Ocular Pathology

Inflammation
Tissue response to a noxious stimulus.
Inflammation is NOT a synonym for infection

Classifications of inflammation
1. According to response:
- Localized
- Generalized
2. According to stimulus
- Infectious : viral, bacterial, fungal, or parasitic
- Non-infectious:
* Exogenous: Cause outside eye e.g. penetrating trauma, alkali chemical injury, or external allergens
* Endogenous. Cause inside eye e.g.
• Uveitis secondary to leaked lens matter (phacoantigenic uveitis),
• Spread from adjacent structures (the sinuses in orbital cellulitis)
• Haematogenous spread.

Types of inflammation
• Acute inflammation
• Chronic inflammation

Acute inflammation
Immediate response to noxious stimulus
1. Local tissue damage & release of inflammatory mediators
2. The inflammatory response:
A. Vascular phase: formation of fluid exudate
B. Cellular phase: formation of cellular exudate
- Exudation of blood leucocytes
- Activation of tissue histeocytes
Acute inflammation is considered as a mechanism of innate immunity, as
compared to adaptive immunity, which is specific for each pathogen
= NON specific
= NO memory
(Acute inflammation will NOT be quicker & more pronounced on 2nd exposure)
Vascular  cellular
Acute inflammation

1. Local tissue damage & release of inflammatory mediators
Acute inflammation
Chemical mediators
Any messenger that acts on blood vessels, cells or other cells to
contribute to an inflammatory response
1. Cell-derived
2. Plasma-derived
3. Bacterial products

Chemical mediators
1. Cell-derived
- Vaso-active amines:
• Histamine: Vasodilatation,  vascular permeability, endothelial activation
• Serotonin: Vasodilatation,  vascular permeability
- Archidonic acid metabolites
• PG: Vasodilatation,  vascular permeability
• Leucotrienes:
- Cytokines: e.g. TNF & IL-1
- NO: V.D, Inhibits platelet adhesion & aggregation
Acute inflammation
1. Endothelial effects
• Endothelial activation
• WBC binding & recruitment
• Pro-coagulant activity
• Increase in IL-1,IL-6,IL 8,PDGF
eicosanoids
2. Fibroblast effects
• Activates tissue fibroblasts
• Increases proliferation
• Production of collagen &ECM

Chemical mediators
2. Plasma-derived
- Kinins e.g. bradykinin
- Complement: C3a & C5a
- Clotting system
- Fibrinolytic system e.g. plasmin
Acute inflammation

Chemical mediators
2. Plasma-derived
Acute inflammation
Hageman factor ( Factor XII )
– A protein synthesized by the liver
– Circulate in inactive form in plasma
– Activated by collagen, basement membrane or activated platelets
– Activated Hageman factor (factor XIIa) further actives:
– Kinin system (vasoactive kinins)
– Clotting system (activation of thrombin, fibrinopeptides & factor X)
– Fibrinolytic system (plasmin production & inactivating thrombin)
– Complement system (anaphylatoxins C3a & C5a)

Chemotactic factors [Plasma-derived]
Acute inflammation

Kinin system
• Bradykinin
– ↑ vascular permeability
– Arteriolar dilation ??? (
– Branchial smooth muscle contraction
– Pain
• Kallikrein
– Chemotatic activity
– Potent activator of Hageman factor  link with clotting system
HMW KININOGEN BRADYKININ
KALLIKREIN

Clotting system
• Activated thrombin
– Fibrin clot
– Enhance leukocytes adhesion
– Cleave C5  C5a ( link with complement system )
• Fibrinopeptide
– ↑ vascular permeability
– Chemotatic for leukocytes
• Factor Xa (intermediate in clotting cascade)
– ↑ vascular permeability & leukocyte emigration
Fibrinogen
Activated thrombinThrombin
Fibrin Clot
Fibrinopeptide

Fibrinolytic system
• Plasmin
– Multifunctional protease that cleaves fibrin
– Fibrin degradation product will ↑ permeability
– Cleaves C3  C3a (vasodilation & ↑ vascular permeability)
– Activate Hageman factor, thus amplify the entire set of responses
• Activated
concurrently with
activation of clotting
system
• Serve to limit
clotting

Complement
15% of total serum proteins !
Production: liver, and various epithelial cells in the body.
Once cleaved into their active form they act on the next complement and
activate it.
- C1 – C9
Functions:
1. Opsonisation
2. Chemo-attractants (Small fragments of complement that have been cleaved)
3. Creating membrane attack complex, which creates pores in bacterial cells.
Essential in
innate &
acquired
immunity
Complements exist as pro-enzymes (zymogens) until they are activated.

Details on Functions of complement
(1) Vascular effect:
-C3a & C5a induce release of histamine  V.D  ↑ vascular permeability
-C5a also activates lipoxygenase pathway of AA
(2) Leucocyte activation, adhesion & chemotaxis:
-C5a, C3a & C4a (lesser extent)
-potent chemotatic agent for neutrophils, monocytes, eosinophil & basophil.
(3) Phagocytosis:
-C3b & iC3b act as opsonins  ↑ phagocytosis
(4) MAC  cell lysis

Notes on complement
- Classical or alternative pathways, both of which are stimulated by
plasmin
- C5a is approximately 1000 times more active than C3a
- C567 is chemotactic to polymorphs
- C5b6789 causes cell lysis

Complement cascade
1. Classical pathway: initiated by binding of C1q directly to:
(a) Bacteria and antibody complexes (antigen antibody complex) 
(b) Bacteria and C-reactive protein complexes
(c) Bacterial surface (Gram + ve)
2. Alternative pathway: spontaneously activated complement binds directly
to pathogen surfaces.
3. Lectin-binding pathway: Plasma lectin bind to mannose residues on microbes &
activates the early component of classical pathway

Membrane attack complex
A protein structure formed from activated complement protein, creating a pore
in the membrane of bacteria  disruption in the proton gradient across the
cell membrane and allows various enzymes, including lysozymes, to enter the
cell.

Membrane attack complex
• Component C5b binds to C6 and C7 to create C5b, 6, 7.
[ The C7 component of this structure binds to the bacterial cell wall]
• C8 molecules then bind to the complex, followed by multiple C9 molecules,
which traverse the entire cell wall [Up to 16 C9 molecules then bind to create a pore
in the membrane]

However, inappropriate or excessive activation of complement can also lead to:
● Inflammation
● Anaphylaxis
● Autoimmunity.
To avoid excessive complement activation
The system contains a number of regulatory complement components which
act as a negative feedback loop at various stages of complement activation

Exapmles:
• Chemotactic factors for PMNL:
• Bacterial products (mainly from cocci)
• C3a & C5a
• Neutrophil components
• Lymphokines
Chemotactic factors for monocytes:
• Bacterial products (mainly from bacilli)
• C3a & C5a
• Neutrophil components
• Lymphokines
Acute inflammation
Chemotactic for neutrophils
Chemical mediatorMolecular
weight
prostaglandin ELow
C5a and C5 derived
peptides
Intermediate
lymphokines
partly denatured
proteins
High

Chemotaxis follows a concentration
gradient of such factors
Acute inflammation

Mechanism of chemotaxis
Acute inflammation

A. Vascular phase: formation of fluid exudate
1. Transient vaso-constriction [d.t. irritation of vessel wall]
2. Vasodilatation  redness + hotness (flare phenomena)
3.  vascular permeability & formation of exudate
4. Vascular slowing [important step in leucocytes exudation]
Leucocytes can NOT leave blood vessels in rapid blood flow!
Peak effectEffectMaterial
5 minutes,
Last for 15 minutes
V.D. (venules)Histamine
4-24 hours
(Produce delayed persistent
vascular response)
V.D. (Capillaries + venules)Kinin
V.D. (Arteriole)PG E2
Acute inflammation

B. Cellular phase: formation of cellular exudate
The most common inflammatory cell is:
- Neutrophil (in bacterial infection)
- Esinophil (parasitic infection – allergic)
- Monocytes (in viral infection)
Steps of cellular exudation
1. Margination & pavementation
2. Emigration of leucocytes
3. Diapedisis (escape of RBCs)
4. Chemotaxis
5. Phagocytosis
Acute inflammation

1. Marignation
1. Slowing of blood flow  margination of cells
2. Adhesion (pavementation) of cells to endothelium of vessel wall
Receptors on leucocytes & endothelium is responsible for the
adhesion:
• Selectins
• Integrins
BOTH neutrophils & endothelium has a –ve charge
Acute inflammation

1. Marignation
1. Rolling phase: Cytokines (e.g. TNF- α & IL-1) will be secreted  upregulate expression of selectin ligand
on endothelial cells (lining the blood vessel)  loose endothelial– neutrophil adhesion
2. Activation of endothelial cells 
- Production of Beta integrins and ICAM 1 and 2 (Integrin–cell adhesion molecule )  firm endothelial–
neutrophil adhesion.
- Platelet-activating factor  activates neutrophils and induces expression of β integrins
- Production of IL-8  powerful chemoattractant that enhances transmigration
3. Transmigartion (Extravasation): mediated by expression of PECAM-1 (CD31) on both the leukocyte and the
endothelium [which has been hypothesized to disrupt the intercellular tight (occludin) junctions and adherens
junctions] Acute inflammation
Histamine, thrombin, and leukotrienes induce expression of further selectins on
endothelial cells  Stabilising these bonds

Chemotaxis
Directional & purposive movement of phagocytic cells towards the area of tissue
damage or bacterial invasion
Two phases:
1. Reception of chemotactic signals
2. Cellular response to the signals (Transduction)
Chemotactic materials bind to specific receptors on leucocytes
Acute inflammation

5. Phagocytosis
1. Recognition & attachment of bacteria (opsonisation)
- Bacteria is coated by an opsonin (IgG or C3b)
- Phagocytes have a specific receptors for these opsonins
2. Engulfment: phagocyte surround opsonized bacteria by pseudopodia
[Fusion of pseudopodia  phagocytic vacuole = phagosome)]
Phagosomes fuse with lysozymal granules  discharge granule content 
phago-lysosome  kill bacteria
3. Degradation
Opsonisation: process where microbes are chemically modified to be made
more "Delicious" for inflammatory phagocytosis.

