keratosis
  • epidermal dysplasia
  • elastosis
  • inflammation
  • hyperkeratosis, parakeratosis
  • clinically: raised, scaly, sometimes erythematous
  • precursor of squamous cell carcinoma

Clinical clues to underlying pathology

• Color
• Surface topography
• Lesions that don't follow rules: Basal Cell CA, Squamous Cell CA

Color of Skin Lesions

• Red or pink- increased quanities of oxygenated RBC’s
  • nevus flammeus:
    • Sturge-Weber syndrome
    • telangiectatic vessels in dermis
  • capillary hemangioma of childhood
    • may be present at birth or develop rapidly in first six months
    • most cases regress by age 6 or 7
  • pyogenic granuloma- inflammatory granulation tissue
  • dacryocystitis
    • swelling does not extend above medial canthal ligament. tumors may project above this mark
  • pre-septal cellulitis
    • inflammation that dissects through tissue planes
  • chalazion
• Blue- hemosiderin or deep melanin
  • Basal cell carcinoma
    • locally infiltrative
    • may gain access to orbit
• Brown or black- superficial melanin
  • nevi
  • melanoma precursors and melanoma
  • abundant keratin in keratoacanthoma
• Grey or white- increased keratin
• Yellow- lipid or elastic tissue
  • Xanthalasma
  • Necrobiotic Xanthogranuloma
    • yellow deposits and skin necrosis
    • may harbor or later develop multiple myleoma
    • immunoelectrophoresis and bone marrow biopsy necessary
  • Pseudoxanthoma elasticum
    • associated with angioid streaks
    • prone to have GI bleeds

Surface topography of Skin Lesions

Lesions arising from epidermis

• edges abruptly elevated
• epidermal topography exaggerated
• eg. squamous papilloma, seborrheic keratosis

Lesions arising from dermis

• streach of overlying epidermis giving a smooth surface
• edges slope and blend with adjacent tissue
• dermal deposits
  • amyloid
    • waxy plaques
    • purpuric hemorrhage from deposits around vessels causing them to be fragile
    • reflects systemic pathology as opposed to conjunctival amyloid
  • lipoid protenosis
    • waxy nodules usually at eyelid margins
  • hyalin material
    • similar lesions around vocal cords can cause hoarsness
  • xanthalasma
    • yellow plaques on upper and lower eyelids
    • dermal lipid filled macrophages around venules
    • don’t necessarily have elevated serum lipids
• tumors
  • syringoma
    • small nodules beneath eyelids
    • arise from eccrine sweat glands
  • neurofibroma
    • plexiform neurofibroma
      • can occur in eyelid
      • follows a nerve trunk
      • "S"-shaped ptosis of upper lid
      • diagnostic for neurofibromatosis type I (von Recklinghousen disease)
    • solitary neurofibromas not associated with neurofibromatosis
• cysts
  • epidermal inclusion cyst
  • dermoid cyst
  • sudoriferous cyst- translucent
  • chalazion -focus of lipogranulomatous inflammation in tarsus

Skin Lesions that don’t follow the rules

Basal Cell Carcinoma

• arise from epithelium but does not thicken this layer
• invades the dermis and occupies space in the dermis
• sloping, curved edges, central umbilication
• may be nodular or cystic

Squamous Cell Carcinoma

• epithelium thickened
• AND infiltration into dermis causing dermal space occupying pattern as well

Specific Eyelid Skin Conditions

• Inflammations
• Cystic lesions
• Other lesions
• Non-pigmented Malignancies
• Lid tumors of sup-epidermal tissues
• Nevi
• Melanoma

Chalazion

• inflammation of tarsus sometimes breaking through to the skin
• sebacious carcinoma may mimic clinical appearance
• pink skin and dermal mass lesion
• granulomatous inflammation around lipid with giant cells

Hordeolum (Stye)

• suppurative (acute) inflammation
• usually centered around glands of Zeis associated with an eyelash

Cellulitis

• inflammation passing through tissue planes

Abscess

• localized zone of suppurative inflammation frequently assoicated with necrosis

Herpes Simplex and Zoster

• intact and crusted vesicles
• vesicles form within the epidermis
• lysis of acanthocyte layer (prickle cells) "acantholysis"
• characteristic intranuclear inclusion bodies

Molluscum Contagiosum

• solitary or multiple elevated white umbilicated lesions
• seen in children commonly and in immunocompromised adults
• viral particles may shed into conjuntival cul-de-sac causing a follicular conjunctivitis
• epidermal thickening- acanthosis
• cells infected with DNA poxvirus
• basophilic and eosinophilic inclusion bodies

Lid Lesions- Cysts

• Epidermal inclusion cyst
• Dermoid cyst
• Sudoriferous cyst
• Cystic Basal cell carcinoma

Epidermal inclusion cyst

• subepidermal (in dermis)
• freely mobile, opaque
• filled with white, maloderous, greasy material
• lined by stratified squamous epithelium, no dermal elements
• filled with keratin
• may spontaneously rupture leading to a granulomatous inflammation to the keratin

Dermoid cyst

• example of choristoma- heterotopic rest of tissue
• lined by keratinizing stratified squamous epithelium
• cyst wall also contains other dermal elements eg. hair and sebacious glands

Sudoriferous cyst

• at lid margin or near canthi
• contain secretions of sweat glands
• transmit light well
• formed by eccrine or apocrine glands
• lined by bilayer of flattened epithelium

Cystic basal cell carcinoma

• basal cell carcinoma that has undergone central necrosis
• can clinically mimic epithelial inclusion cyst
• tumor may be attached to adjacent tissue making shelling out of contents difficult
• doesn’t transilluminate
• hemosiderin accounts for blue color
• perepherial palasading nuclei
• cracking artifiact- separation of tumor from dermis
• Benign lesions arrising from epidermis

Lid Lesions- Other Epidermal lesions

• Squamous papilloma
• Seborrheic keratosis
• Inverted follicular keratosis
• Keratoacanthoma
• Syringoma

Squamous papilloma

• prominent hyperkeratosis
• fronds may be seen with magnification
• similar to verruca (true viral verruca rare on eyelids)
• acanthosis (hyperplasia) of epitheithelium and thrown into folds over cores of dermal fibrovascular connective tissue

Seborrheic keratosis

• complex groved surface, "stuck on" appearance
• may be pigmented especially in dark races
• appearance of sudden multiple lesions may be marker of internal malignancy
• acanthosis
• base of lesion flat- noninvasive
• no dysplasia
• lamellar hyperkeratosis
• pseudo keratin inclusions- formed by grooves on surface of lesion
• variable papillomatosis

Inverted follicular keratosis

• presents as a "cutaneous horn"
• some call them irritated seborrheic keratosis
• may be some acantholysis just above basal layer
• squamous eddies- whorls of benign squamous cells just above acanthocytes

Keratoacanthoma

• rapid growth of cup shaped lesion (weeks to months)
• frequently central black plug of keratin causing central crater
• usually regresses without treatment
• sometimes hard to distinguish from squamous cell carcinoma
• SCC usually lacks central crater and come on less quickly and don’t resolve spontaneously
• SCC has infiltration at base of lesion
• biopsy should include edge of lesion and central crater
• acanthosis, hyperkeratosis, dyskeratosis, mitotic figures, some cytologic atypia possible, no infiltration at base, inflammation at base
• biologically could be a self-regressing squamous cell carcinoma
• a.k.a- squamous cell carcinoma-keratoacanthoma type

Non-pigmented malignancies of epidermis

• Actinic keratosis
• Squamous cell carcinoma
• Basal cell carcinoma

Actinic keratosis (pre-malignant)

• acanthosis, hyperkeratosis, parakeratosis, dysplasia, small lymphocytic infiltrate possible

Squamous cell carcinoma

• may occur anywhere on eyelid skin
• 40 times less common than basal cell carcinoma
• hyperkeratosis may cause grey-white scale
• low potential for regional lymph node metastasis
• atypical squamous cells infiltrate dermis

