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  1. 1. Pathology Dr. Ahmed Omara
  2. 2. Inflammation
  3. 3. Inflammation Tissue response to a noxious stimulus. Inflammation is NOT a synonym for infection
  4. 4. 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.
  5. 5. Types of inflammation • Acute inflammation • Chronic inflammation
  6. 6. Acute inflammation B. Cellular phase: formation of cellular exudate - Exudation of blood leucocytes - Activation of tissue histeocytes Immediate response to noxious stimulus 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) 1. Local tissue damage & release of inflammatory mediators 2. The inflammatory response: A. Vascular phase: formation of fluid exudate Vascular  cellular Acute inflammation
  7. 7. Acute inflammation
  8. 8. 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
  9. 9. 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,IL8,PDGF eicosanoids 2. Fibroblast effects • Activates tissue fibroblasts • Increases proliferation • Production of collagen &ECM
  10. 10. Chemical mediators 2. Plasma-derived - Kinins e.g. bradykinin - Complement: C3a & C5a - Clotting system - Fibrinolytic system e.g. plasmin Acute inflammation
  11. 11. 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)
  12. 12. Chemotactic factors [Plasma-derived] Acute inflammation
  13. 13. 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
  14. 14. 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
  15. 15. 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
  16. 16. 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.
  17. 17. Details on Functions of complement (1) Vascular effect: -C3a & C5a induce release of histamine  V.D  ↑ vascular permeability -C5a also activates lipoxygenase pathway ofAA (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
  18. 18. 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
  19. 19. 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
  20. 20. 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.
  21. 21. 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]
  22. 22. 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
  23. 23. 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 Molecular Chemical mediator weight Low prostaglandin E Intermediate C5a and C5 derived peptides High lymphokines partly denatured proteins
  24. 24. Chemotaxis follows a concentration gradient of such factors Acute inflammation
  25. 25. Mechanism of chemotaxis Acute inflammation
  26. 26. Acute inflammation
  27. 27. A. Vascular phase: formation of fluid exudate 1. Transient vaso-constriction [d.t. irritation of vessel wall] 2. Vasodilatation  redness + hotness (flare phenomena) Material Effect Peak effect Histamine V.D. (venules) 5 minutes, Last for 15 minutes Kinin V.D. (Capillaries + venules) 4-24 hours (Produce delayed persistent vascular response) PG E2 V.D. (Arteriole) 3. vascular permeability & formation of exudate 4. Vascular slowing [important step in leucocytes exudation] Leucocytes can NOT leave blood vessels in rapid blood flow! Acute inflammation
  28. 28. 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
  29. 29. 1. Marignation 1. Slowing of blood flow  margination of cells 2. Adhesion (pavementation) of cells to endothelium of vessel wall BOTH neutrophils & endothelium has a –ve charge Receptors on leucocytes & endothelium is responsible for the adhesion: • Selectins • Integrins Acute inflammation
  30. 30. 1. Marignation junctions] Acute inflammation 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 Histamine, thrombin, and leukotrienes induce expression of further selectins on endothelial cells  Stabilising these bonds 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
  31. 31. 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
  32. 32. 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 Opsonisation: process where microbes are chemically modified to be made more "Delicious" for inflammatory phagocytosis. 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
  33. 33. 5. Phagocytosis
  34. 34. 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)
  35. 35. 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
  36. 36. Acute inflammation
  37. 37. 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
  38. 38. 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
  39. 39. Fate of acute inflammation According to organism, host response, and extent of necrosis. • Resolution • Repair with scarring • Chronic inflammation. Acute inflammation
  40. 40. Fate of acute inflammation Acute inflammation
  41. 41. Fate of acute inflammation • Labile cells: Can divide & proliferate throughout post-natal life • Stable cells: Quiescent & may be stimulated to divide • Permanent cells: Proliferate ONL Y during fetal life Acute inflammation
  42. 42. 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). NO vascular phase • Chronic inflammation may start as chronic or result from acute inflammation. • NOT always d.t infection (may be d.t. sutures, wood ….) Chronic inflammation
  43. 43. Chronic phase • Types chronic inflammation: • Specific (e.g. T.B) • Non-specific (may arise from acute inflammation) • Types chronic inflammation: • Granulomatous • Non-granulomatous.