5. Phagocytosis
3. Degradation:
- Oxygen dependent mechanisms: “Respiratory burst”
formation of H2O2 & superoxide
- Non oxygen dependent mechanisms:
 Lysosomal hydrolysis
  pH
 Lactoferrin
Killing effect of H2O2 increased 50-fold by the action of
myeloperoxidase (which is found in lysozymes)

Local signs of acute inflammation
5 cardinal signs:
1. Redness (rubor) : caused by increased blood flow
2. Hotness (calor) : caused by increased blood flow
3. Mass (tumour) oedema: caused by leakage of fluid and cells
4. Pain (dolor)
5. Loss of function.
Acute inflammation

Systemic signs of acute inflammation
1. Leucocytosis
2. Fever:
Pyrogenic factors (e.g. IL-1 & TNF)  disturb thermo-regulatory centres  V.C of
skin blood vessels  fever (reduce heat loss)
Acute inflammation

The triple response of acute inflammation
Behavior of blood vessels in damaged tissue
1. Flush = red spot : d.t. capillary dilatation
2. Flare: in the surrounding area due to arteriolar dilatation
3. Wheal: Fluid leakage from capillaries and local tissue swelling
Acute inflammation

Fate of acute inflammation
According to organism, host response, and extent of necrosis.
• Resolution
• Repair with scarring
• Chronic inflammation.
Acute inflammation

Acute inflammation

• Labile cells: Can divide & proliferate throughout post-natal life
• Stable cells: Quiescent & may be stimulated to divide
• Permanent cells: Proliferate ONLY during fetal life
Acute inflammation

Chronic inflammation
• It is a proliferative inflammation characterized by a cellular infiltrate of
lymphocytes and plasma cells
(Mostly macrophage & macrophage-derived cells)
(sometimes PMNs or eosinophils).
• Chronic inflammation may start as chronic or result from acute inflammation.
• NOT always d.t infection (may be d.t. sutures, wood ….)
NO
vascular
phase
Chronic inflammation

Chronic phase
• Types chronic inflammation:
• Specific (e.g. T.B)
• Non-specific (may arise from acute inflammation)
• Types chronic inflammation:
• Granulomatous
• Non-granulomatous.

Granulomatous
• The characteristic cell type in granulomatous inflammation is the
epithelioid or giant cell.
• Classic examples: T.B. & sarcoid.

Granuloma of T.B.
• Inner core:
- micro-organism
- Epitheloid cells
- Caseation ( Typical feature of T.B.)
• Sourrounded by
• Activated macrophages
• T-lymphocytes
• Outer layer:
• Fibroblasts
• Giant cells (Giant cells may be present in central core of young granulomas)

Macrophage
Derived from: monocytes
Modification over monocytes:
- Enlargement
-  lysosymes
- Prominent Gologi apparatus & endoplasmic reticulum
Activation of macrophage by:
- C3b

Activated macrophage
•  phagocytic capacity
•  hydrolytic enzymes
• Production of pyrogens & interferon (block translation of viral mRNA)
+
• Proliferation of fibroblast
•  production of PMNL
• Secrets lymphocytes activating factor  + T-helper  secrete lymphokine
 aids recruitment of macrophage to site of infection
• Secrete nitrous oxide (NO) which is an anti-microbial factor (so, activated
macrophages have potent antibacterial and antiprotozoal activity)

Epithelioid cells
• Derived from monocytes or macrophages
[ macrophage with increased secretory capacity]
• They have abundant eosinophilic cytoplasm and tend to blend
together in palisades around areas of necrosis. They can interact
with T cells and phagocytose and bind complement and
immunoglobulin.
NOT with increased
phagocytic activity

Giant cells
• Formed by fusion of macrophages [ phagocytic activity]
• Forms:
1. Langhans’ giant cell: typically found in tuberculosis and shows a
homogenous, eosinophilic central cytoplasm and peripheral rim of
nuclei
2. Foreign body giant cell: containing foreign material
3. Touton giant cell: has a rim of foamy cytoplasm peripheral to a rim
of nuclei and is seen in lipid disorders such as juvenile
xanthogranuloma.

Macrophage & granulomatous
inflammation

Patterns of chronic granulomatous inflammation
1. Diffuse type: sympathetic uveitis, juvenile xanthogranuloma, Vogt–
Koyanagi–Harada syndrome, toxoplasmosis.
Epithelioid cells are distributed randomly against a background of
lymphocytes and plasma cells.
2. Discrete type: sarcoidosis, tuberculoid leprosy, military tuberculosis.
Nodules or tubercles form due to accumulation of epithelioid or giant cells
surrounded by a narrow rim of lymphocytes and plasma cells.
3. Zonal type: caseous necrosis of tuberculosis, chalazion, ruptured
dermoid cyst, reaction to suture material, rheumatoid scleritis, toxocara.
A central area of necrosis surrounded by a palisade of epithelioid cells. In
addition, PMNs, Langhan’s giant cells, and macrophages are in turn
surrounded by lymphocytes and plasma cells

Non-granulomatous
• Examples: include the many forms of anterior and posterior uveitis,
Behcet’s disease, multiple sclerosis, retinal vasculitis, and endocrine
exophthalmos.
• Cell types: may include:
o T and B lymphocytes
o Plasmacytoid cells (a variation of the plasma cell)
o Plasma cells with a Russell body.
A Russell body is an inclusion in a plasma cell whose
cytoplasm is filled and enlarged with eosinophilic
structures. The nucleus is eccentric or absent.
These are seen in B cell lymphomas.

Acute Chronic
Causative agent Bacterial pathogens, injured tissues
Persistent acute inflammation due to non-
degradable pathogens, viral infection,
persistent foreign bodies, or autoimmune
reactions
Major cells
involved
neutrophils (primarily), basophils
(inflammatory response), and
eosinophils (response to helminth worms
and parasites), mononuclear cells
(monocytes, macrophages)
Mononuclear cells (monocytes,
macrophages, lymphocytes, plasma cells),
fibroblasts
Primary
mediators
Vasoactive amines, eicosanoids
IFN-γ and other cytokines, growth factors,
reactive oxygen species, hydrolytic enzymes
Onset Immediate Delayed
Duration Few days Up to many months, or years
Outcomes
Resolution, abscess formation, chronic
inflammation
Tissue destruction, fibrosis, necrosis

Wound healing “Full thickness corneal laceration”
1. Immediate phase:
- Retraction of Descemet’s membrane and stromal collagen
- Anterior and posterior wound gaping
- Fibrin plug formation from aqueous fibrinogen
- Stromal oedema.
2. Leukocytic phase: at around 30 minutes
PMNL (from the conjunctival vessels & aqueous) invade the wound.
These can transform to fibroblasts after 12–24 hours.
Limbal wounds have an invasion of PMNL from limbal vessels.