Basal cell carcinoma

• clinical features
  • usually lower eyelids
  • metastasis extremely rare
  • local invasion into orbit, sinus, frontal cranial fossa
  • nodular
  • nodular-ulcerative
  • cystic
  • sclerosing- borders difficult to identifiy
  • pigmented- melanin elaborated by benign melanocytes entrapped in tumor
• pathology
  • islands, nests and chords of cells with scant basophilic cytoplasm
  • perepherial palasading nuclei
  • cracking artifact- separation of tumor from stroma
  • arborizing strands of tumor within stroma with abundant fibrous stroma may represent sclerosing variant
• nevoid basal cell carcinoma syndrome
  • autosomal dominant
  • multiple basal cell carcinomas at a young age
  • systemic associations
    • bifid ribs
    • ovarian lesions
    • odontogenic jaw cysts
    • pitting of the palms
• management
  • do incisional biopsy before planning surgery to establish diagnosis
  • completely remove tumor
  • if margins contain tumor recurrance rate 8-10%
    • can observe or excise scar
  • check margins with frozen section (Mohs)

Tumors arising in sub-epidermal Lid tissues

Sebaceous carcinoma

• Clinical Features
  • may present as nodule in eyelid and mimic chalazion
    • biopsy and submit recurrent chalazion material
  • may present as nodule in caruncle
  • may present as chronic unilateral (blepahro) conjunctivitis
  • may be accompanied by madarosis (loss of eyelashes)
  • marker of internal malignancy
• Pathology
  • arise from meibomian glands, glands of Zeis (assoicated with eyelash), or sebacious glands in caruncle
  • may be multicentric
  • Pagetoid spread (upward spread to epithelium, also seen in melanoma)
    • can be mistaken for carcinoma-in-situ or chronic inflammation
  • bubbly cytoplasm, not foamy lipid-filled cytoplasm
  • full thickness lid biopsy to look at meibomian glands and Zeis glands may be necessary
  • Oil-red-O stain on fresh or formalin fixed tissues can identify fat
• Prognostic parameters
  • size
  • orgin (better if from glands of Zeis)
  • differentiation
  • presence or absence of infiltration
  • location (better if from lower lid)

Syringoma

• multiple small (2-3mm) plaques on or beneath lower lids in young or middle aged women
• benign tumor of eccrine glands
• fibrous stroma and glandular elements

Lid Lesions-Nevi

Congenital

• split nevus of eyelid
• melanocytes migrate over eyelid before separation of eyelids in utero
• may add bulk to eyelid and cause ambylopia
• tendancy for cutaneous melanoma to develop at this site

Acquired

• stages of maturation
  • junctional nevus
    • nests of nevus cells at juction of dermis and epidermis
    • clinically flat
  • compound nevus
    • cells drop off epidermis
    • nests in dermis and epidermis
    • lesion becomes elevated
  • intradermal nevus
    • all cells in dermis
    • lesion elevated
• smooth, dome shaped lesions
• may be pigmented or not
• hairs frequently protrude from surface
• posterior surface molds or contours to surface of eyelid

Lid Melanoma

Lentigo maligna

• seen in older patients after extreme sun exposure
• flat, irregular borders, variable pigmentation
• may overlap into adjacent conjunctiva

• Anatomic relationships
• Pathologic changes
• Tumors of the Optic Nerve

• Contrast to peripheral nerve
• Laminar zones
• Cross-sectional anatomy
• Axoplasmic transport

Contrast Optic nerve to peripheral nerve

optic nerve

• mylenated by olgiodendroglia
• tumors are glioma and meningioma
• no regeneration
• scarring and repair: gliosis
• gliosis= glial cells proliferate and produce intracellular material. Also occurs in retina

perepherial nerve

• mylenated by Schwann cells
• tumors are Schwannoma, neurofibroma
• regeneration possible following transection
• scarring and repair: fibrosis
• fibrosis= fibroblasts secrete extracellular material (i.e., collagen)

Laminar Optic Nerve Zones

• Prelaminar
  • lamina retinalis and lamina choroidalis
  • some blood supply from choroidal vessels
• Intralaminar
  • lamina scleralis a.k.a lamina cribrosa
  • position of lamina scleralis can give clues to clinical picture
• Retrolaminar
  • mylenated by oliodendroglia

Cross-sectional Optic Nerve Anatomy

• dura
  • continuous anteriorly with the sclera and posteriorly with the periosteum of orbital bones
• subdural space
  • continuous with same space in brain
  • subdural hemorrhage of brain can track back along optic nerve in this space (as in shaken baby syndrome)
• arachnoid
  • continuous with arachnoid of brain
  • contains arachnoid epithelium forming "granulations"
  • have "clearing"of nuclei
  • meningiomas form from epithelium
• subarachnoid space
  • continuous with same space in brain
• pia
  • intimately surrounds nerve
  • compartmentalize nerve and carry small vessels into it

Axoplasmic transport

• axons originate from ganglion cells and terminate in lateral geniculate body
• orthograde transport- flow of material from cell body down axon
• when transport is interrupted, axoplasmic flow procedes from cell body to site of interruption. Organelles especially mitochondria pool next to the interruption. cytoplasm swells.

Optic Nerve Pathologic changes

• Nerve fiber layer infarct
  • collection of cytoid bodies in layer= pink on H&E
  • usually occur in retina but can occur in lamina retinalis of optic nerve
  • clinically a cotton wool spot
• Papilledema
  • swelling of optic nerve head associated with increased intracranial pressure
  • lamina retinalis swells due to stasis of axoplasmic transport
  • photoreceptors displaced laterally
  • dilation of epipapillary vessels
  • fluid accumulates in extracellular compartment
  • lamina scleralis position
  • anterior bowing
  • elevated intracranial pressure
  • compression of optic nerve from orbital or optic nerve tumor
  • ocular hypotony
  • posterior bowing in acute IOP elevations
• Drusen
  • calcific masses, usually anterior to lamina scleralis
  • focal burried masses
  • sharp optic nerve border
  • often vessel anomalities
  • absence of cup
  • "giant drusen" in tuberous sclerosis are calcified astrocytic hamartomas
  • scleral canal may be congenitally narrowed which may lead to stasis of axoplasmic transport
  • calcified mitochondria may be extruded from axons causing calcific masses
  • 75% get visual field defects
• Optic atropy and gliosis
  • cells or tissues already present decrease in size or mass
  • loss of axons
  • widening of subdural space
  • hypoplasia
  • structure not formed completely
  • double ring sign = ring of sclera around small optic nerve
  • crushed nerve may appear histologically as atrophy or gliosis. some of the nerve contents can also be squeezed subretinally and into blood vessels "myelin artifact"

• Optic Nerve head tumors
• Tumors arising from the Optic Nerve

Optic nerve head Tumors

• Tumors associated with phacomytoses
  • Astrocytic Aamartoma
    • may be calcified and apper like drusen
    • seen in tuberous sclerosis
  • Hemangioblastoma
    • can mimic a hemorrhage
    • seen in Von Hippel-Lindau disease
• Melanocytoma
  • jet black lesions of optic nerve head
  • feathery borders often
  • more prevalent in black patients
  • may increase in size
  • benign
  • may develop elsewhere in uveal tract
  • nevus cells densly packed with melanin granules
  • spindle and large polygonal cells seen after melanin bleaching
• Secondary
  • invasion with retinoblastoma

Tumors arising from the Optic Nerve

• Meningioma
• Glioma
• Pilocytic astrocytoma

Optic Nerve Meningioma

• middle aged women most common
• prognosis usually good for primary optic nerve meningioma of adulthood
• can be seen in children
• tumors usually more aggressive in children
• optociliary shunt vessels
• optic nerve head edema can occur
• irregular distention of optic nerve sheath on imaging
• arise from meningothelial cells in arachnoid
• may invade into and beyond dura
• psammoma body- mengiothelial cells form sand like granules of focal calcifications
• tend to grow around and compress optic nerve causing atrophy

Optic Nerve Glioma

• axial proptosis
• associated with neurofibromatosis
• indolent in childhood and more aggressive in adulthood
• develops from and expands the substance of the optic nerve
• meningial hyperplasia may accompany glioma
  • can be histologically indistinguishable from meningioma
  • doesn’t spread outside the dura as opposed to meningioma
  • tend to be intradural

