PathologyDr. Ahmed Omara

Inflammation

InflammationTissue response to a noxious stimulus.

Inflammation is NOT a synonym for infection

Classifications of inflammation1. 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 inflammationImmediate 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

Acute inflammation

1. Local tissue damage & release of inflammatory mediators

Acute inflammation

Chemical mediatorsAny 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 mediators1. 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

eicosanoids2. Fibroblast effects • Activates tissue fibroblasts• Increases proliferation• Production of collagen &ECM

Chemical mediators2. Plasma-derived- Kinins e.g. bradykinin

- Complement: C3a & C5a

- Clotting system

- Fibrinolytic system e.g. plasmin

Acute inflammation

Chemical mediators2. 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 BRADYKININKALLIKREIN

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 thrombin

Thrombin

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

Complement15% 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. Opsonisation2. 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 cascade1. 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 complexA 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 activationThe 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• LymphokinesChemotactic factors for monocytes: • Bacterial products (mainly from bacilli)• C3a & C5a• Neutrophil components• Lymphokines Acute

inflammation

Chemotactic for neutrophilsChemical mediator Molecular

weight prostaglandin E Low

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

Acute inflammation

A. Vascular phase: formation of fluid exudate1. 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 effect Effect Material

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 exudateThe most common inflammatory cell is:- Neutrophil (in bacterial infection)- Esinophil (parasitic infection – allergic)- Monocytes (in viral infection)

Steps of cellular exudation1. Margination & pavementation2. Emigration of leucocytes3. Diapedisis (escape of RBCs)4. Chemotaxis5. Phagocytosis Acute

inflammation

1 .Marignation1. 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 .Marignation1. 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

ChemotaxisDirectional & 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. Phagocytosis1. 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

5. Phagocytosis3. 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

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 inflammationAccording to organism, host response, and extent of necrosis.

• Resolution• Repair with scarring• Chronic inflammation.

Acute inflammation

Fate of acute inflammation

Acute inflammation

Fate of 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)

MacrophageDerived from: monocytes Modification over monocytes:- Enlargement- lysosymes- Prominent Gologi apparatus & endoplasmic reticulumActivation 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 material3. 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 lymphocyteso 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.

Russell body

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 DelayedDuration Few days Up to many months, or yearsOutcomes Resolution, abscess formation,

chronic inflammation Tissue destruction, fibrosis, necrosis

Wound healing

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 minutesPMNL (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 andmucopolysaccharides 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 corneaHealing Structure

Regenerates at the limbus and spreads rapidly across cornea

Epithelium

Does not regenerate Bowman’s layer

Keratocytes form fibroblasts to heal stromal wounds Stroma

Does not regenerateIs 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 incisionEpidermis:

Epithelialization in 3 steps:

(i) Cell migration

(ii) Cell proliferation

(iii) Cell differentiation

Healing of skin incisionDermis

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 conjunctivaCan form granulation tissue d.t.:

- Vasculature

- Lymphatic system

- RES

Epithelium heals by sliding and proliferation similar to skin or cornea

Healing of irisFibrinolysins in the aqueous inhibit fibrin clot formation,

hence the patency of iris defectsHealing occurs ONLY if the edges of a wound are apposedOr 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 lensEpithelium responds to trauma by fibrous metaplasia

Healing of choroid & CBMelanocytes do not proliferate after traumaGranulation tissue followed by scar tissue forms from fibroblasts

Healing of scleraScars formation

[by fibroblasts from episcleral and uveal tissue]Sclera itself has NO role in healing !!

Healing of retina & optic nerve

GliosisGlial 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 fibrosisExcept if lesion is complicated by hemorrhage or

infection ?As mesodermal elements may produce granulation

tissue & collagen scar

Hypersensitivity

set of undesirable reactions produced

by the normal immune system,

including allergies and autoimmunity.

Type I HypersensitivityThis 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 conjunctivitisMechanism: 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 HypersensitivityThis is an ‘allergic’ reaction that immediately follows contactwith an antigen, which would normally not cause a marked

immune response (an allergen).Examples: Seasonal & perennial allergic conjunctivitisMechanism: 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 hypersensitivity1. 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 release3. 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).

DefinitionsMetaplasia: transformation of one type of tissue intoanother type (e.g. in anterior subcapsular cataract fibrousmetaplasia of the lens epithelium).Cause: chronic irritation Change: columnar or cuboidal epithelium → squamous epithelium.