Wound healing “Full thickness corneal laceration”
3. Epithelial phase: at 1 hour
Full thickness ingrowth is inhibited by healthy endothelium.
4. Fibroblastic phase: Central corneal wound fibroblasts are derived
from keratocytes. They produce collagen and
mucopolysaccharides to form an avascular matrix.
5. Endothelial phase: at 24 hours
endothelial sliding allows for coverage of the posterior aspect of the
wound.
Stroma & Bowman’s membrane are NOT able to regenerate  replaced by scar
tissue

Healing of cornea
HealingStructure
Regenerates at the limbus and spreads rapidly across corneaEpithelium
Does not regenerateBowman’s layer
Keratocytes form fibroblasts to heal stromal woundsStroma
Does not regenerate
Is elastic and can recoil at the edge of a deficit
Descemet’s
membrane
Fills in defects by sliding and therefore deposits secondary layers in
Descemet’s
Endothelium

Healing of skin incision
Epidermis:
Epithelialization in 3 steps:
(i) Cell migration
(ii) Cell proliferation
(iii) Cell differentiation

Healing of skin incision
Dermis
1. Invasion of fibrin clot
[ by buds of endothelial cells from intact capillaries at wound edge]
2. Formation of new vessels within 1 week
3. Macrophages and fibroblasts invade wound
 Macrophages clear clots
 Fibroblasts produce collagen and glycosaminoglycans
 Myofibroblasts allow wound contraction by around 1 week

Healing of conjunctiva
Can form granulation tissue d.t.:
- Vasculature
- Lymphatic system
- RES
Epithelium heals by sliding and proliferation similar to skin or cornea

Healing of iris
Fibrinolysins in the aqueous inhibit fibrin clot formation, hence the
patency of iris defects
Healing occurs ONLY if the edges of a wound are apposed
Or if there is co-existing infection or hemorrhage
- Stroma: heal by granulation tissue
- Epithelium: heal by a single layer (rather than normal double layer)

Healing of lens
Epithelium responds to trauma by fibrous metaplasia

Healing of choroid & CB
Melanocytes do not proliferate after trauma
Granulation tissue followed by scar tissue forms from fibroblasts

Healing of sclera
Scars formation
[by fibroblasts from episcleral and uveal tissue]
Sclera itself has NO role in healing !!

Healing of retina & optic nerve
Gliosis
Glial cells replace damaged nerve cells, which are derived from
perivascular astrocytes and Muller cells
RPE can become metaplastic and proliferate and form fibrous tissue,
for example preretinal membranes
NOT healed by fibrosis
Except if lesion is complicated by hemorrhage or infection ?
As mesodermal elements may produce granulation tissue &
collagen scar

Hypersensitivit
y
set of undesirable
reactions produced by
the normal immune
system, including
allergies and
autoimmunity.

Type I Hypersensitivity
This is an ‘allergic’ reaction that immediately follows contact with an
antigen, which would normally not cause a marked immune response
(an allergen).
Examples: Seasonal & perennial allergic conjunctivitis
Mechanism:
 Mast cells bind IgE via their Fc receptors.
 On encountering antigen the IgE becomes crosslinked.???
 This leads to degranulation and release of mediators such as
histamine, serotonin, platelet-activating factors, and eosinophil
chemotactic factors.
Histamine then acts as a mediator of negative feedback to inhibit mast cell degranulation

Type I Hypersensitivity
This is an ‘allergic’ reaction that immediately follows contact
with an antigen, which would normally not cause a marked immune
response (an allergen).
Examples: Seasonal & perennial allergic conjunctivitis
Mechanism:
 Mast cells bind IgE via their Fc receptors.
 On encountering antigen the IgE becomes crosslinked.???
 This leads to degranulation and release of mediators such as
histamine, serotonin, platelet-activating factors, and eosinophil
chemotactic factors.

Type II (antibody-dependent cytotoxicity)
hypersensitivity
This arises from antibody directed against antigens expressed on an
individual’s own cells.
Examples:
- Incompatible blood transfusions
- Rhesus incompatibility of the newborn
- Hyper acute graft rejections
- Myasthenia gravis

Type III hypersensitivity
1. Immune complexes are deposited in the tissue.
2. Complement is activated and polymorphs are attracted to the site of
deposition, causing acute inflammation.
Examples:
- Persistent infections (viral hepatitis)
- Some autoimmune diseases e.g. rheumatoid arthritis & SLE
- Arthus reaction.
The mechanism is dependent on:
1. Turbulent blood flow allowing for deposition of immune complexes, e.g. kidney,
2. ↑ vascular permeability due to histamine release
3. Specific antigen–antibody complexes to a single organ.

Arthus reaction
How? Injection of antigen intradermally in individuals who
have previously been exposed (e.g. in immunization) and
therefore have high antibody levels.
Result: Deposition of antigen–antibody complex → acute
inflammatory reaction lasting between 4 and 10 hours

Type IV (cell-mediated) hypersensitivity
[Antigen-sensitized T cells] release cytokines following a second contact with the same
antigen. These cytokines induce inflammatory reactions and attract and activate
macrophages to release mediators.
Examples:
• Contact hypersensitivity by an epidermal reaction via Langerhans’ cells. This peaks
at 48 hours.
• Tuberculin type hypersensitivity (Mantoux test) caused by a subdermal injection of
tuberculin producing a reaction in the dermis that peaks at 48–72 hours.
• Cell-mediated hypersensitivity results in a granulomatous reaction and is usually
caused by persistent antigen in macrophages (Tb). Reaction peaks at 4 weeks.
• Giant papillary conjunctivitis, vernal keratoconjunctivitis, and atopic
keratoconjunctivitis, all of which are part type I and type IV reactions.

Cellular and
tissue reactions
Cells respond in
various ways to stress

Definitions
 Hypertrophy: an ↑ in size of cells, fibres, or tissues without an
increase in number (e.g. RPE hypertrophy).
 Atrophy: a ↓ in size of cells, fibres, or tissues.
 Hyperplasia: an ↑ in the number of individual cells in a tissue; their
size may or may not increase. Growth will reach equilibrium and is
not indefinite (e.g. RPE hyperplasia secondary to trauma).
 Hypoplasia: arrested development of a tissue during embryonic life
(e.g. aniridia).
 Aplasia: lack of development of a tissue in embryonic life
(e.g. aplasia of the optic nerve).

Definitions
Metaplasia: transformation of one type of tissue into
another type (e.g. in anterior subcapsular cataract fibrous
metaplasia of the lens epithelium).
Cause: chronic irritation
Change: columnar or cuboidal epithelium → squamous epithelium.
Dysplasia: abnormal growth of tissue with increased
mitoses and reduced differentiation (e.g. retinal dysplasia).
Dysplastic tissue is NOT invasive and will NOT pass through the basement
membrane.

Definitions
o Dystrophy is a primary, inherited disorder that can occur at any age!
Dystrophies may involve a single matrix component.
o Degeneration is a secondary phenomenon resulting from previous
disease. It occurs in tissue that has reached its full growth and can come
in many forms.
It commonly involves connective tissue components such as collagen,
elastin, and proteoglycans.

Hyaline degeneration
Replacement of normal cells with an acellular, amorphous,
eosinophilic material
Example: Walls of arteriolosclerotic small vessels of the eye (in
ageing, benign hypertension, and diabetes)

Elastotic degeneration
Defective fibroblast function leads to an altered elastic matrix and
reduced elasticity
Example:
- Skin in ageing individuals
- Pterygium
- Pseudoxanthoma elasticum [in which ruptures in Bruch’s membrane
expose the choroid (angioid streaks)]

Calcification degeneration
Calcium is deposited as hydroxyapatite crystals, which can be metastatic in
hypercalcaemic states or dystrophic in normocalcaemic states
Example:
- Band keratopathy [calcification of Bowman’s layer and the superficial stroma]
- Cataracta ossea: calcification in the fibrous & degenerative
cortex of the lens
- Bruch’s membrane can be calcified in Paget’s disease
- Phthisis bulbi: ossification of the metaplastic fibrous tissue derives from
proliferation of the RPE in a hypotonic eye
Woven and lamellar bone is located on the inner surface of Bruch’s membrane
Ossification can extend into the vitreous and choroid

Amyolid degeneration
Insoluble protein deposited in tissue around blood vessels and basement membranes
In H&E stains amyloid has a homogeneous pink appearance, staining with Congo red followed by
examination with a polarized light, giving an apple green birefringence appearance
Amyloid deposition can be localized or systemic
Localized:
o Eye:
- Solitary nodule in eyelid, orbit, conjunctiva
- Cornea: seen in lattice dystrophy and gelatinous drop-like dystrophy
o Amyloid from polypeptide hormones in endocrine tumours
o Amyloid from prealbumin leads to cerebral deposits in Alzheimer’s diease

Amyolid degeneration
Systemic:
o Pseudoexfoliation syndrome: an amorphous, eosinophilic
substance is deposited on the anterior capsule of the lens, ciliary
processes, iris surface, and trabecular meshwork, leading to
secondary glaucoma
it is also deposited in the skin and viscera
o Waldenstrom’s macrogloblinaemia: amyloid is light-chain derived
from immunoglobulin
o Rheumatoid arthritis and familial Mediterranean fever amyloid is
derived from serum protein, an acute phase reactant in inflammation

Mnemonics of corneal dystrophy

Hydropic degeneration
Reversible change
Cells are enlarged, containing cytoplasmic vacuoles
Examples:
- Infection
- Intoxication,
- Anaemia or circulatory disturbance

Cloudy swelling
Reversible change
Cells are enlarged and filled with granules or fluid, representing
intracellular oedema
Examples:
- Mild Infection
- Intoxication,
- Anaemia or circulatory disturbance

Fatty change
Fat accumulates in cells for unknown reasons or after damage by a variety
of agents
Examples:
- Arcus senilis of the cornea: fatty infiltration of the peripheral corneal
stroma
- Xanthelasma: lipid within clumps of macrophages in the dermis of the
eyelid seen in ageing and hypercholesterolaemia
- Atheroma: Deposition of lipid and cholesterol in the intima of arteries

Glycogen infiltration
Glycogen infiltration into tissue → structural change
Examples:
• Diabetes mellitus: lacy vacuolation of iris pigment epithelium
• Long-standing neural retinal detachment due to lack of nutrition and
in proliferating RPE cells

Neoplasia and
preneoplastic
conditions

Neoplasia
Uncontrolled cell growth
N.B.
Tumors continue proliferation even after cessation of the stimuli that
evoked the change.
Tumors continue proliferation even if patient is starving !
Hyperplasia is a controlled cell growth

Cause of neoplasia
1. Upregulation of proliferation
(excessive or inappropriate oncogene action)
Or
2. Failure of mechanisms that lead to cell death
(tumour suppressor genes).