Pilocytic Astrocytoma

• proliferating glia are delicate and elongated like hairs
• Rosenthal fibers= degenerated eosinophilic glial fibers
• microcysts may form and coalesce suddenly leading to sudden proptosis and doesn’t indicate malignancy

• Anatomy and Pathologic response to injury
• Retinal vascular diseases
• Peripheral retinal degenerations
• Retinal Detachment
• Proliferative Vitreoretinopathy
• Macular Diseases
• Pathology of Vitreous

• Retinal Layers
• Regional variations in anatomy
• Retinal Blood Supply

Retinal Layers

• limiting membranes
  • internal limiting (ILM)
    • true basement membrane- PAS positive
    • produced by Mueller cells
    • normally no cells or tissue line ILM
    • new vessels break through in neovascularization
    • membranes lie over ILM in proliferative vitreoretinopathy and may wrinkle retina underneath
  • extenal limiting
    • not a true basement membrane
    • adhesions of Mueller cells with photoreceptors
    • defines lumen in Flexner-Wintersteiner rosettes
    • at level of inner and outer segments of photoreceptors
• nerve fiber layer
  • contains axons of ganglion cells
  • hemorrhage appears flame shaped in this layer
  • thins in end-stage glaucoma
• ganglion cell layer
  • nuclei of axons contined in nerve fiber layer
  • multiple cells thick in macula
  • accumulation of storage material in neuronal storage diseases such as Tay-Sachs disease
  • loss of nuclei in end-stage glaucoma
• inner plexiform layer
  • cell processes between ganglion cells and inner nuclear layer
• inner nuclear layer
  • nuclei of Mueller cells
  • astrocytes
  • bipolar cells
  • other neurons
• outer plexiform layer
  • aka. Henle’s layer
  • oriented obliquely in normal macula causing appearance of macular "star" when exudates accumulate here
  • cell processes between photoreceptors and inner nucelar layer
  • hemorrhage here appears dot-like
  • well circumscribed ("hard") exudate occur here
• outer nuclear layer
  • nuclei of the photoreceptors
• photoreceptor layer
  • inner and outer segments separated by outer limiting membrane
• retinal pigment epithelium (RPE)
  • phagocytosis of outer segments of photoreceptors
  • blood retinal barrier
  • exchange of light and heat energy
  • derived from outer layer of optic cup
  • responds to injury by hyperplasia
  • hexagonal cells
  • form drusen
  • contributes to formation of pre- and retro-retinal membranes
  • osseous metaplasia-RPE can deposit bone in phthisis
• Bruch’s membrane
  • basement membrane of RPE
  • inner aspect of choriocapillaris
  • middle elastic layer may calcify and fragment in
  • angioid streaks
  • macular degeneration
  • aging
• choroid
  • derived from mesoderm; fibroblasts and vessels
  • populated by melanocytes; neural crest
  • melanocytes are capable of neoplastic responses

Regional variations in retinal anatomy

• macula
  • thickness of ganglion cell layer
  • oblique orientation of Henle’s layer
  • thickening of RPE
• perepherial retina
  • non-pigmented ciliary epithelium merges into retina
  • vitreous base straddles perepherial retina and pars plana

Retinal Blood Supply

• retinal vessels
  • supply up to inner 2/3 of inner nuclear layer
  • interruption in BRAO causes retinal necrosis and atrophy only in these areas
  • in contrast glaucoma causes only atrophy in nerve fiber and ganglion cell layers
• choriocapillaris -supplies outer 1/3 of inner nuclear layer and outer layers
  • no cross communication between retina and choroidal circulation

• Fundamentals
• Vascular Occlusive Disorders
• Diseases of Microcirculation

Retinal Vascular Fundamentals

• Arteriosclerosis
• Vascular Occlusion
• Hypertension
• Neovascularization

• generic term meaning "hardening of arteries"
• encompases the following
• athrosclerosis
  • narrowing of lumen,
  • athrosclerotic plaque (athroma)
  • inside internal elastic lamina
  • made of cholesterol and can calcify
• arteriolosclerosis
  • thickening of walls of arterioles
  • copper wiring
  • silver wiring
• calcific medial sclerosis
  • deposition of clacium at level of internal elastic lamina and/or media
  • vessel may become palpable
  • associated with aging

• thrombosis
  • intravascular clotting
  • thromboembolism- piece of clot breaks off and travels distally
• clot
  • extravascular blood and blood products
  • hyphema is an example
• embolus
  • material that has been carried through the vessels to a distant intravascular site
  • calcific
    • originate from calcific heart valves or calcified athromatous plaques
    • intravascular white refractile bodies
    • stain dark red on H&E
  • athromatous or cholesterol
    • yellow intravascular plaques
    • seen ophthalmologically as Hollenhorst plaques
    • usually originate from carotid athrosclerotic plaques
  • thromboemboli
    • source cardiac or cartoid arteries
    • seen as small intravascular grey-white opacities
    • referred to as "fibrin-platelet" emboli
  • fat
    • complicate trauma to long bones
    • oil-red-o stain
  • talc- seen in IV drug abusers

Hypertension

• affects major vessels as well as microcirculation of retina and choroid
• arteriolosclerosis with sustained mild to moderate hypertension
• malignant hypertension
  • retinal hemorrhages in outer retinal layers
  • exudates- fibrin and other proteins collect in retina especially in outer plexiform layer (Henle’s layer)
  • nerve fiber layer infarcts
  • Eschnig spots- choroidal infarct
  • optic nerve head edema – lateral displacement of photoreceptors
  • serous retinal detachment
  • macular star with oblique orientation of exudates in Henle’s layer

Neovascularization

• response to conditions that produce retinal ischemia
• vascular endothelial growth factor (VEGF) is upregulated in retinal hypoxia
• intraretinal vascular proliferation precedes neovascularization
• growth of blood vessels into the vitreous side of internal limiting membrane
• with no posterior vitreous detachment (PVD) and intact hyloid face vessels remain in the plane between the hyloid and ILM
• if a PVD occurs the vessels can be streached and bleed
• if hyloid face is not intact vessels can grow into vitreous
• may lead to tractional retinal detachment because
• myofibroblasts in membrane contract
• blood from the membrane organizes and contracts
• neovascularization of the disc
  • optic nerve head lined by membrane analogous to the ILM
  • vessels on vitreous side of this membrane are noevascularization
• iris neovascularization
  • ectropion uveae
  • fine vessels at pupil margin
  • eccentric pupil
  • effacement of iris crypts
  • tissue lining anterior border of iris leaving iris border flat
  • myofibroblasts may contract causing perpeherial anterior synechais and neovascular glaucoma
  • are fragile and may bleed producing hyphema

Vascular occlusive disorders

• Retinal artery occlusion
• Retinal vein occlusion

• first leads to death of retinal neuronal elements
• retinal becomes opaque rather than transparent
• cherry red spot
  • color of normal choroid is transmitted through fovea
  • surrounding retina is thick and edematous
  • in Tay-Sachs disease spot is due to acclumulation of acclumulation of material in ganglion cells and relative lack of ganglion cells in fovea transmits choroidal color
• box carring of arterioles- result of stagnant flow
• post necrotic retinal atrophy of inner retinal layers
• no reactive gliosis

• arteriole and venule share same adventitia in optic nerve and retina
• arterolosclerosis compresses venule resulting in stasis
• gradual progression to poor perfusion, ischemia
• ischemia of the pericytes and endothelial cells of microcirculation leads to weakness and retinal hemorrhages of nearly full retinal thickness
• leakage of fluid occurs causing exudation and edema
• retinal ischema may lead to neovascularization of iris, disc or retina

Diseases of microcirculation

• Diabetes
• Sickle cell disease
• Retinopathy of Prematurity
• Coat's Disease

• basement membranes
  • increased amounts of basement material is layed down throughout body. Thickening of basement membrane of ciliary body epithelium in pars plicata retinal vessels and choroidal vessesl is characteristic
  • interface between corneal epithelium and basement membrane my be disturbed causing recurrent erosions
• microcirculation changes
  • decreased number of pericytes
  • microaneurysms
    • often too small to see ophthalmologically
    • most of what is called microaneurysm is dot heme
    • better seen by flourscein angiography
  • increase permeability leading to
    • macular edema
    • exudates- tend to settle in outer plexifom layer
    • hemorrhages
• neovascularization
• lacy vacuolization of iris pigment epithelium accompanies hyperglycemic states