  44. 44. Granulomatous • The characteristic cell type in granulomatous inflammation is the epithelioid or giant cell. • Classic examples: T.B. & sarcoid.
  45. 45. 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)
  46. 46. Macrophage Derived from: monocytes Modification over monocytes: - Enlargement -  lysosymes -Prominent Gologi apparatus & endoplasmic reticulum Activation of macrophage by: - C3b
  47. 47. 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)
  48. 48. 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
  49. 49. 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.
  50. 50. Macrophage & granulomatous inflammation
  51. 51. 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
  52. 52. 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.
  53. 53. Russell body
  54. 54. 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
  55. 55. Wound healing
  56. 56. 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. Limbal wounds have an invasion of PMNL from limbal vessels. These can transform to fibroblasts after 12–24 hours.
  57. 57. 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
  58. 58. Healing of cornea Structure Healing Epithelium Regenerates at the limbus and spreads rapidly across cornea Bowman’s layer Does not regenerate Stroma Keratocytes form fibroblasts to heal stromal wounds Descemet’s membrane Does not regenerate Is elastic and can recoil at the edge of a deficit Endothelium Fills in defects by sliding and therefore deposits secondary layers in Descemet’s
  59. 59. Healing of skin incision Epidermis: Epithelialization in 3 steps: (i) Cell migration (ii) Cell proliferation (iii) Cell differentiation
  60. 60. 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
  61. 61. Healing of conjunctiva Can form granulation tissue d.t.: - Vasculature - Lymphatic system - RES Epithelium heals by sliding and proliferation similar to skin or cornea
  62. 62. 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)
  63. 63. Healing of lens Epithelium responds to trauma by fibrous metaplasia
  64. 64. Healing of choroid & CB Melanocytes do not proliferate after trauma Granulation tissue followed by scar tissue forms from fibroblasts
  65. 65. Healing of sclera Scars formation [by fibroblasts from episcleral and uveal tissue] Sclera itself has NO role in healing !!
  66. 66. 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
  67. 67. y set of undesirable reactions produced by the normal immune system, including Hypersa ell ner sgi ie ts iva in td autoimmunity.
  68. 68. 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
  69. 69. 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.
  70. 70. 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
  71. 71. 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.
  72. 72. 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
  73. 73. 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.
  74. 74. Cells respond in Ce v l a l r u i o l u a s r w a a n y s d t ostress tissue reactions
  75. 75. 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).
  76. 76. 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.
  77. 77. Degeneration and dystrophy
  78. 78. 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.
  79. 79. 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)
  80. 80. 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)]
  81. 81. 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
  82. 82. 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
  83. 83. 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
  84. 84. Mnemonics of corneal dystrophy
  85. 85. Hydropic degeneration Reversible change Cells are enlarged, containing cytoplasmic vacuoles Examples: - Infection - Intoxication, - Anaemia or circulatory disturbance
  86. 86. Cloudy swelling Reversible change Cells are enlarged and filled with granules or fluid, representing intracellular oedema Examples: - Mild Infection - Intoxication, - Anaemia or circulatory disturbance
  87. 87. 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
  88. 88. 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
  89. 89. Neoplasia and preneoplastic conditions
  90. 90. 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
  91. 91. 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).
  92. 92. A neoplasm may be benign or malignant ‫ل‬ ‫و‬ ‫دج‬
  93. 93. Carcinogenesis Environmental carcinogenesis: Non-lethal genetic damage → damage to a cell → neoplastic change. - DNA deletion Genetic damage may be: - DNA mutation - DNA amplification - DNA translocation - DNA insertion which leads to loss or gain in function. 1. Chemical carcinogenesis 2. Physical carcinogenesis 3. Microbial carcinogenesis.
  94. 94. 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
  95. 95. 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
  96. 96. 2. Physical carcinogenesis 1. Prolonged exposure to ultraviolet rays (sun): skin cancers e.g. BCC, Sq.CC & melanoma 2. Ionizing radiation: leukemia
  97. 97. 3. Microbial carcinogenesis Some viruses are oncogenic Examples:  Epstein–Barr virus → orbital Burkitt’s lymphoma and intraocular large B-cell lymphoma in the immunosuppressed. ?? ‫??????????????????????نيم‬ • may cause conjunctival papillomas (type 16) or lacrimal • papillomas (type 11)
  98. 98. ‫بوتكمال‬ ‫عم‬ ‫اهط‬ ‫ب‬ ‫زا‬ ‫ىقبا‬ ‫ه‬ .. ‫اوش‬ ‫نم‬ • 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
  99. 99. ‫بوتكمال‬ ‫عم‬ ‫اهط‬ ‫ب‬ ‫زا‬ ‫ىقبا‬ ‫ه‬ .. ‫اوش‬ ‫نم‬ • Ras oncogens are the most commonly observed oncogenes in human tumors
  100. 100. 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 DNAcan 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 ).