A neoplasm may be benign or malignant
‫جدول‬

Carcinogenesis
Non-lethal genetic damage → damage to a cell → neoplastic change.
Environmental carcinogenesis:
1. Chemical carcinogenesis
2. Physical carcinogenesis
3. Microbial carcinogenesis.
Genetic damage may be:
- DNA deletion
- DNA mutation
- DNA amplification
- DNA translocation
- DNA insertion
which leads to loss or gain in function.

Carcinogenesis
Mechanism of neoplastic transformation
(Multistep theory)
1. Initiation: induction of certain irreversible changes in genome of
cells [NO autonomous growth] [=latent tumor cells]
2. Promotion: further irritation to latent tumor cells →
autonomous proliferation (reversible at early phases)
3. Neoplastic transformation: abnormal differentiation +
irreversible autonomous proliferation

1. Chemical carcinogenesis
Examples:
1. Benzopyrenes,
2. Polycyclic hydrocarbons,
3. 2-naphthylamine after liver hydroxylation
4. Nitrosamines in gastric carcinoma
5. Cyclophosphamide
6. Aflatoxins
7. Arsenic

2. Physical carcinogenesis
1. Prolonged exposure to ultraviolet rays (sun): skin cancers e.g.
BCC, Sq.CC & melanoma
2. Ionizing radiation: leukemia

3. Microbial carcinogenesis
Some viruses are oncogenic
Examples:
 Epstein–Barr virus → orbital Burkitt’s lymphoma and intraocular
large B-cell lymphoma in the immunosuppressed.
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• may cause conjunctival papillomas (type 16) or lacrimal
• papillomas (type 11)

‫شوا‬ ‫من‬..‫المكتوب‬ ‫مع‬ ‫ازبطها‬ ‫هابقى‬
• Proto-oncogenes regulate the normal cell division
• Oncogenes are derived from normal proto-oncogene
• Mutated proto-oncogenes are associated with cancer
• Mutation of proto-oncogenes can be brought by :
- Point mutation
- Viral insertion
- Gene translocation
- Gene amplification

‫شوا‬ ‫من‬..‫المكتوب‬ ‫مع‬ ‫ازبطها‬ ‫هابقى‬
• Ras oncogens are the most commonly observed oncogenes in human
tumors

Gene control in neoplasia, including retinoblastoma
Proto-oncogenes and tumour-suppressor genes act normally to balance cell growth,
regeneration, and repair. This balance is lost in neoplasia.
In addition a loss of the ability to control apoptosis or repair DNA can lead to neoplasia.
Proto-oncogenes
Proto-oncogenes code for proteins involved in cell proliferation, including growth factors
and their receptors, signal transducers, and nuclear regulating proteins. In neoplasia, proto-
oncogenes become oncogenes through structural change, chromosomal translocations, or
amplification ( Table 4.2 ).

Tumour-suppressor genes, including the retinoblastoma gene
Tumour-suppressor genes switch off cell proliferation.
Loss of both copies of a tumour-suppressor gene is required for
neoplasia to develop.
The gene in neurofibromatosis type 1 is located on the long arm of
chromosome 17 and acts as a tumour-suppressor gene.
In addition to this the retinoblastoma (Rb) and p53 gene are good
clinical examples of mutated tumour-suppressor genes that lead to
neoplasia

The Knudson ‘two hit hypothesis’ describes a theory in neoplasia such
as retinoblastoma that can be inherited or sporadic. In the inherited
form one gene is already defective n the germ line (the first ‘hit’). The
second ‘hit’ is due to a mutation in the second allele. Sporadic
mutations involve two ‘hits’ in somatic cells

Retinoblastoma and control of the cell
cycle
Control of the cell cycle is regulated by the retinoblastoma protein (pRB) and E2F
proteins ( Fig. 4.5 ):
● E2F activates transcription of genes involved with DNA synthesis and production of
cell cycle regulators.
● pRB binds to E2F and inhibits the activation of transcription by E2F.
● pRB/E2F complex binds E2F promoters and prevents unbound E2F initiating
transcription.
● pRB can be inactivated by phosphorylation, mutation, or viral oncogene binding.
● Cyclin D1 and cdk4 mediate the phosphorylation of pRB.
● Cyclin D1/cdk4 complex is most active in the G1 phase of the cycle, causing
phosphorylation of pRB and release of E2F. This allows for the G1 phase to enter the
S phase.
● P16 is a cyclin-dependent kinase inhibitor that indirectly prevents phosphorylation
of pRB.

p53 and the cell cycle
The p53 gene is located on chromosome 17p13.1. It is the
most common target for genetic alteration in human
tumours. The major functions of p53 in response to DNA
damage are cell cycle arrest and initiation of apoptosis.

Loss of control of apoptosis
Cell survival is regulated by genes that promote or inhibit
apoptosis. The BCL/BAX family of genes is an example.
BCL-2 is expressed in high levels in follicular B cell lymphoma.
A translocation t (14:18) produces a fusion
between the bcl-2 gene and the heavy chain gene. This
leads to overexpression of bcl-2 protein, enhanced B cell
survival, and neoplasia. Bcl-2 protects the cell from apoptosis
through the mitochondrial pathway. The apoptosis
repressor effects are counteracted by the BAX gene family,
which induces apoptosis. BCL-2 and BAX can form
homodimers and heterodimers. The ratio of homodimers
to heterodimers will determine whether apoptosis occurs
or not ( Fig. 4.6 ).

Defects in DNA repair
In addition to possible DNA damage from environmental
agents, the DNA of normal dividing cells is susceptible to
alterations resulting from errors that occur spontaneously
during DNA replication.
Genomic instability occurs when both copies of these
genes are lost; thus they resemble tumour-suppressor
genes.
Defects can occur in three types of DNA repair systems:
● mismatch repair
● nucleotide excision repair
● recombination repair.

Pre-neoplastic conditions
1. Hamartomas
2. Choristomas

1. Hamartomas
Non-neoplastic malformation that consists of a
mixture of tissue normally found at a particular site.
Two main types exist:
1. Haemangiomas: Proliferation of vascular channels with a lobulated
growth pattern.
Types:
- Capillary haemangiomas [ may spontaneously regress ]
- Cavernous haemangiomas: involve large thick-walled caliber
vessels. [do NOT regress]
Site: eyelid, orbit, or choroid.
Extensive haemangiomas occur as part of Sturge–Weber syndrome.

1. Hamartomas
2. Naevi: abnormal migration, proliferation, and maturation of
melanocytes.
Shape: static flat brown or black areas
Site:
- Conjunctiva
- Iris
- Choroid
Naevi at any site can progress to melanoma
Normally,
Melanocytes
migrate through
dermis to reach
epithelial cells

2. Choristomas
Non-neoplastic malformation consisting of a mixture of tissues NOT normally
present at a particular site.
Example:
 Epibulbar dermoids: smooth white nodule + hair
Site: bulbar conjunctiva or at outer angle of the bony orbit
Made up of: fibrous tissue, fat, hair, and sweat glands.
 Phakomatous choristoma: nodule in the eyelid.
It consists of epithelial and basement membrane cells
resembling a lens capsule in a fibrous stroma.

Thrombosis,
emboli, and
atheroma
Vascular disorders
can be inflammatory
(giant cell arteritis)
or degenerative
(diabetic retinopathy)

Thrombosis
Platelet structure.
Platelets are made up of 4 zones:
1. Peripheral:
- Rich in glycoproteins [needed for platelet adhesion and aggregation] ‫يلزق‬ ‫سكر‬
- Contains platelet factor 3 [which promotes clotting during aggregation]
2. Sol-gel: contains microtubules and microfilaments
3. Organelle:
- α granules, which contain factor VIII, factor V, fibrinogen, fibronectin, platelet-derived growth
factor, and chemotactic factors
- Dense bodies that contain ADP, calcium, and 5HT

Thrombosis
Fate of thrombus:
1. Detach from the vessel wall forming an embolus
2. Lysed by plasmin
3. Persist at the vessel wall to form an occlusive thrombus
recanalization can occur through an occlusive thrombus
4. Form a mural thrombus covered by smooth muscle cells which
then becomes vascularized by blood vessels from the main lumen.