• retinopathy unusual in SS disease but occurs in SC, Sthal and in S trait
• neovascularization
• may produce "sea-fans" that may produce vitreous hemorrhage
• hemorrahges
  • salmon patches- fresh intraretinal hemorrhage
  • iridescent spots- hemosiderin from previous hemorrhage
  • black sunburst- subretinal hemorrhage with RPE hyperplasia

• temporal retinal circulation incompletely developed at term
• elevated levels of oxygen may lead to vasospasm then distal retinal ischema.
• Retinal neovascularization can occur leading to tractional retinal detachment

Coat’s Disease

• usually unilateral exudative retinal detachment
• retinal telangiectasis- very leaky
• no neovascularization
• foam cells and cholesterol clefts in subretinal space- not specific

• Lange's fold
• Pavingstone degeneration
• Lattice degeneration
• Pars plana cysts
• Peripherial cystoid degeneration
• Retinoschisis

Lange’s fold

• artifact in infants
• rolled up retina at the ora

Pavingstone degeration (cobble stone)

• presumably related to abnormalties in choroidal circulation
• clinical features
  • common in later life
  • up to 25% of autopsy eyes
  • bilateral in 30%
  • well demarcated circular areas 0.5 to 2 disc diameters in size
  • center pale, edges have variable pigmentation
• histologic features
  • atropy of outer retinal layer, RPE and choriocapillaris
  • RPE hypertrophy may be seen at the edges

Lattice degeneration

• clinical features
  • linear, circumferentially oriented zones of retinal thinning between ora and equator
  • most commonly occur superiorly, unusual in horizontal meridians
  • 6-11% of population
  • may be pigmented
  • may be crossed by fine white lines and sclerotic vessels
  • liquefaction of ovelying vitreous
  • may contain atrophic holes that aren’t predisposed to retinal detachment
  • traction by vitreous after PVD can cause a horseshoe tear and rhegmatogenous retinal detachment (RRD)
  • 30% of RRD associated with lattice although it is uncommon for someone with lattice to develop an RRD
• histologic features
  • involves the vitreoretinal interface
  • focal discontinuity of ILM
  • thinning of inner retinal layers leading to round atrophic holes
  • sclerotic vessels
  • liquifaction pocket of vitreous overlying lattice
  • strong adhesions of vitreous to margins of lattice

Pars plana cysts

• clinical features
  • seen in up to 16% of normal population
  • increase in incidence with age
  • more numerous in patinets with myleoma or other dysproteinemic states
  • clear in vivo
  • opaque after formalin fixation
• histologic features
  • may contain hyaluronic acid
  • may immunoglobulins in myleoma

Perepherial cystoid degeneration

• typical cystoid degeneration
  • clinical features
  • very common; up to 87% in autopsy series
  • pathology located immediately posterior to ora
  • colescence of cysts may lead to typical retinoschisis
  • histologic features
  • cyst-like spaces at level of outer plexiform layer
  • demarcated by columns of Mueller cells
  • contain hyaluronic acid
• reticular perepherial cystoid degeneration
  • seen in 18% of the population
  • located posterior to a zone of typical cystoid degeneration
  • may appear to follow course of retinal vessels
  • may predispose to reticular (bullous) retinoschisis
  • split in the neve fiber layer as opposed to outer plexiform layer

• a split within the layers of the retina as opposed to a retinal detachment with is a split between the neurosensory retina and RPE
• Typical degenerative retinoschisis
  • clinical features
    • present in 1% of population
    • bilateral in 35% of affected
    • affects inferior temporal quadrant usually
    • adjacent to area of typical cystoid degneration
    • smooth surface with domed elevation, cavity is optically negative
  • histologic features
    • split in outer plexiform layer
• Reticular (bullous) retinoschisis
  • clinical features
    • ususally found in assoication with reticular cystoid degeneration
    • bullous intraretinal cavity
  • histologic features
    • split in nerve fiber layer of retina
• Congenital X-linked retinoschisis
  • clinical features
    • x-linked
    • most common inferior temporally
    • may involve macula
    • wide split in retina may be mistaken for vitreous veils
    • blood vessels bridging schisis cavitiy can bleed
    • macular stellate lesion
  • histologic features
    • split within nerve fiber layer

• Separation between neurosensory retina and RPE
• Categories
  • non-rhegmatogenous
    • not caused by a retinal break
    • types:
      • exudative- caused by retinal vascular anomalies
      • solid- caused by choroidal neoplasms
  • rhegmatogenous
    • caused by a retinal break
    • pathophysiology
      • vitreous adherent to retina in three zones
        • vitreous base
        • optic nerve
        • along major vessels
      • in certain conditions, vitreous more adherant e.g. lattice degeneration
      • in a PVD clean separation usually happens but retina can tear along areas of strong attachment
      • the edge of the tear is held open by the anteriorly displaced vitreous
• Retinal breaks
  • tears- caused by traction
  • holes
• Atrophic changes: usually don’t cause detachment
• Traction
• Preretinal membranes- can cause either rhegmatogeous or non-rhegmatogenous retinal detachments
• Artifact vs. Real
  • artifact
    • good presentation of photoreceptor
    • pigment adherent to photoreceptors
    • subretinal fluid is usually missing. (subretinal fluid is a variable finding in RD)
    • sharp edges
  • real
    • rounded edges
    • photoreceptors missing- indicating chronic RD
    • subretinal fluid is a variable finding
• retinal changes in detachment
  • early: photoreceptor degeneration
  • later
    • gliosis
    • intraretinal cysts

• preretinal membranes over the ILM derived from glial cells that have migrated through breaks in ILM
• RPE cells that have migrated through a full thickness retinal break
• "hylocytes" of the cortical vitreous
• myleofibroblastic elements contract distorting retina and cause fixed retinal folds
• retroretinal membranes- just under photoreceptor layer

• Age-related Macular Degeneration (AMD)
• Cystoid Macular Edema

Age-related macular degeneration (AMD)

• Clinical aspects
  • most common cause of blindness in elderly in USA
  • atrophic changes
  • drusen
  • loss of macular reflex
  • pigment epithelial atrophy
  • exudative and hemorrhagic changes- choroidal neovascular membrane
    • organization of blood with scar
    • glial elements
    • fibroblasts from choroid, through break in Bruch’s membrane
    • hyperplastic and metaplastic RPE
• Pathology
  • Age-related changes
    • the phagocytosed photoreceptor elements are digested and the by-products deposited in Bruch’s membrane by the RPE causing thickening of Bruch’s membrane
    • collagen and basement membrane material is layed down by the choriocapillaris leading to compression and partial dropout of the vascular layer
    • with age Bruch’s may calcifiy and crack
    • RPE and choriocapillaris function as a unit
      • destruction of the RPE can lead to atropy of choriocapillaris
      • widespread atrophy of choriocapillaris can lead to atropy of RPE
  • Atrophic macular degeneration
    • drusen and RPE atrophy
  • Exudative macular degeneration
    • neovascularization from choriocapillaris breaks through Bruch’s membrane leaking fluid into sub-RPE space= serous pigment epithelial detachment (PED)
    • physiologic barrier between sub-RPE space and sub-retinal space may become disrupted causing a serous retinal detachment
  • Hemorrhagic macular degeneration
    • neovascularization in the sub-RPE space may hemorrhage and break into the sub-retinal space or even vitreous
    • sub-RPE hemorrhage can be mistaken for a melanoma
  • Disciform degeneration
    • organized scar partially by RPE
    • color of scar depends upon amount of RPE reaction
    • bone may be deposited by osseous metaplasia of the RPE