Dysplasia: abnormal growth of tissue with increasedmitoses and reduced differentiation (e.g. retinal dysplasia).

Dysplastic tissue is NOT invasive and will NOT pass through the basement membrane.

Degeneration and

dystrophy

Definitionso 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 degenerationReplacement 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 degenerationDefective fibroblast function leads to an altered elastic matrix

and reduced elasticityExample: - Skin in ageing individuals- Pterygium - Pseudoxanthoma elasticum [in which ruptures in Bruch’s

membrane expose the choroid (angioid streaks)]

Calcification degenerationCalcium is deposited as hydroxyapatite crystals, which can be metastatic in

hypercalcaemic states or dystrophic in normocalcaemic statesExample:- Band keratopathy [calcification of Bowman’s layer and the superficial stroma] - Cataracta ossea: calcification in the fibrous & degenerativecortex 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 degenerationInsoluble protein deposited in tissue around blood vessels and basement

membranesIn 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 dystrophyo Amyloid from polypeptide hormones in endocrine tumourso Amyloid from prealbumin leads to cerebral deposits in Alzheimer’s diease

Amyolid degenerationSystemic: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 degenerationReversible change

Cells are enlarged, containing cytoplasmic vacuolesExamples:- Infection- Intoxication,- Anaemia or circulatory disturbance

Cloudy swellingReversible change

Cells are enlarged and filled with granules or fluid, representing intracellular oedema

Examples:- Mild Infection- Intoxication,- Anaemia or circulatory disturbance

Fatty changeFat accumulates in cells for unknown reasons or after damage by a

variety of agentsExamples:- 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 infiltrationGlycogen 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

NeoplasiaUncontrolled 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 neoplasia1. Upregulation of proliferation

(excessive or inappropriate oncogene action) Or2. Failure of mechanisms that lead to cell death

(tumour suppressor genes).

A neoplasm may be benign or malignant

جدول

CarcinogenesisNon-lethal genetic damage → damage to a cell → neoplastic change.

Environmental carcinogenesis: 1. Chemical carcinogenesis2. Physical carcinogenesis3. 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 carcinogenesisExamples:1. Benzopyrenes,2. Polycyclic hydrocarbons,3. 2-naphthylamine after liver hydroxylation4. Nitrosamines in gastric carcinoma5. Cyclophosphamide6. Aflatoxins7. Arsenic

2 .Physical carcinogenesis1. Prolonged exposure to ultraviolet rays (sun): skin cancers

e.g. BCC, Sq.CC & melanoma2. Ionizing radiation: leukemia

3 .Microbial carcinogenesisSome viruses are oncogenic

Examples: Epstein–Barr virus → orbital Burkitt’s lymphoma and

intraocular large B-cell lymphoma in the immunosuppressed.

?????????????????????? مين ??• may cause conjunctival papillomas (type 16) or lacrimal• papillomas (type 11)

من شوا .. هابقى ازبطها مع المكتوب• 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

من شوا .. هابقى ازبطها مع المكتوب• 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 cycleControl 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 themost common target for genetic alteration in humantumours. The major functions of p53 in response to DNAdamage are cell cycle arrest and initiation of apoptosis.

Loss of control of apoptosisCell survival is regulated by genes that promote or inhibitapoptosis. 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 fusionbetween the bcl-2 gene and the heavy chain gene. Thisleads to overexpression of bcl-2 protein, enhanced B cellsurvival, and neoplasia. Bcl-2 protects the cell from apoptosisthrough the mitochondrial pathway. The apoptosisrepressor effects are counteracted by the BAX gene family,which induces apoptosis. BCL-2 and BAX can formhomodimers and heterodimers. The ratio of homodimersto heterodimers will determine whether apoptosis occursor not ( Fig. 4.6 ).

Defects in DNA repair

In addition to possible DNA damage from environmentalagents, the DNA of normal dividing cells is susceptible toalterations resulting from errors that occur spontaneouslyduring DNA replication.Genomic instability occurs when both copies of thesegenes are lost; thus they resemble tumour-suppressorgenes.Defects can occur in three types of DNA repair systems:● mismatch repair● nucleotide excision repair● recombination repair.

Pre-neoplastic conditions1.Hamartomas2.Choristomas

1. HamartomasNon-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. Hamartomas2. 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. ChoristomasNon-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)

ThrombosisPlatelet structure.