Thrombosis
Thrombosis occurs
d.t. imbalance

 Protein C [Vitamin-K-dependent serine protease]
Role: Strongly inhibits factors Va and VIIIa.
 Factor V Leiden is a variant (mutated form) of human factor V that causes an
increase in blood clotting (hypercoagulability) [ Autosomal dominant]
Mutated form of factor V that cannot be as easily degraded by activated Protein C
Five per cent of the white population are carriers.
 Protein S
Role: Co-factor of activated protein C [= inactivation of factor Va and VIIIa]
Protein C deficiency is inherited as an autosomal dominant trait and
clinically affected individuals are heterozygous, with a protein C
concentration of 50%.
Prevalence is 6–8% of young patients with venous thrombosis.
Protein S deficiency inheritance is autosomal dominant
Prevalence in young patients is 5–8%.

Thrombosis
Risk factors for thrombosis: ”Virchow’s triad”
1. Change in blood flow e.g. venous stasis, arrhythmia,
valvular disease.
2. Change in the vessel wall, e.g. atherosclerosis, trauma,
inflammation, or neoplastic change.
3. Change in blood constituents, e.g. an increase in the
number of platelets or altered platelet function.

Emboli
An embolus is an abnormal mass of matter carried in the
bloodstream that is large enough to occlude a vessel

Atheroma
= Fibro-lipid = atherosclerotic plaque
Platelets adhere to the endothelium
Smooth muscle proliferation
platelet-derived growth factor
Breakdown in the endothelial cell barrier → Intracellular & extracellular lipid
accumulation → atherosclerotic plaque

Atheroma
= Fibro-lipid = atherosclerotic plaque
One school of thought believes that the plaques are derived from fatty streaks,
which can be seen as early as 10 months of age

Atheroma complications
1. Aneurysm: d.t. thinning of adventitia media
[Growth of the plaque can lead to necrosis and softening of the
plaque base]
2. Plaque fissures:
- Small fissures → microthrombi
- Larger fissures → emboli.

Risk factors for atherosclerosis
Reversible or irreversible.
Reversible risk factors:
1. Cigarette smoking
2. Hypertension
3. Diabetes
4. Hyperlipidaemia
Irreversible risk factors:
Age, male sex, and race
High levels of high-density lipoprotein (HDL) are protective

Additional
examples of
basic ocular
pathology

Definitions
Endophthalmitis: inflammation of one or more coats of
the eye and adjacent cavities
Panophthalmitis: is inflammation of all three coats of the eye
and can spread to orbital structures.

Mind Map
Granulomatous:
• Sympathetic uveitis or ophthalmia
• Phaco-anaphylactic endophthalmitis
• Non-granulomatous & autoimmune diseases:
• Suppurative endophthalmitis
• Non-suppurative uveitis and endophthalmitis
• Sjogren’s syndrome
• Rheumatoid eye disease
• Thyroid eye disease

Sympathetic uveitis or ophthalmia
Bilateral diffuse granulomatous inflammation T-cell-mediated panuveitis
Cause: Penetrating eye injury [associated with traumatic uveal incarceration
or prolapse]
Etiology: (Unknown) may be delayed type hypersensitivity related to an
uveal reaction to antigens localized on the RPE or uveal melanocytes.
Certain human leukocyte antigen (HLA) types are associated with its
development, including HLA DRB1*04, DQA1*03, and DQB1*04.
Pathology: Granulomatous uveitis develops with the appearance of mutton
fat keratic precipitates. These are collections of epithelioid cells plus
lymphocytes, macrophages, multinucleated giant cells, or pigment on the
endothelium of the cornea
Inflammation also involves the retinal pigment epithelium with accumulation
of macrophages, here called Dalen– Fuchs’ nodules.
Time: anytime from 5 days to many years after trauma
Granulom
atous

Phaco-anaphylactic endophthalmitis
Autoimmune, zonal granulomatous inflammation
Cause: rupture of the lens capsule → reaction to the lens material.
This may result from the breakdown of tolerance at the T-cell level and
consequently the formation of an antibody–antigen reaction. ??????
Macrophages and lymphocytes enter the anterior chamber (from
dilated blood vessels in the iris and ciliary body). The macrophages
engulf the lens matter and can block the anterior chamber angle,
leading to phacolytic glaucoma.
Summary: Macrophages come & engulf lens materials → Block angle →
phacolytic glaucoma
Granulom
atous

Suppurative Endophthalmitis
Suppurative: describes a tissue necrosis + presence of
PMNL infiltration into the involved tissues.
Source of inflammation may be:
● Exogenous: sources originate outside the eye and body
e.g. surgical trauma, penetrating trauma, radiation, and
chemical injury
or
● Endogenous: sources originate inside the eye,
e.g. inflammation due to cellular immunity such as Behcet’s disease,
spread from contiguous structures, or haematogenous spread.
Non-
Granulom
atous

Non-suppurative uveitis and endophthalmitis
The inflammation is generally termed anterior, intermediate, or posterior,
although all three may be affected in a panophthalmitis.
Source of inflammation may be:
● Exogenous: sources originate outside the eye and body
e.g. traumatic anterior uveitis in blunt trauma, penetrating injury inducing a
sterile inflammation secondary to foreign body exposure
or
● Endogenous: sources originate inside the eye,
idiopathic (the most common form), inflammation associated with viral or
bacterial infection or local ocular disease such as pars planitis and
Posner–Schlossman’s syndrome or inflammation associated with systemic
disease such as Reiter’s syndrome, Crohn’s disease, or ulcerative colitis.
Non-
Granulom
atous

Sjogren’s syndrome
Types:
1ry
2ry : to systemic disease e.g. rheumatoid arthritis.
Pathology: autoimmune disease against acinar glands of the
conjunctiva, lacrimal gland, and oral mucosa.
Lymphocytic infiltrate of lacrimal gland & conjunctival goblet cells →
impaired tear secretion and dry eyes.
Autoimm
une

Rheumatoid eye disease
This is an immune complex and T-cell-mediated mechanism.
1. Sclera: scleritis
- Necrotizing scleritis
- Brawny scleritis due to inflammation and a reactive fibrosis
- Posterior scleritis, which can lead to macular oedema.
- Scleromalacia perforans due to thinning of the sclera and exposure of the
underlying uveal tract, although perforation is rare
(this is usually due to arteriolar infarction)
2. Cornea:
- Peripheral corneal ulceration due to immune complex deposition, which leads to
complement activation, PMN infiltration, collagenase production, and corneal melt
[ Sometimes it may occurs spontaneous corneal ulceration with or without
inflammatory cell infiltrate]*
Autoimm
une

Thyroid eye disease
Can occur in hyperthyroidism, hypothyroidism, & euthyroid !
Bilateral (asymmetrical)
Pathology:
- Active stage: Perivascular lymphocytic infiltration with mast cells and glycosaminoglycan accumulation within and around the
extraocular muscles and fat. In the later
- Fibrotic stage: fibrosis
Signs:
 Soft tissue involvement:
- Dry eye due to corneal exposure,
- Conjunctival chemosis
- Superior limbic keratoconjunctivits
 Eyelid retraction and lid lag
 Proptosis
 Compressive optic neuropathy.
 Squint
Autoimm
une

Trauma to eye
1. Physical trauma:
- Mechanical
 Blunt
 Penetrating
- Radiation
- Thermal damage e.g. cryotherapy
2. Chemical trauma

Mechanical trauma (Blunt)
● Angle recession glaucoma: d.t separation of the ciliary muscle attachment to the scleral
spur → trabecular meshwork collapse
● Retinal oedema = Commotio retinae:
Mechanism: (theories)
1. Retinal vessel spasm → ischaemia and endothelial cell damage with leakage into tissue
Or
2. Transient interruption of axoplasmic flow in the ganglion cell processes
● Pseudoretinitis pigmentosa: shearing of photoreceptors → reactive RPE proliferation

Radiation
Photophthamia:
Corneal epithelium is damaged
Cause:
- Arc
- Snow (Snow blindness)
After Pan-retinal photocoagulation
Reactive proliferation of RPE at the edge of the burn leads to
pigmentation around a white scar formed by glial cells

Ionizing radiation
Ionizing radiation may be charged, uncharged, or electromagnetic.
The unit (gray, Gy) is a measure of the amount of energy absorbed by the tissue.
For melanoma either proton beam therapy or electromagnetic therapy ( γ -rays) can be
used at up to 110 Gy.
For retinoblastoma X-rays and γ –rays are used with a level of 40–60 Gy.
Side effects of radiation to the eye:
● Endarteritis due to infiltration of the vessel wall by inflammatory cells and proliferation of
spindle cells within the internal elastic lamina (this contributes to tumour necrosis but also can
lead to telangiectasia and leakage of plasma into surrounding tissue)
● Irradiation of the orbit, leading to dry eye due to lacrimal gland damage
● An increased risk of mutations, which can lead to second malignancy or congenital defects
● Cataract

Chemical injury
Acid burns:
Coagulative necrosis of protiens → Limit penetration through the
cornea and sclera
Alkali burns
Liquefactive necrosis → easily penetration →
. Severe corneal damage and limbal ischaemia
The high pH destroys cells of the lens, uveal tract, and retina.