Cystoid macular edema

• Clinical features
  • related to intraocular inflammation
  • post-surgery (Irvine-Gass syndrome)
  • secondary to perepherial retinal anomalities or tumors
• Histologic features- cyst-like spaces in outer plexiform layer seen in late cases
• Pathogenesis- two theories:
  • vascular instability leads to leakage of intravascular fluids into the retina which pool in the outer plexiform layer
  • focal hydropic degeneration of the Mueller cells in th e region of the macula, colescence of these degenerating cells leads to cyst-like spaces

• syneresis cavities
• posterior vitreous separation
• asteroid bodies
• calcified saponified fats
  • usually bilateral but may be asymmetrical
  • vision loss uncommon
• synchesis scintillans (cholsesterolosis bulbi)
  • result of vitreous hemorrhage
  • usually unilateral

arise from uveal melanocytes

uveal melanocytes vs. RPE

derived from neural crest

rare hyperplasia

form nevi and melanoma

derived from optic vesicle

frequent hyperplasia

rarely form adenomatous neoplasms

cell types

normal uveal melanocytes are spindle shaped and dendritic

spindle shaped like normal melanocytes

nuclei lack nucleoli

lack conspicuous nucleoli

basophilic stripe along long axis of elongated nucleus

lesions composed exclusively of spindle A are considered nevi

have conspicuous nuclei

elongated nuclei

not spindled

look the least like normal uveal melanocytes

abundant cytoplasm

large nuclei with prominent nucleoli

uveal melanoma classification based on cell type (modified Callender classification)

all spindle A

excellent prognosis

composed of spindle B or mixture of spindle A and B

good prognosis

both spindle cells and epithelioid cells

intermediate prognosis

cell type cannot be determined

intermediate prognosis

composed of epithelioid cells

worst prognosis

variant of spindle cell melanoma

resembles Antoni A pattern of Schwanomma

no prognostic significance

metastasis- likelyhood increases with increasing proportion of epitheloid cells

clinicopathologic correlations

cutaneous/conjunctival nevus

derived from melanocytes

stages of development; junctional, compound, intradermal

congential nevi are larger than acquired nevi and have greater tendancy to give rise to melanoma

most acquired nevi will not evolve to melanoma

uveal nevi

derived from melanocytes

grow without stages of development

most are acquired

congeniatal ocular melanosis more diffuse than focal nevus and may be prone to develop uveal melanoma

most acquired nevi will never develop into melanoma

tend to develop in blue-eyed people in inferior one-half of iris

may distort the pupil

may grow but usually not progressively and they don’t usually encroach on the angle

iris melanoma probably have little risk of metastasis

clinical features

relatively flat and small

may be associated with overlying drusen or small subretinal fluid pockets

histologic features

no scleral invasion or extraocular extension

contain bland spindle cells and no spindle B or epithelioid cells

metastasis generally first appear in liver

rarely gain access to sub-conjunctival space and spread to lymph nodes via lymphatics

iris melanomas

excellent prognosis because they are usually found early and probably don’t metastasize often

if they invade into the angle, may cause elevation of intraocular pressure

ciliary body and choroidal melanomas

may arise from pre-existing nevi, congenital ocular melanosis or de novo

prognosis for life depends upon

rarely spread into optic nerve as opposed to retinoblastoma

changes to other ocular structures

most common intraocular tumor of childhood

shows no predilection for race, gender or laterality

up to 30% of cases are bilateral

clinical presentations

differential diagnosis- congenital cataract, PHPV, Coat’s disease, coloboma, retinopathy of prematurity, toxocara

strabismus- exotropia or esotropia

heterchromia- secondary to iris neovascularization

genetics

all cells in the body contain the gene mutation

may or may not have family history

seconday primary tumors may develop within or outside field of radiation treatment

retinoblastoms may appear as a solitary tumor, multiple tumors, unilateral, bilateral, or trilateral (involving pineal gland)

bilateral and trilateral are markers of heritable disease

tumors appear 13-16 months

mutation confined to retina

no family history

not transmissable

second primary tumors do not develop

solitary tumor confined to one eye

tumors appear 20-27 months

gene: long arm chromosome 13, two alleles

normal functioning gene supresses tumor formation

development of retinoblastoma requires both alleles to be abnormal

when one allele is inherited higher likelyhood of developing tumor from a new mutation in the other allele

the mutation in the second allele must have occurred early in embryogenesis in order for the second allele to be passed on to offspring.

endophytic- growth of tumor into vitreous

exophytic- growth into the subretinal space

tumors may display elements of both endophytic and exophytic growth

seeding into vitreous and even anterior chamber simulating hypopion

may grow into choroid or optic nerve and travel through CSF and seed in the subarachnoid space

may also grow outside the eye

may undergo partial or complete regression

calcium can be seen in the tumor by ultrasonography

alternating zones of viable tumor centered around blood vessels and necrosis

basophilic layer around tumor vessels is DNA from dead tumor cells, this layering can be seen in blood vessels away from the tumor

calcium deposition

poorly differentiated cells as well as more differentiated zones can be seen

Homer Wright rosettes

no central lumen, center occupied by a neurofibrillary tangle

not specific to retinoblastoma, also seen in meduloepithelioma and neuroblastoma

Flexner-Wintersteiner rosettes

one row of cells with a central clearing

contrast to dysplastic retina which has multiple layers of cells forming rosettes

specific for retinoblastoma

Fleurettes

marker of photoreceptor differentiation

tumors with fleurettes may be more resistant to radiation

non-rhegmatogenous retinal detachment

iris neovascularization- acquired heterochromia and hyphema may develop

eye fills with tumor

most important: presence or absence of tumor outside of eye

tumor to surgical margin of resection of optic nerve

orbital extension

worse if tumor invades sclera, choroid or optic nerve even if margins are clear

tumor may spread along optic nerve into CNS

undergo hematogenous spread to other organs

spread through lymphatic system if extends into subconjunctival space

retinoma or retinocytoma- possibly benign variant of retinoblastoma or a well differentiated retinoblastoma

depends upon size, location and presence or absence of seeding

Reese-Ellsworth classification

metastasis to the choroid as a group is most common intraocular tumor in adults

most common sources: breast in women, lung in men

more common in the posterior pole but may affect the iris

prognosis for life is poor after metastisis to the eye

RPE is more prone to hyperplasia than neoplasia

occasionally RPE responses may simulate melanoma

Primary lymphoma of the retina and CNS

presents as unilateral or bilateral uvetitis but eye is not red

ocular findings may precede development of lymphoma in the brain

less commonly primary CNS lymphoma precedes retinal involvement

retina is primarily involved but there is often spillover into the vitreous making vitreous biopsy a way to make a diagnosis

vitreous biopsy shows atypical lymphocytes that are almost always B-lymphocytes

lymphocytes aggreagate in retina and sub-RPE space

cells in the choroid are usually benign lymphocytes

treatment: palliative radiation of the eye and brain

prognosis for life is poor

Secondary involvement of the Choroid in systemic lymphoma

involves primarly the choroid not the retina

Reactive lymphoid hyperplasia of the choroid

diffuse uveal thickeing by mature lymphocytes

germinal centers may be present

may spill over into epi-scleral tissues

clinically may mimic metastatic lesions, uveal melanoma, or posterior scleritis

usually follows a benign course

Phacomatoses

• Definition: group of conditions characterized by disseminated hamartomas
• Neurofibromatosis
• Tuberous Sclerosis
• Angiomatosis Retinae
• Encephalotrigeminal angiomatosis
• Ataxia-telangiectasia
• Wyburn-Mason syndrome