Platelets are made up of 4 zones:

1. Peripheral:

- Rich in glycoproteins [needed for platelet adhesion and aggregation] سكر يلزق

- 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

4. Membrane: contains the dense tubular system responsible for platelet contractile functions and prostaglandin synthesis.

ThrombosisThrombus formation

ThrombosisFate of thrombus:

1. Detach from the vessel wall forming an embolus2. Lysed by plasmin3. Persist at the vessel wall to form an occlusive thrombus

recanalization can occur through an occlusive thrombus4. Form a mural thrombus covered by smooth muscle cells which then becomes vascularized by blood vessels from the main lumen.

ThrombosisThrombosis 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]

Prevalence of anti-thrombin III deficiency in young patients with venous thrombosis is 0–5%.

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%.

ThrombosisRisk 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 thenumber of platelets or altered platelet function.

Emboli

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

Emboli

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

Atheromatous plaque formation

Atheroma complications1. 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 atherosclerosisReversible or irreversible.

Reversible risk factors: 1. Cigarette smoking2. Hypertension3. Diabetes4. HyperlipidaemiaIrreversible risk factors:Age, male sex, and race

High levels of high-density lipoprotein (HDL) are protective

Additional examples of basic ocular pathology

DefinitionsEndophthalmitis: inflammation of one or more coats ofthe eye and adjacent cavities

Panophthalmitis: is inflammation of all three coats of the eye and can spread to orbital structures.

Mind MapGranulomatous: • 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 ophthalmiaBilateral 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 corneaInflammation also involves the retinal pigment epithelium with accumulation of macrophages, here called Dalen– Fuchs’ nodules.

Time: anytime from 5 days to many years after traumaSymptoms: blurred vision and photophobia in the non-injured eye.

Granulomatous

Phaco-anaphylactic endophthalmitisAutoimmune, 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

Granulomatous

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, andchemical 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-Granulomatous

Non-suppurative uveitis and endophthalmitisThe 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-Granulomatous

Sjogren’s syndromeTypes:1ry2ry : 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.

Autoimmune

Rheumatoid eye diseaseThis 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]*

Autoimmune

Thyroid eye diseaseCan 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: fibrosisSigns: Soft tissue involvement: - Dry eye due to corneal exposure,- Conjunctival chemosis- Superior limbic keratoconjunctivits Eyelid retraction and lid lag Proptosis Compressive optic neuropathy. Squint

Autoimmune

Trauma to eye1. 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

RadiationPhotophthamia:

Corneal epithelium is damagedCause:- Arc- Snow (Snow blindness)

After Pan-retinal photocoagulationReactive proliferation of RPE at the edge of the burn leads to pigmentation around a white scar formed by glial cells

Ionizing radiationIonizing 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

● Radiation retinopathy

Chemical injuryAcid 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.

Corneal dystrophiesلسه 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 tomutations in the transforming growth factor- β -inducedgene ( BIGH1 ) on chromosome 5q31, particularly the dystrophiesinvolving Bowman’s layer and stromal layers.BIGH1 codes for a protein expressed on the cell membraneof corneal epithelium and stromal keratocytes, which aidswith wound healing. Mutations cause abnormal folding forthe proteins and amyloid or non-fi brillar deposits. All areautosomal dominant with complete penetrance.

Corneal endothelial dysfunctionIridocorneal 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 SyndomeVariants of ICE syndrome:

1. Chandler Syndrome: The most common 50% corneal pathology with associated corneal edemamajority 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

Iris Nevus / Cogan-Reese

Bullous keratopathyCorneal 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 cataract دلوقتي تزبطه الزم مش سهلCataract 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.

In addition cataracts vary in their level of maturity:

● Immature: incomplete opacifi cation of the lens.

● Mature: dense, white cataract which obstructs the red

refl ex and fundal view.

● Hypermature: mature cataract ages and leaks water,

causing shrinkage of the lens capsule.

● Morgagnian: cortical lens matter liquefi es, with inferior

displacement of the nucleus in the capsular bag.

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 toblack 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 chaperoneactivity. They bind to unfolded proteins but lack the abilityto refold β γ -crystallins. These changes lead to increased insoluble proteins, amino acid oxidation, increased chromophores, and loss of α A-crystalline andγ 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.

Glaucoma

Primary open-angle glaucomaThe 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.

Primary open-angle glaucoma

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).

Primary open-angle glaucoma

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.