‫لسه‬Corneal dystrophies
Group of inherited, bilateral, and progressive diseases that lead to corneal
opacification.
Types: [According to the layer affected]: ………..
Many of the corneal dystrophies are linked to
mutations in the transforming growth factor- β -induced
gene ( BIGH1 ) on chromosome 5q31, particularly the dystrophies
involving Bowman’s layer and stromal layers.
BIGH1 codes for a protein expressed on the cell membrane
of corneal epithelium and stromal keratocytes, which aids
with wound healing. Mutations cause abnormal folding for
the proteins and amyloid or non-fi brillar deposits. All are
autosomal dominant with complete penetrance.

Corneal endothelial dysfunction
Iridocorneal endothelial syndrome (ICE syndrome)
Unilateral, sporadic, and occurs in adults.
Pathology:
- Degenerate endothelial cells which may be surrounded by normal
cells.
- The endothelial cells form blebs and can acquire numerous
microvilli on their posterior surface.
These abnormal cells can act to form a membrane over the angle
structures.
The late outcome is corneal decompensation and oedema with or
without glaucoma.

ICE Syndome
Variants of ICE syndrome:
1. Chandler Syndrome: The most common 50%
corneal pathology with associated corneal edema
majority of patients have NO iris changes at all, making the diagnosis a
challenge.
2. Essential / Progressive Iris Atrophy: Polycoria, corectopia, iris hole
formation, ectropion uveae, and iris atrophy
3. Iris Nevus / Cogan-Reese Syndrome: The anterior surface of iris has tan
pedunculated nodules or diffuse pigmente lesions. However, iris atrophy is
uncommon with these particular patients.

Essential / Progressive Iris Atrophy

Bullous keratopathy
Corneal oedema, which progresses from stromal to epithelial microcystic and
then epithelial macrocystic (bullous) oedema.
Examination shows stromal oedema with Descemet’s folds followed by
epithelial oedema, subepithelial scarring, and corneal neovascularization.
Causes:
- Fuchs’ endothelial dystrophy
- Intraocular surgery e.g. aphakic or pseudophakic bullous keratopathy
more likely to occur following complications or placement of an anterior
chamber lens
- Endothelial cell inflammation due to herpes simplex or zoster
- Corneal graft failure/rejection
- Chronic anterior uveitis
- Trauma.

Acquired cataract‫تزبطه‬ ‫الزم‬ ‫مش‬ ‫سهل‬
‫دلوقتي‬
Cataract can be divided into congenital and acquired.
Acquired cataract has many possible causes.
Cataract can have a variety of morphologies, which are
sometimes related to their aetiology.
Some of the more common morphologies include the
following:
● Nuclear: this is the most common type of age-related
cataract. It can cause increasing myopia as it matures.
● Cortical: these have a more radial appearance in the cortical
zone of the lens.
● Subcapsular: posterior subcapsular can occur due to corticosteroid
use.

Cellular changes in cataract
● Loss of cell organization
● Formation of vacuoles within lens fibres
● Water accumulation within the lens
● Disruption of lens crystallin organization and formation of lens
protein aggregates
● Accumulation of protein aggregates and chromophores,
which leads to changes in colour from yellow to red to
black and reduced transmission of light.

Mechanism of age-related cataract
● Breakdown of the antioxidant mechanisms in the lens, mainly ↓
glutathione levels
●  proteolytic activity
● UV light absorbed by lens tryptophan, which is then converted to
compounds that act as photosensitizers and cause free radical
formation
— free radicals down regulate Na/K -ATPases in the lens epithelium
 water influx.

  function of the MIP26 or aquaporin molecule  water influx.
 as α -cystallins denature they have reduced chaperone
activity. They bind to unfolded proteins but lack the ability
to refold β γ -crystallins. These changes lead to increased insoluble
proteins, amino acid oxidation, increased chromophores, and loss of α A-
crystalline and
γ S-crystalline.

Mechanisms of diabetic cataract
formation
High glucose & galactose concentrations in the aqueous  
intracellular glucose in the lens  overwhelms the anaerobic glycolysis
pathway [Hence prevents the normal aldose reductase inhibition of the
polyol pathway.
This leads to an up regulated polyol pathway and accumulation of polyols
(sorbitol) in the cells. This acts to drag water into the cell.
Aquaporin of MIP26 is then activated. This leads to reduced ATP and
glutathione, and hence oxidative damage.

Primary open-angle glaucoma
The most common form of glaucoma
It is an age-related disease and is the leading cause of irreversible blindness in
the developed world.
Risk factors include:
● Smoking
● Diabetes
● Hypertension
● Hypercholesterolaemia
● Myopia.

POAG has been linked to mutations in chromosomes 1 and 3p.
Individuals with the mutation have an earlier age at onset, higher
peak intraocular pressure (IOP), and are more likely to need surgery
The GLC1A gene (chromosome 1 open-angle glaucoma gene) codes
for a protein known as TIGR (trabecular meshwork inducible
glucocorticoid response) or MYOC (myocillin).

High IOP is a risk factor for POAG.
 IOP is d.t. resistance to outflow of aqueous.
 IOP usually slow and progressive.
The nerve fibre bundles passing into the optic nerve head
above or below the horizontal line on the temporal side of
the disc and the prelaminar optic nerve fibres are
selectively damaged.

Mechanism of damage in POAG:
1. Pressure-induced ischaemia of the capillary bed of the optic nerve
2. Direct mechanical pressure reducing axoplasmic flow in the axons passing through the
lamina cribrosa.
In addition this
 IOP may be accompanied by occlusive disease  poor perfusion of the posterior ciliary
arteries  ischaemic optic atrophy.
The combination of poor perfusion due to occlusive disease and pressure-induced
ischaemia causing prelaminar nerve fibre atrophy leads to enlargement of the optic nerve
head in the vertical plane and field loss, for example a nasal step or arcuate scotoma.

Primary angle-closure glaucoma
Predisposing factors:
- Old age
- Hypermetrope (small eyes)
- Following blunt trauma, where the angle may already be damaged
Mechanism: Iris bombe
Stages:
-Acute
- Chronic
- Intermittent

Secondary open-angle glaucoma
The angle is obstructed by matter, for example:
● Cells and protein in inflammation (uveitis)
● Haemorrhage in trauma
● Tumour cell infiltration
● Lens matter or macrophages containing lens matter (phacolytic
glaucoma).

Secondary angle-closure glaucoma
Example:
● Tumours of the eye, e.g. melanoma, forcing the lens forward
● Anterior or posterior synaechiae in uveitis
● Rubeotic glaucoma caused by fibrovascular proliferation
in the angle due to retinal ischaemia.

Retinal microvascular
occlusion
Diabetes mellitus is the most common cause of
blindness in the working population.
Diabetes predominantly affects the retinal circulation
but can also affect other tissues, leading to
vacuolation of iris pigment epithelium, thickening of
ciliary process basement membranes, and cataract.
Diabetic retinopathy

It is a microangiopathy affecting pre-capillary arterioles,
capillaries, and post-capillary venules.
Pathology:
1. Leakage stage: Degeneration of endothelial cells and pericytes
 Micoanerysm, odema, exudate & hemorrhage
2. Occlusion stage: d.t Thickening of the basement membrane &
abonormal RBCs & platelets  capillary non-perfusion and tissue
ischaemia.

Ischemia
VEGF
Neovessels
(Fragile)

Microaneurysms: ischaemia of the capillary bed  weakening of the wall by
necrosis of the pericyte  bulging of the vessel wall
Haemorrhage: breakdown of vessel walls  leakage of RBCs
■ Flame haemorrhage: rupture of a small arteriole  leakage into the nerve
fibre layer
■ Dot haemorrhage: rupture of capillaries in the outer plexiform layer
■ Blot haemorrhage: larger than dot haemorrhages; bleeding from capillaries
with tracking between photoreceptors and the RPE.

Micro-infarction = fluff y white swellings = cotton wool spots in the retina.
These are swollen ends of interrupted axons. The infarct mainly involves the nerve
fibre layer.
Hard exudates:  perfusion of the vascular bed and damage to the endothelium of
the deep capillaries causes plasma leakage into the outer plexiform layer.
This results in a yellow, well-circumscribed area known as exudates.
Histologically these are eosinophilic masses containing foamy macrophages with
lipid.