Neurofibromatosis (see Neuro notes: Neurofibromatosis)

von-Recklinghausen disease

autosomal dominant with irregular penetrance

some sporatic cases

systemic features

six or more

greater than 1.5mm in dameter

axillary freckling

benign overgrowth of Schwann cells, endoneural fibroblasts and axons in perepherial nerves

an isolated neurofibroma doesn’t make diagnosis

however plexiform neurofibroma is sufficent to make diagnosis of neurofibromatosis

scoliosis

schwannoma or malignant schwannoma

pheochromocytoma

malignant neurofibrosarcoma

ophthalmic features

prominent corneal nerves

glaucoma with possible buphthalmos- possible causes:

involvement of angle structures by neurofibroma

defective innervation of angle structures

immature angle

nevi of anterior iris stroma

diagnostic

may appear in childhood and be an early manifistation

neurofibromas and schwannomas of the uvea

optic nerve glioma

malignant schwannoma of orbit

hypoplasia of greater wing of sphenoid

permits transmission of pulsations of CSF

pulsating proptosis

Tuberous Sclerosis

Bourneville’s diesease

autosomal dominant

Systemic features

angiofibroma of the sebaceous glands

commonly seen on cheeks and around nasolabial folds

may be mistaken for acne

roughened skin, like an orange peel

frequently seen on the back

areas of skin hypopigmentation frequently on the back

lesion in the shape of an ash-leaf

may be the earliest sign

rhabdomyomas of the heart

angiomyolipomas of the kidney (an example of a hamartoma)

brain frequently involved by:

astrocytic hamartoma

some are mentally retarded

ophthalmic features

focal overgrowth of astrocytes (glial cells) in the retina

sometimes incorrectly identified as giant drusen of optic nerve

Angiomatosis Retinae

when no CNS involvement called: von Hippel’s disease

when CNS is involved called: von Hippel-Lindau disease

autosomal dominant

systemic features

contain capillaries with foamy stromal cells of uncertain origin

ophthalmic features

bilateral in 50%

have feeding vessels; arteriole and vein

retinal exudation

contain capillaries and foamy stromal cells of uncertain origin

may involve the optic nerve head

Encephalotrigeminal angiomatosis

Sturge-Weber syndrome

Associated with glaucoma (see Sturge-Weber in Glaucoma notes)

systemic features

skin lesion

telangiectasis, not an angioma

involment of the skin in distribution of first division of cranial nerve V suggests intraocular involvement

may cause seizures

meningeal calcification seen radiographically

ophthalmic features

choroidal, diffuse cavernous hemangiomas

may lead to elevated episcleral venous pressure and glaucoma

malformation of angle

• Defects of embryologic development
• Chromosomal Syndromes
• Secondary to infection

Defects of embryologic development

• Aplasia: total failure of a structure to form
  • Anophthalmos: absence of the globe
    • Primary: optic vessicle doesn’t envaginate, rare and sporadic. serial sections through orbit needed to confirm absence of eye
    • Secondary: malformation in the anterior portion of the neural tube resulting in failure of optic vessicle to form, lethal malformation
    • Consecutive: optic vessicle forms then degenerates.
    • Not to be confused with cryptopththalmia which may involve: absence of separate eyelids, microphthalmia, smooth skin over globe, corneal fusion to skin over globe
• Hypoplasia: incomplete development of a structure, contrast with atrophy- loss of a substance
  • Aniridia
• Abnormality of fusion
  • Cyclopia: total fusion of globes, associated with holoprosencephaly (failure of lobes of brain to separate-a lethal condition)
  • Synophthalmia: abnormal fusion of the eyes, more common than cyclopia, also associated with holoprosencephaly,
• Failure of an embryonic structure to close
  • Coloboma: cleft or defect in the normal continuity of a structure
    • typical coloboma: occurs along the inferionasal portion of eye
    • iris or ciliary body: ciliary body coloboma may occur with formation of cartilage, usually found in Trisomy 13
    • retinal-choroidal coloboma:  retinal detachment at edge of coloboma may be difficult to repair, absence of uvea and RPE, retina remains as a thin overlying glial membrane
    • Often associated with a cyst which can be larger than the eye itself
    • atypical coloboma: occur outside the inferonasal portion of the eye and location of the embryonic fissure. May result from congenital infections such as toxoplasmosis
• Failure of an embryonic structure to regress
  • hyloid system: regression normally begins centrally and continues both anteriorly and posteriorly
    • Bergmeister’s papilla: failure of posterior portion of hyloid system to regress, comes off optic nerve head
    • Mittendorf’s dot: failure of anterior portion of hyloid system to regress
• Abnormal development of a structure
  • Retinal dysplasia: multilayered rosettes, accompanies Trisomy 13
  • Anterior chamber
    • Designated as anterior chamber cleavage syndrome or "mesodermal" dysgenesis syndrome
    • May be from abnromal migration of neural crest tissues
    • Posterior embryotoxin: prominent anterior position of Schwalbe’s line (in up to 15% normal)
    • Anterior embryotoxin is the same as juvenile arcus- deposition of lipid
    • Axenfeld’s anomality: posterior embryotoxin + prominent iris processes, glaucoma in up to 50%, displaced pupil
    • Reiger’s anomality: posterior embryotoxin + prominent iris processes + hypoplasia of iris
    • Reiger’s syndrome: Reiger’s anomality plus dental and skeletal anomalies
    • Peter’s anomality: central absence of Decemet’s membrane and endothelium, associated with adhesions of iris or lens to posterior corneal defect

Chromosomal Syndromes

• Trisomy 21
  • Epicanthal folds
  • Brushfield spots: seen in as many as 85%
    • may be seen in the normal population
    • normal or hypercellular areas of iris stroma adjacent to areas of stromal hypoplasia
  • Keratoconus with a tendancy for hydrops
  • Retinoblastoma
  • Cataracts
• Trisomy 13
  • Uveal coloboma- cartilage may be found in the coloboma
  • Persistant hyperplastic primary vitreous
  • Retinal dysplasia- multi layered rosettes

Congenital anomalities secondary to infection

• Congenital syphilis
  • Systemic findings
    • mental retardation
    • saddle deformity of the nose
    • Saber shins
    • dental malformations
  • Ocular findings
    • chorioretinal scars
    • optic atrophy
    • interstitial keratitis (delayed finding) and assoiciated glaucoma
• Congenital rubella
  • Systemic findings: congential heart disease, deafness
  • Ocular findings
    • congenital cataract
    • retention of lens epithelial nuclei in nucleus of lens
    • virus can be harbored in the lens
    • congenital glaucoma
    • hypoplasia of the iris dilator- meiosis
    • "salt and pepper" pigmentary retinopathy- alternating hypertrophy and atrophy of RPE
• Cytomegalic inclusion disease
  • Systemic findings
    • intracranial calcifications
    • hepatosplenomegaly
    • anemia
  • Ocular findings: chorioretinitis
• Congenital toxoplasmosis
  • Sytemic findings
    • intracranial calcifications
    • seizures
    • mental retardation
  • Ocular findings: bilateral chorioretinal macular scars secondary to chorioretinitis

closed epithelial system

lens epithelium basement membrane is the lens capsule

lens epithelium "infoliates" instead of exfoliates

constant accumulation of lens epithelium causes continued lens thickening and cataract of maturity

nuclear sclerotic cataract- accumulation of urochrome pigment in nucleus

homogeniztion of lens neucleus is histologic marker of nucelar sclerosis

vision cannont be predicted by histologic appearance of the lens

avascular

epithelium is totally dependant upon acqueous for nutrition

high IOP can shut down acqueous flow and cause focal necrosis of lens epithelium

seen in acute angle closure glaucoma

glaucomflecken- antrior evanescent lens opacities that resolve with lowering IOP

posterior synechias may cover lens epithelium walling off acqueous causing epithelial necrosis

lens sensitive to abnormalities in chemical composition of acqueous

high levels of glucose as in diabetes can lead to sorbitol accumulation through the aldose reductase pathway, high levels of sorbital may play a role in diabetic cataract formation by altering the osmolarity of the lens

high levels of galactose in galactosemia leads to an accumulation of galactitol which may lead to cataract by same pathway as in diabetes

lens proteins are sequestered from the immune system perhaps explaining the pathogenesis if phacoantigenic (a.k.a phacoanaphylactic) endophthalmitis

changes in size and shape

excessive lens thickening may lead to pupillary block and glaucoma- phacomorphic glaucoma

microspherophakia

increased risk of pupillary block with iris miotics

laxity of zonules allows lens to become incarcerated in the pupillary aperature

nanophthalmos- lens is normal size but the globe is small, therefore the lens is too big for the eye- inappropriate size of lens may lead to pupillary block and glaucoma

lens zonules

originate from the pars plana and insert on lens capsule

physiology of accomodation involves anterior/posterior shortning of zonules rather than circumferential constriction of a ring

may weaken leading to subluxation- malpositioning of the lens in the posterior chamber or luxation (dislocation) of the lens into the anterior chamber or vitreous.