  101. 101. 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
  102. 102. 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
  103. 103. 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.
  104. 104. 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.
  105. 105. 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 ).
  106. 106. 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.
  107. 107. Pre-neoplastic conditions 1. Hamartomas 2. Choristomas
  108. 108. 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.
  109. 109. 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
  110. 110. 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.
  111. 111. Thrombosis, emboli, and atheroma Vascular disorders can be inflammatory (giant cell arteritis) or degenerative (diabetic retinopathy)
  112. 112. Thrombosis Platelet structure. Platelets are made up of 4 zones: 1. Peripheral: - Rich in glycoproteins [needed for platelet adhesion and aggregation] ‫ي‬ ‫ل‬ ‫ز‬ ‫ق‬ ‫ركس‬ - 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
  113. 113. Thrombosis Thrombus formation
  114. 114. 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.
  115. 115. Thrombosis Thrombosis occurs d.t. imbalance
  116. 116.  Protein C [Vitamin-K-dependent serine protease] RPolreo: teS it nr o n Cg l dy ei n fih ci b iei t nscf a yc t io sr s inV ha ea rin td edV I aI I a s.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.  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 Protein S deficiency inheritance is autosomal dominant Role: Co-factor of a Pc t ri v ea vt e ad lep r no ct e ei niC n[ y =oi n ua c nt i gv a t pi o an to iefnfa tc st o irsV a 5–a n 8d %V I .II a ]
  117. 117. 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.
  118. 118. Emboli An embolus is an abnormal mass of matter carried in the bloodstream that is large enough to occlude a vessel
  119. 119. Emboli
  120. 120. 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
  121. 121. 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
  122. 122. Atheromatous plaque formation
  123. 123. 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.
  124. 124. 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
  125. 125. Additional examples of basic ocular pathology
  126. 126. 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.
  127. 127. 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
  128. 128. 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
  129. 129. 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
  130. 130. 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
  131. 131. 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. Granulom atous
  132. 132. 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
  133. 133. 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
  134. 134. 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
  135. 135. Trauma to eye 1. Physical trauma: - Mechanical  Blunt  Penetrating - Radiation - Thermal damage e.g. cryotherapy 2. Chemical trauma
  136. 136. 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
  137. 137. 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
  138. 138. 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
  139. 139. 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.
  140. 140. Corneal dystrophies ‫هسل‬ 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.
  141. 141. 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.
  142. 142. 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.
  143. 143. Essential / Progressive Iris Atrophy
  144. 144. Iris Nevus / Cogan-Reese
  145. 145. 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.
  146. 146. ‫هط‬ ‫ب‬ ‫زت‬ ‫مز‬ ‫ال‬ ‫شم‬ ‫لهس‬ Acquired cataract ‫د‬ ‫ل‬ ‫و‬ ‫ق‬ ‫ت‬ ‫ي‬ 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.
  147. 147. 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.
  148. 148. 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.
  149. 149.   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.
  150. 150. 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.
  151. 151. Glaucoma
  152. 152. 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.
  153. 153. 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 GLC1Agene (chromosome 1 open-angle glaucoma gene) codes for a protein known as TIGR (trabecular meshwork inducible glucocorticoid response) or MYOC (myocillin).
  154. 154. 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.
  155. 155. Primary open-angle glaucoma 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.
  156. 156. 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
  157. 157. 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).
  158. 158. 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.
  159. 159. 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. Retinal microvascular occlusion Diabetic retinopathy
  160. 160. Micro- angiopathy
  161. 161. 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.
  162. 162. Ischemia VEGF Neovessels (Fragile)
  163. 163. Diabetic retinopathy 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.
  164. 164. Diabetic retinopathy 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.