Neovascularization:
Newly formed vessels grow from the venous side of the capillary bed within an area of arteriorlar
nonperfusion otherwise known as intraretinal microvascular abnormalities (IRMAs).
These vessels leak on fluorescein angiography and can progress to vasoproliferative retinopathy.
Vasoproliferative retinopathy: ischaemic areas of retina release vaso-formative factors which
diffuse into the retina and vitreous. These stimulate endothelial cells to proliferate at the edge of the
ischaemic area. New vessels form in the prevenular capillaries and venules, and proliferate within and on
the surface of the retina. If the vitreous is detached, the fibrovascular tissue grows on the inner surface of the
retina. The membrane can then contract and lead to retinal detachment. Proliferation within vitreous leads to
haemorrhage and formation of traction bands.
Diffusion of vasoformative factors to the iris surface and trabecular meshwork can lead to rubeosis iridis

Retinopathy of prematurity
In a premature infant on supplemental oxygen the hypoxic drive is reduced 
inhibition of the extension of the normal vascular bed
Excessive proliferation of blood vessels occurs when the infant returns to
normal oxygen levels. In addition the peripheral non-vascularized retina is
now ischaemic, hence further driving neovascularization from the peripheral
vessels, which grow rapidly and in a disorganized manner within the retina
and vitreous. This can lead to a bilateral retinal detachment if left untreated
In intrauterine life, blood vessels grow from the disc towards the
periphery driven by a relative hypoxia.

Retinal
macrovascular
occlusion
Macrovascular occlusion
refers to obstruction of
vessels equal to or
greater than a medium-
sized arteriole

Hypertensive retinopathy
1. Hyalinization of blood vessels  appearance of ‘copper or silver wiring’.
2. Narrowing of the vessels with spasm produces an ischaemic effect on the
endothelial cells distal to the constriction.
3. As the endothelium swells and degenerates, leakage of fibrin into the vessel
wall  further narrowing of the lumen  fibrinoid necrosis of the choroidal and
retinal vessels.
Accelerated or malignant hypertension is characterized by haemorrhage,
exudates, cotton wool spots, and papilloedema.
If the choriocapillaris is involved lobular infarcts form what is known
as Eschnig’s spots.

Hypertensive retinopathy
“Elshnig spot”

Central retinal artery occlusion
The central retinal artery is an end artery.
Causes:
Inside artery: Thrombosis - Embolus [most typically from an atheromatous
plaque of the carotid artery]
Wall of artery: Giant cell arteritis
Symptoms: Sudden painless loss of vision
Signs:
Pupil reflex: TAPD
Fundus: Cherry red spot (coagulative necrosis of ganglion cell layer which is
NOT present at macula)

Central retinal artery occlusion
Neovascularization and rubeotic glaucoma are extremely rare
in cases of CRAO.

Central retinal vein occlusion
The radius of the central vein is smallest in the lamina cribosa 
narrowing  turbulence and an increased risk of thrombosis

Posterior vitreous detachment (PVD)
Age-related degeneration of the vitreous commences in the teenage years.
Liquefaction of the collagen gel  vitreous syneresis  vitreous is separated
from the optic nerve head (P.V.D)
The vitreous base provides the centre of energy whilst the posterior vitreous
responds to the energy.If the pull on the peripheral retina is sufficient it can
cause a retinal tear or hole. In a U-shaped tear the base of the tongue of the
retina is anterior because the vitreous first separates posteriorly, tearing the
retina at a point of adhesion. The action of the vitreous extends the tear
anteriorly towards the vitreous base.

Retinal detachment
Separation between the neural retina and the retinal pigment epithelium.
Causes:
1. Rhegmatogenous RD
2. Exudative RD
3. Tractional RD

Age-related macular degeneration (AMD)
Dry age-related macular degeneration
Incidence: 90% of AMD
Age: risk  with age and is most common ˃ 70 years
Risk factors:
● smoking
● female
● hypertension
● high fat and cholesterol intake

Dry AMD
Signs:
● Pigment disturbances due to clumps of pigmented cells at the level of the RPE.
● Drusen—round yellow spots represent abnormal thickening of the inner aspect of Bruch’s
membrane. Hard drusen (small and well-defi ned) do not predispose to advanced ARMD.
Soft drusen (larger than 63 μm with ill-defi ned borders) increase in size and number with age
and are a risk factor for advanced ARMD.
● Geographic atrophy—late stages of dry ARMD representing atrophy of the RPE.
● Histological examination of the macula reveals atrophy of the photoreceptors over well-
defi ned eosinophilic mounds beneath the RPE in hard drusen and more linear granular bands
in diff use drusen. These are situated between the cell basement membrane and Bruch’s
membrane.

Dry AMD
A basal linear deposit refers to a deposit between the RPE cell membrane and
its basement membrane. This deposit type has been linked to the start of
neovascularization or wet ARMD.
In addition, Bruch’s membrane is thickened or calcified, and occasionally
choriocapillaris is replaced by degenerative fibrosis.
At the cellular level macrophages and endothelial cells proliferate in the
deposits beneath the RPE

Wet age-related macular degeneration
This leads to a sudden onset of central visual loss and the
patient may have been aware of the fact they suff ered
from dry ARMD. Following a cellular infi ltration by macrophages
and endothelial cells a proportion of cases develop
new capillaries and choroidal or subRPE neovascularization
develops. Rupture of these vessels leads to oedema
and haemorrhage, thus attracting more macrophages and
further neovascularization. The RPE undergoes a fi brous

Retinitis pigmentosa
Inheritance: AD, AR, or X-linked recessive
Pathology:
1. Outer nuclear layer:
- At the fovea: appears as a single layer of cells with stunted photoreceptors.
- Towards the periphery: replaced by Muller cells, which fuse with the RPE.
2. RPE cells react by proliferation and migration into the retina to become
distributed around the hyalinized vessels, giving a bone spicule appearance.
AD forms are associated with mutations in the gene coding for rhodopsin on the
long arm of chromosome 3q and in the peripherin gene on chromosome 6p.

Retinitis pigmentosa
Symptoms:
• Night blindness
• Progressive  in visual field from the periphery towards the posterior pole
 tunnel vision
Fundus examination:
-Retinal atrophy
- Narrowing and opacification of retinal vessels
- Mixed, coarse strands of pigmentation.

Best’s disease
This is an AD heredomacular degeneration
Symptoms: Loss of central visual acuity
Signs: Disc of yellow tissue at the macula.
Pathology: Accumulation of lipofuscin in the RPE cells and atrophy of the
photoreceptor layer of the retina

Stargardt’s disease
AR inherited macular dystrophy.
The photoreceptor gene ABCA4 or ATP binding cassette transporter-retina also known as
STGD1 on chromosome 1p21 is mutated.
This leads to abnormal transport of metabolites across the disc membrane of the
photoreceptors  accumulation of lipofuscin in rod and cone disc spaces  destruction of
RPE and hence photoreceptors.
Fundus: macular atrophy + small yellow flecks.
At the early stages,
- RPE is enlarged by accumulation of lipofuscin and melanin.
- Outer layer of the retina is lost and the pigment epithelium is absent, causing
fusion of gliotic retina with Bruch’s membrane.

Stargardt’s disease
 Interestingly 
Around 18.7% of cases of dry AMD have mutations in the ABCA4 gene;
therefore the role of this set of genes in the pathogenesis of macular dystrophy and
degeneration is thought to be extensive.

Mind map: Ocular neoplasia
● Papillomas of the lids and conjunctiva
● Adenomas of the lids
● Basal cell carcinoma of the lids
● Squamous cell carcinomas of the lids
● Sebaceous gland carcinomas of the
lids
● Pleomorphic adenoma of the lacrimal
gland
● Adenoid cystic carcinoma of the
lacrimal gland
● Teratomas of the orbit
● Melanomas of the conjunctiva, uvea,
iris, ciliary body, and choroid
● Neural tumours, including
retinoblastoma
● Myomas and myosarcomas
● Lymphomas of the ocular adnexa
● Metastatic tumours.

Papillomas of the lids and conjunctiva
Benign epithelial cell tumours.
Cause: mostly associated with:
- Human papilloma virus 
- Molluscum contagiosum
In the eyelid: the most common tumours are
basal cell & squamous cell papillomas.
In the conjunctiva: pedunculated or sessile

Adenomas of the lids
Benign tumours from a gland of lid or conjunctiva
Derived from: sweat glands, pilosebaceous hair follicles, or
sebaceous glands.
Example: sebaceous adenomas are proliferations of lipid-
laden sebaceous cells and most commonly occur as a yellow
mass at the caruncle.

Basal cell carcinomas of the lids
This is the most common form of malignant tumour seen by ophthalmologists.
[90% of all eyelid tumours]
Incidence: [as any BCC in body]
- Age: ˃ 50 years
- Race: more common in Caucasians
- Associated with UV exposure
Site: Lower lid ˃ medial ˃ upper ˃ lateral
$: I’m slow

Shape of BCC: (nodular lesion) = classical type
Central ulcer with a rolled edge.
Basal cell carcinoma is locally aggressive and requires wide local excision to
prevent recurrence or extension of the tumour into the orbit.
Basal cell carcinoma is rarely metastasize

Squamous cell carcinomas of the lids
Malignant epithelial cell tumours.
[5% of all eyelid tumours]
Present as a more rapidly growing nodular ulcer or can appear papillomatous
with an overlying keratinous horn.
Incidence: [as BCC]
- Age: ˃ 50 years
- Race: more common in Caucasians
- Associated with UV exposure, HPV and immunosuppression.