Primary open-angle glaucomaMechanism 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 glaucomaPredisposing factors:

- Old age

- Hypermetrope (small eyes)

- Following blunt trauma, where the angle may already be damaged

Mechanism: Iris bombe

Stages:

-Acute

- Chronic

- Intermittent

- Absolute

Secondary open-angle glaucomaThe 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 glaucomaExample:

● 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

Micro-angiopathy

Diabetic retinopathyIt 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)

Diabetic retinopathyMicroaneurysms: 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.

Diabetic retinopathyMicro-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.

Diabetic retinopathyNeovascularization: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 occlusionMacrovascular occlusion refers to obstruction of

vessels equal to or greater than a medium-sized

arteriole

Hypertensive retinopathy1. 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 occlusionThe 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.

تاني زبط

Retinal detachmentSeparation 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

● blue iris and abnormal skin sun sensitivity

Symptoms: Gradual reduction in central vision.

Retinal damage is limited to the foveomacular area.

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 AMDA 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

metaplasia with deposition of collagen, leading to a discshaped

mass beneath the macular known as disciform

degeneration.

Retinitis pigmentosaInheritance: 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 pigmentosaSymptoms:

• 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 diseaseThis 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 diseaseAR 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 conjunctivaBenign 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 lidsBenign 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 lidsThis 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

Basal cell carcinomas of the lidsShape 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

Basal cell carcinomas of the lids

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.

In the lids they present as a more rapidly growing nodular ulcer or can appear papillomatous with an overlying keratinous horn.

Lymphatic spread can occur to preauricular (upper lids) and

submandibular lymph nodes (lower lids).

Squamous cell carcinomas of the lids

Sq.C.C. Can arise from conjunctiva and cornea:

At lid : BCC ˃ Sq. CCAt conjunctiva: BCC ˂ Sq. CC Yanoff

Squamous cell carcinoma can metastasizeLymphatic spread can occur to:- Preauricular (upper lids)- Submandibular lymph nodes (lower lids).

Squamous cell carcinomas of the 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 tumors

Pleomorphic adenoma of the 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 carcinomaSo, 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

Teratomas of the orbitOrbital 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 melanomaMalignant 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 melanomaShape: 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 melanomasMalignant 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.

Amelanotic melanoma of iris

Iris melanomaGrowth: 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 melanomasGrowth:

• 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.

Ciliary body & choroidal melanomasClassification (according to their cell type) :

• Spindle

• Epitheloid

• Mixed (The majority)

Uveal melanomas

Ciliary body & choroidal melanomasVascular 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

Ciliary body & choroidal melanomasTreatment: 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.

PrognosisUveal

melanomas

Neural tumours

Neurofibromas and schwannomaThese arise from within the orbit. They are normally benign.

Neurofibromas are derived from endoneurium and schwannomas from the Schwann cells surrounding axons.

Neurofibromas and schwannomaHistology 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 gliomaJuvenile 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 nerveCause:

• 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

RetinoblastomaThis 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

● persistent hyperplastic primary vitreous

● endophthalmitis

● toxocara or toxoplasma retinitis.

The tumour arises from embryonic retinal cells and can

be unilateral or bilateral. Macroscopic appearance is of a

smooth-surfaced white mass that can show endophytic

growth into the vitreous or exophytic growth into the subretinal

space. Yellow areas of necrosis or fl ecks of calcifi cation

may be seen ( Fig. 4.13 ).

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 )

● fl eurettes: primitive photoreceptor bodies in a ‘fl eur de

lys’ shape, which are usually found in irradiated tumours.

Prognostic indicators are tumour size, degree of diff erentiation,

choroidal invasion, and optic nerve invasion.

Early diagnosis and modern treatment in the form of

irradiation, chemotherapy, and enucleation give cure rates

of 90%. However, it is important to remember that the

abnormal gene carries a risk of pineal tumour in childhood,

soft tissue and osteogenic sarcoma in early adult life, and

carcinoma in later life.

Myomas and myosarcomasLeiomyoma 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 adnexaOrigin: 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 2rySo, 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

● diff use large B-cell lymphoma—these tend to be aggressive

and can be associated with systemic disease

● primary intraocular lymphoma, which involves the retina,

subretinal space, vitreous, and optic nerve—these are

rare and are normally diff use large B-cell lymphomas

that are associated with primary CNS lymphoma in older

people.

Metastatic tumorsIn adults In children

• Breast• Prostate• Lung• GIT

• Neuroblastoma• Ewing sarcoma• Wilms’ tumour• Rhabdomyosarcoma

Most common origin

Uveal tract Orbit Main site of metastasis