subluxation/luxation seen in:

syphilis

Marfan’s syndrome

Weill-Marchesani syndrome

homocystinuria

sulfite oxidase deficency

sectoral absence of zonules can be seen in coloboma

capsule

thins causing either anterior or posterior bulging = anterior or posterior lenticonus

true exfoliation - capsule may split in response to infrared radiation

pseudoexfoliation

basement membrane material deposits

this material accumulates on iris, ciliary body, zonules as well as throughout the body

it accumulates even after lens is removed

may cause glaucoma and weaken zonules

pigment may deposit on capsule

copper may deposit within lens capsule

sunflower cataract- Wilson’s disease

intraocular foreign body

may be focally thickened- "excrescence" on internal surface of lens seen in Lowe’s syndrome, Down syndrome and Miller syndrome

epithelium

necrosis- as in glaukomflecken

fibrous metaplasia-

anterior subcapsular cataract

often after posterior synechias induce pupillary block and decreased acqueous flow to lens epithelium

iron accumulation- siderosis bulbi

normally lens epithelium not seen posterior to equator

epithelial cells can migrate posterior to equator, lose contact inhibition and assume an altered morphology = Wadl cells or balloon cells in posterior subcapsular cataract

posterior subcapsular opacity- epithelium may grow over capsule after cataract extraction

Sommerring’s ring cataract- accumulation of corticle material in fornices of capsule after cataract extraction

Elschnig’s pearls- accumulation of lens material on lens capsule after cataract extraction

cortex

may partially liquify leading to bubbles or clefts

seen histologically as fragmented lens fibers

artifactitious cracking has squared off edges to the clefts

Morganian cataract

cortex totally liquifies

opacification of nucleus by nuclear sclerosis

sinking of nucleus inferiorly

calcium oxalate may accumulate in nucleus

liquified cortical material is non-antigenic but may seep though capsule and be engulfed by macrophages which can clog the trabecular meshwork leading to phacolytic glaucoma

lens protien laden macrophages may be demonstrated by examining aqueous from anterior chamber paracentesis- macrophages have a granular eosinophilic cytoplasm

the denatured lens protein itself can also clog the meshwork

phacolytic glaucoma v. phacoantigenic endophthalmitis

phacolytic glaucoma

phacoantigenic endophthalmitis

see typeIII hypersensitivity

hypermature catract

cortical material has liquified and escaped

lens becomes shrunken and possibly calcified

nucleus

thickens through process of "infoliation" leading to nuclear sclerosis

accumulation of urochrome gives brown color

homogenization of nucleus is a marker of nuclear sclerosis

any opacity of the lens

pathogenesis

diabetes and galactosemia

prolonged corticosteroid use in posterior subcapsular cataract

congenital rubella (Gregg’s syndrome)

can see retention of epithelial nuclei in anatomic nucleus of lens

may be related to antioxidants, light exposure, diet

sinus related

ethmoid sinusitis most common source of infection

preseptal cellulitis can progress to orbital cellulitis but less commonly than from sinus disease

may result in orbital absecess

proptosis and erythema

CT scan can show sinus disease and abscesses

chronic sinusitis results in blockage of sinus drainage channels

sinus becomes distended with pressure and may erode into orbit

frontal, ethmoid and rarely sphenoid sinuses affected in adults

usually develops as a sinus infection in a debilitated patient

diabetics in DKA, leukemics, immunocompromised

however patient need not be debilitated

organism tends to invade vessels causing infarction of tissues

organism is non-septate with branching hyphae of variable widths that form branches at 90 degrees, wider than aspergillosis

systemic conditions

orbital involvement can occur in hypo-, hyper- or euthyoid Graves’ disease

most common cause of unilateral or bilateral proptosis

disease is bilateral but may be very asymmertric

lid retraction and injection around rectus muscle insertions

may result in massive enlargement of rectus muscles, most typically inferior rectus

histologically muscles are infiltrated by lymphocytes and plasma cells, expanded by fibrosis and accumulation of acid mucopolysaccharides

thickening of muscles at the orbital apex may cause compressive optic neuropathy

may present in the orbit in conjunction with pulmonary and renal involvement or may be confined to the eye and orbit at the time of presentation

histologically vasculitis is prominent feature accompanied by granulomatous reaction to necrotic collagen

lesions consist of lymphoepithelial lesions of the lacrimal gland with following characteristics

destruction of acini of gland

lymphoid stromal infiltrate frequently with lymphoid follicles

lesion may evolve into lymphoma

hyperplasia of myoepithelial cells-epimyoepithelial islands

Orbital pseudotumor

may be generalized or localized to a portion of the orbit

abrupt onset characterized by pain. Graves’ and lymphoid lesions appear gradually

both pseudotumor and Graves’ can affect children

lymphoma is a disease of adults, except Burkitt’s lymphoma

pseudotumor responds promptly to high dose steroids

Graves’ and lymphoid hyperplasia/ neoplasia do not respond as dramatically

depend upon stage of disease

early

dominant element may be lymphoid follicles mixed with other cells including eosinophiles

T-cells are present in higher porportions than B-cells

vasculitis may be prominent

later

repair becomes noticable feature

deposition of fibrous connective tissue

inflammation still present

very late

lymphoid component diminishes and fibrous component dominates

at this point sometimes called "sclerosing" pseudotumor

could be a co

mpartmentalized form of orbital pseudotumor

inflammation of muscle involves the tendon which is not the case in Graves’ disease

histologically there is inflammation between surrounding muscle fibers

pseudotumor localized to the lacrimal gland

localization to Tenon’s capsule is visible on echo or CT

clinical presentation

middle-aged adults most common except in Burkitt’s lymphoma

onset gradual, no pain

predilection for involvement of lacrimal gland

lesions tend to "mold" around contour of globe

spectrum of pathology

reactive lymphoid follicles with germinal centers and surrounding mature lymphocytes

no reactive scarring, as opposed to pseudotumor

predominance of T-lymphocytes

B-lymphocytes demonstrate a polyclonal proliferation

15-25% may develop systemic lymphoma

most are B-cell tumors

Hodgkin’s disease and mycosis fungoides have been reported in the orbit

diffuse or follicular (nodular) patterns

frequently monoclonal proliferations detectable by testing for immunoglobulin markers or gene rearrangement studies

75% of cytologically malignant orbital lymphoma will develop systemic lymphoma

not benign but not clearly lymphoma

since there is no normal lymphoid architecture in the orbit to compare with so these lesions can be hard to sort out

marker studies used to differentiate these tumors

up to 50% will develop systemic lymphoma before obtaining a biopsy

sheets of well differentiated lymphocytes many of which have cytologic features suggestive of plasma cells