Sq.C.C. Can arise from conjunctiva and cornea:
At lid : BCC ˃ Sq. CC
At conjunctiva: BCC ˂ Sq. CC Yanoff
Squamous cell carcinoma can metastasize
Lymphatic spread can occur to:
- Preauricular (upper lids)
- Submandibular lymph nodes (lower lids).

Classification: according to their degree of differentiation.
1. Well-differentiated: have a glassy, pink cytoplasm and intercellular
bridges with keratin pearls
2. Poorly differentiated: lose these characteristics.
The spindle cell morphology is sometimes seen
and this is more aggressive

Sebaceous gland carcinomas of the lids
1–5% of all eyelid tumours.
Age: Older ♀
Site:
- Meibomian glands (MOST common) 
- Zeiss glands or other sebaceous glands of the lids.
Clinically: may look very much like a basal cell or squamous cell carcinoma, or
can appear similar to chalazions or a chronic blepharoconjunctivitis !!
Remember the patient with chronic unilateral blepharitis !!

Sebaceous gland carcinomas of the lids
Subtypes:
● Nodular: lobules of tumour cells with foamy or vacuolated cytoplasm
● Diffuse: individual tumour cells spreading within the surface epithelium
(pagetoid) and adnexal structures.
Prognosis: Poor d.t. diffuse nature of these tumors.
So, Early diagnosis obviously improves this.
These are then graded according to their degree of differentiation

lacrimal gland
Benign mixed tumour
The most common epithelial cell tumour of the lacrimal gland.
It is slow growing and pseudoencapsulated.
Age: most commonly occurs in late to middle age.
Histology: Consists of :
- Epithelial elements
- Mesenchymal elements: myxoid tissue, cartilage fat, and sometimes
even bone.
Can undergo malignant change to produce a pleomorphic carcinoma
So, adequate excision is a must

Adenoid cystic carcinoma of the lacrimal gland
The most common malignant lacrimal gland tumor
The tumour is more rapidly growing
Age: middle-aged or older patients (Can be seen in younger patients)
C/P: proptosis, parasthesia, pain, and diplopia d.t. orbital invasion
Histology: the most common form is a cribiform or Swiss cheese appearance.
It is aggressive, requiring surgery with radiotherapy or chemotherapy

Teratomas of the orbit
Orbital teratomas are rare and occur in neonates.
The majority are benign.
Origin: derived from totipotent germ cells and can occur at any site in the
mid-line where germ cells have stopped on their migration to the gonads.
C/P: proptosis.
Histology: tissue derived from the three embryonic germ cell layers such as
respiratory or gastrointestinal epithelium, stroma containing fat, cartilage and
bone, and neuroectodermal tissues.

Conjunctival melanoma
Malignant tumour of melanocyte
Origin: “Controversial”
- Primary acquired melanosis
- Pre-existing naevus
- De novo .
Primary acquired melanosis (PAM)
Unilateral or bilateral diffuse flat areas of conjunctival pigmentation in middle-
aged to older patients.
Types:
- PAM without atypia
- PAM with mild atypia (mild malignant transformation)
- PAM with severe atypia (highly malignant transformation)

Conjunctival melanoma
Shape: raised, pigmented, or fleshy conjunctival lesion.
Teatment: Complete excision + topical chemotherapy such as mitomycin C.
Prognosis: poor if tumors thicker than 5 mm and is located in the fornix.
It can metastasize to regional lymph nodes, the brain, and other organs.

Uveal melanomas
Malignant tumor of melanocytes in the iris, C.B and choroid.
Choroidal tumours make up 80% of these.
Tumours are usually unilateral and grow as pigmented or non-pigmented
lesions !!
Metastatic spread is usually to the liver and occurs within 2–3 years.

Iris melanoma
Growth: slow-growing nodular tumours.
Spread: diffusely on the iris surface and around the chamber angle (may 
2ry glaucoma d.t. trabecular meshwork infiltration)
Histology: small, spindle-shaped cells with surface or stromal invasion.
Uveal melanomas

Ciliary body & choroidal melanomas
Growth:
• Ovoid
• Nodular
• Mushroom shape: d.t. tumour spread in the subretinal space after braking
Bruch’s membrane.
Uveal melanomas
Tumours can be amelanotic, light grey/brown, or heavily pigmented.
Large tumours may undergo spontaneous necrosis.

Classification (according to their cell type) :
• Spindle
• Epitheloid
• Mixed (The majority)
Uveal melanomas

Vascular patterns are assessed using the periodic acid-Schiff (PAS) stain.
There are nine patterns, including parallel, parallel with crosslinking, and
closed vascular loops.
In addition to histology and vascular patterns immunohistochemistry will
usually be positive for S100, HMB45, and Melan A.
Uveal melanomas

Treatment: Enucleation + radiotherapy.
Alternatively, proton beam therapy can be used for smaller tumours.
Uveal melanomas
Haematogenous spread can be via collector channels, vortex veins,
or short ciliary vessels.

Neurofibromas and schwannoma
These arise from within the orbit. They are normally benign.
Neurofibromas are derived from endoneurium and schwannomas from the
Schwann cells surrounding axons.

Neurofibromas and schwannoma
Histology of neurofibromas shows spindle cells with wavy nuclei and collagen.
Occasional axons run through the tumour.
Neurofibromas may be associated with neurofibromatosis type 1.
Histology of schwannomas shows a palisaded arrangement of spindle cells
(Antoni A) and myxoid (Antoni B) areas and there are occasional axons running
through the peripheral part of the tumour. Occasionally schwannomas contain
melanin: making the distinction between them and spindle cell melanoma should
be considered.

Optic nerve glioma
Juvenile and adult forms of optic nerve glioma can occur.
Adult forms are rare and carry a poor prognosis d.t. extensive intracranial extension.
Site:
- Orbital portion: 50% (Most common)
- Intracranial or chiasmal portions can be involved.
- Pathology: areas of myxoid degeneration and eosinophilic masses representing a modified process of an astrocyte
otherwise known as Rosenthal fibres.
Orbital portion optic nerve glioma
Signs: proptosis, optic disc swelling, and visual loss.
Investigation: CT or MRI [To show the extent of the tumour]
TTT: If the tumour is causing visual loss it will require surgical excision, which
if complete carries a good prognosis.

Meningioma of the optic nerve
Cause:
• 1ry
• 2ry [Extension of an intracranial meningioma]
Pathology:
Psammoma bodies with a transitional pattern.
Unlike glioma,
Meningiomas tend to show slow progressive growth in adults
and are more aggressive in children

Retinoblastoma
This is a malignant tumour of infancy affecting 1 in 20,000
live births. It is lethal if left untreated. The classical presentation
is the fi nding of leukocoria, often picked up on photographs.
The infant may otherwise appear well.
Diff erential diagnoses of leukocoria also include:
● Coats’ disease
● astrocytic hamartoma
● retinopathy of prematurity

Histological examination reveals small cells with scanty
cytoplasm. There is a high mitotic rate with prominent
apoptosis and necrosis within the tumour, indicating high cell
turnover. Diff erentiation may be seen in the form of:
● Homer–Wright rosettes: a multilayered circle of nuclei
surrounding eosinophilic fi brillar material ( Fig. 4.14 )
● Flexner–Wintersteiner rosettes: a circle of cells limited
internally by a continuous membrane ( Fig. 4.15 )

Myomas and myosarcomas
Leiomyoma can arise from the smooth muscle of the iris and
ciliary body. The malignant form leiomyosarcoma is rare.

Rhabdomyoma and rhabdomyosarcoma can arise from
striated muscle in the eyelid and orbit, although rhabdomyoma
is extremely rare. Rhabdomyosarcoma is the most
common orbital malignancy in childhood. It usually arises
before the age of 20 and causes a proptosis and squint.
Macroscopic examination reveals tan-coloured fl eshy tissue.
Histopathological examination reveals one of three
subtypes:
● embryonal (most common)
● alveolar
● pleomorphic (rare, usually adults).
Immunohistochemisty for MyoD1, a muscle regulatory
gene, can help with the diagnosis. Treatment is with a combination
of chemotherapy and radiotherapy.

Lymphomas of the ocular adnexa
Origin: Conjunctiva, eyelids, lacrimal gland, and orbit.
Conjunctival lesions are associated with a lower incidence of
systemic disease compared to the orbit (35%), lacrimal
gland (40%), or eyelid (67%). ???? ‫ايه‬ ‫يقصد‬‫؟؟‬
It may be 1ry or 2ry
So, full haematological investigations should be done

The most common lymphoproliferative lesions include:
● benign lymphoid hyperplasia
● extranodal marginal zone lymphoma (EMZL)—the most
common type of ocular lymphoma this is a low-grade
B-cell lymphoma derived from mucosal associated lymphoid
tissue that may rarely transform to a high-grade
lymphoma
● follicular lymphoma is usually part of systemic disease

Metastatic tumors
In adultsIn children
• Breast
• Prostate
• Lung
• GIT
• Neuroblastoma
• Ewing sarcoma
• Wilms’ tumour
• Rhabdomyosarcoma
Most common origin
Uveal tractOrbitMain site of metastasis

Ocular Pathology

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