  165. 165. Diabetic retinopathy 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
  166. 166. Retinopathy of prematurity In intrauterine life, blood vessels grow from the disc towards the periphery driven by a relative hypoxia. 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
  167. 167. Retinal macrovascular occlusion Macrovascular occlusion refers to obstruction of vessels equal to or greater than a medium- sized arteriole
  168. 168. 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.
  169. 169. Hypertensive retinopathy “Elshnig spot”
  170. 170. 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)
  171. 171. Central retinal artery occlusion Neovascularization and rubeotic glaucoma are extremely rare in cases of CRAO.
  172. 172. Central retinal vein occlusion The radius of the central vein is smallest in the lamina cribosa  narrowing  turbulence and an increased risk of thrombosis
  173. 173. 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.
  174. 174. Retinal detachment Separation between the neural retina and the retinal pigment epithelium. Causes: 1. Rhegmatogenous RD 2. Exudative RD 3. Tractional RD
  175. 175. Age-related macular degeneration (AMD) Dry age-related macular degeneration Incidence: 90% ofAMD Age: risk  with age and is most common ˃ 70 years Risk factors: ● smoking ● female ● hypertension ● high fat and cholesterol intake
  176. 176. 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 advancedARMD. Soft drusen (larger than 63 μm with ill-defi ned borders) increase in size and number with age and are a risk factor for advancedARMD. ● Geographic atrophy—late stages of dryARMD 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.
  177. 177. Dry AMD Abasal 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 wetARMD. 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
  178. 178. 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 dryARMD. 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
  179. 179. 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.
  180. 180. 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.
  181. 181. Best’s disease This is anAD 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
  182. 182. 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.
  183. 183. 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.
  184. 184. Mind map: Ocular neoplasia ● 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 ● Papillomas of the lids and conjunctiva lacrimal gland ● Adenomas of the lids ● 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.
  185. 185. 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
  186. 186. 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.
  187. 187. 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
  188. 188. Basal cell carcinomas of the lids 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
  189. 189. Basal cell carcinomas of the lids
  190. 190. 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.
  191. 191. Squamous cell carcinomas of the lids 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).
  192. 192. 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
  193. 193. 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 !!
  194. 194. Sebaceous gland carcinomas of the lids Prognosis: Poor d.t. diffuse nature of these tumors. So, Early diagnosis obviously improves this. Subtypes: ● Nodular: lobules of tumour cells with foamy or vacuolated cytoplasm ●Diffuse: individual tumour cells spreading within the surface epithelium (pagetoid) and adnexal structures. These are then graded according to their degree of differentiation
  195. 195. Lacrimal gland tumors
  196. 196. 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
  197. 197. 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
  198. 198. Teratomas of the orbit
  199. 199. 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.
  200. 200. Conjunctival melanoma - De novo . Malignant tumour of melanocyte Origin: “Controversial” - Primary acquired melanosis - Pre-existing naevus 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)
  201. 201. 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.
  202. 202. 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.
  203. 203. Amelanotic melanoma of iris
  204. 204. 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
  205. 205. 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.
  206. 206. Ciliary body & choroidal melanomas Classification (according to their cell type) : • Spindle • Epitheloid • Mixed (The majority) Uveal melanomas
  207. 207. Ciliary body & choroidal 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 MelanA. Uveal melanomas
  208. 208. Ciliary body & choroidal 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.
  209. 209. Prognosis Uveal melanomas
  210. 210. Neural tumours
  211. 211. 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.
  212. 212. 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.
  213. 213. 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.
  214. 214. 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
  215. 215. 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
  216. 216. 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 )
  217. 217. Myomas and myosarcomas Leiomyoma can arise from the smooth muscle of the iris and ciliary body. The malignant form leiomyosarcoma is rare.
  218. 218. 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.
  219. 219. Lymphomas of the ocular adnexa Origin: Conjunctiva, eyelids, lacrimal gland, and orbit. It may be 1ry or 2ry So, full haematological investigations should be done Conjunctival lesions are associated with a lower incidence of systemic disease compared to the orbit (35%), lacrimal gland (40%), or eyelid (67%). ???? ‫؟‬ ‫؟‬ ‫هيا‬ ‫د‬ ‫ص‬ ‫قي‬
  220. 220. 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
  221. 221. Metastatic tumors In children In adults Most common origin • Neuroblastoma • Ewing sarcoma • Wilms’ tumour • Rhabdomyosarcoma • Breast • Prostate • Lung • GIT Main site of metastasis Orbit Uveal tract