Dutsher bodies may be prominent

PAS positive intranuclear inclusions

a cytoplasmic invagination into the nucleus

germinal centers may be seen

dysproteinemia, immunoglobulin electrophoresis recommended

difficult to predict on an individual basis but some of these lesions progress to systemic lymphoma

fresh frozen tissue is prefered for immunohistochemisty and is required for gene rearrangement studies

workup/treatment

general physical exam to detect lymphadenopathy

CBC and diff

immunoglobulin electrophoresis

thoracic and abdominal CT or liver and spleen scans

bone marrow biopsy

peritrabecular lymphoid aggregates may indicate systemic lymphoma

not bone marrow aspirate

shield the globe

2500-3500 rads

separate by age of presentation

tumors of adulthood do not commonly affect children

some orbital tumors of childhood are distinctive for this group

the behavior of the same neoplasm may be different in a child and an adult

therefore one can make the following generalizations:

most common vascular tumor of adulthood is cavernous hemangioma which does not affect children

schwannomas and neurofibromas tend to affect adults

tumors of the lacrimal gland epithelium are seen in adults and are rare in childhood

secondary tumors of the orbit (metastatic tumors and invasion of orbit by sinus tumors) are seen in adults not children

optic nerve meningioma is indolent in middle age

most common vascular tumor of childhood is capillary hemangioma

orbital rhabdomyosarcoma is a tumor of childhood

lesions of orbital bones; eosinophilic granuloma and fibrous displasia tend to appear in childhood

congenital tumors of the orbit; dermoid cyst and orbital teratoma

secondary tumors of orbit reflect tumors of childhood; metastatic neuroblastoma, Ewing’s sarcoma, granulocytic sarcoma

optic nerve meningioma is aggressive in childhood

vascular origin

clinical features

1/3 present at birth and most clinically evident by 6 months old

frequently associated with a cutaneous component which appears red

blanches with pressure unlike nevus flammus (Sturge-Weber syndrome)

rarely presents with proptosis- unlike cavernous hemangioma of adults

most commoly presents with rapid enlargement of the mass without displacement of the globe or proptosis

growth may be rapid up to six months and taper off

mass may be more prominent when child cries

nearly 80% regress with some signs of regression in the first year, most have regressed by age 7

ambylopia is important consideration

pathology

follows clinical course

during rapid growth, sheets of proliferating endothelial cells may be seen

mitoses seen- not a marker of malignancy in this tumor

not encapsulated, unlike cavernous hemangioma, but infiltrative, often frustrating total surgical excision

during period of cessation of growth, capillary like lumina are more apparent

during the phase of regression, cellularity deminishes and more vascular spaces become apparent, collagen is deposited in and around tumor

clinical features

may present in the eyelids, conjunctiva, or orbit

growth is slowly progressive

may have hemorrhage into lesion (chocolate cyst) suddenly worsening proptosis

doesn’t reqress

may enlarge during bouts of upper respiratory infections because of increase in accompaying lymphoid tissue

pathology

there are capillary, cavernous and cystic lymphangiomas

spaces are lined by endothelial cells without pericytes or smooth muscle

associated lymphoid follicles

muscle origin

clinical features

rapid evolving proptosis with our without ptosis

subconjunctival mass in botryoid type

average age of onset 7.8 years

rare over age 20

may arise de novo in the orbit or invade orbit from paranasal sinuses

biopsy should be done as quickly as urgently as possible

tumor may grow within days to weeks

combination radiation and chemotherapy should be started immediately after diagnosis is made

with radiation and chemotherapy the survival rate is 90% but if tumor has spread from orbit to paranasal sinuses survival drops to 55%

pathology

doesn't arise from extraocular muscles but thought to arise from "mesenchymal rests"

types

neural origin

orbital involvement by neurofibromatosis more common in childhood

unencapsulated proliferation of Schwann cells, axons and endoneural fibroblasts

see neurofibromatosis

fibro-osseous lesions of bone

dysplasia of any of the orbital or facial bones leading to facial asymmetry

optic foramen may be narrowed

fibrous stroma with spicules of woven bone often in a "c" shape or resembling Chinese characters

osteoblasts are inconspicuous

malignancy is rare unless lesion is radiated

tends to involve the cortex rather than than medulla as in fibrous dysplasia

expansion of mass from within bone, ground glass appearance on CT scan

fibrous stroma with spicules of lamellar bone

osteoblasts are conspicuous near spicules

hematologic disorders

tends to be located superior temporally

lesion is lytic radiographically

skin is erythematous and indurated

"histiocytosis X" is antequated idea, cell of origin is not a histiocyte but a Langerhans cell with distinctive cell markers

langerhans cell has abundant eosinophilic cytoplasm and a groved nucleus

eosinophiles may be present in varying quantities

mean age 7 years old

not limited to children but much more common in children

most reported cases are from Africa

orbital lesion preceds overt leukemia in most patients and develops within several months

tumor cells infiltrate orbital tissues

chloroma- some of these tumors show a green color on the cut surface that fades with time

von Leder’s esterase stain may help with diagnosis (positive with myeloid precursors and high maginification mast cells)

metastasis to orbit

in most cases the primary tumor has been diagnosed before the orbital metastasis

primary is usually an abdominal tumor

metastasis tend to affect the zygoma

bilateral in 50%

lid ecchymosis may develop because the tumor is very vascular

Homer Write rosettes exist in tumor

metastasis tends to occur following diagnosis of primary tumor rarely the lesion occurs primarily in the orbit

small cells that contain glycogen

affects orbital bones

congenital lesions

develop in the superior and superior temporal aspect of the orbit and anterior to the orbital septum

dermoid cyst, epidermoid cyst, and cysts lined by conjunctival epithelium

dermoid cyst

painless, palpable masses

may be attached to a defect in the adjacent orbital bone

lined by epidermis with dermis-like stroma containing adenexal structures like hair follicles and sebaceous glands

epidermoid cyst- lined by epidermis but no dermis structures found

vascular origin

clinical features

most common vascular tumor of the orbit in adults

usually arises in the intraconal space causing axial proptosis

encapsulated and thus easier to excise than childhood capillary hemangioma

histiologic features

well encapsulated mass composed of large endothelial lined blood containing spaces and intervening thin connective septa

uncommon tumor seen in adults

more rapid developmemt of proptosis than in cavernous hemangioma

proliferating pericytes located outside endothelial cells

on low mag; gaping, staghorn or pouting vascular spaces

potentially malignant but no reliable clues to separate benign from malignant tumors

fibrous tissue origin

most common mesenchymal orbital tumor of adulthood

most are benign

10% have locally aggressive features and uncertain capacity for metastasis thus treated as malignant

grows by expansion compressing surrounding tissue forming a sort of capsule

microscopically spindle shaped cells form a cartwheel (storiform) arrangement.

frequent lipid laden macrophages

neural origin

a.k.a. neurilemoma

may be isolated or found in conjunction with neurofibromatosis

tend to be encapsulated

grow at margin of a nerve

usually present with proptosis

tumor patterns

Antoni A- spindle shaped Schwann cells form a picket-fence (palisading) pattern

Antoni B- looser, more diffuse pattern representing degenerative change

cystic degeneration

usually benign tumors, malignant Schwannomas do exist but are very rare

unencapsulated

most common nerve sheath tumor

see neurofibromatosis

hematologic

spectrum of lesions

benign reactive lymphoid hyperplasia

atypical lesions

malignant lymphoma

must be differentiated from pseudotumor clinically and histologically

see lymphoid lesions

lacrimal gland tumors

50% of lacrimal masses will be inflammatory or lymphoid lesions

50% will be epitheial derived tumors

clinical history and radiologic findings narrow diagnosis

avoid biopsy of a benign mixed tumor because of possible seeding of the orbit with tumor cells and risk of aggressive recurrences

clinical features

presents with painless gradual onset of fullness in the lacrimal fossa

eventually the globe may become displaced

because of slow growth, the periosteum is irritated not destroyed, a thin layer of new bone may be deposited in the lacrimal fossa (cortication)

excivation of lacrimal fossa occurs as well

growth by expansion causes compression of surrounding tissue creating a capsule

tumor cells may however occur in the capsule tissues thus the tumor should never be shelled out

a sudden change in the degree of proptosis in a patinet with many years of stability may signal the development of malignant mixed tumor

adenocarcinoma and adenoid cystic carcinoma may be found within these masses

histologic features

composed of epithelial elements from the lacrimal ducts

proliferation of myoepithelial cells that produce a stroma that resembles cartilage hence the term "mixed tumor"- a combination of epithelial and mesenchymal elements

treatment

incision into the capsule can result in seeding and subsequent recurrences that can be aggressive

treatment consists of complete excision of gland with rim of healty normal tissue

clinical features

more rapid clinical course than benign mixed tumor

fequent complaint of pain

adjacent bone in invaded rather than compressed showing lacrimal fossa erosion

histologic features

infiltrative not encapsulated

patterns

tends to invade surrounding nerves- probably accounts for pain felt by patients

treatment- definitive treatment may requrire orbital exenteration and resection of adjacent orbital bone

orbital metastasis

lung- men

breast- women

metastatic breast carcinoma may result in intense fibrous reaction in the stroma (scirrhous carcinoma) that contracts and leads to enophthalmos and restriction of motility