1. Non-neoplastic globe pathology

2. Case 1

3. White mass in vitreous

4. THIS MASS IN THE VITREOUS CAVITY IS COMPOSED OF WALL-TO-WALL NEUTROPHILS

5. Gram + (dark blue) cocci.

6. Endogenous bacterial endophthalmitis

7. Endophthalmitis Inflammation of one or more coats of the eye and adjacent intraocular spaces. Infectious (exogenous or endogenous) and non-infectious (lens induced, foreign body)

8. Infective endophthalmitis Causes after surgery: Gram + bacteria:Staphs, streps, corynebacterium, propionibacterium Gram- bacteria: pseudomonas, proteus, haemophilus, klebsiella, E-coli, enterobacter. Fungi: Aspergillus, candida, penicillium Causes of endogenous endophthalmitis Fungi: Candida and Aspergillus Bacteria: Neisseria meningitidis, streptococcus, staphs, bacillus cereus, nocardia

9. Case 2

10. History Male adult Leukaemia On chemo. Brain abscess Dies Total body biopsy (Autopsy). Eyes examined by ophthalmic pathologist.

11. Retina in reasonable good shape

12. Full thickness necrosis of neural retina, featuring a homogeneous eosinophilic appearance with loss of cell details and ghost outlines of cells. Very little inflammation.

13. Cysts containing bradyzoites (multiple black dots in pink cysts)

15. TOXOPLASMOSIS Unicellular protozoal parasite. Definitive host is CAT Intermediate hosts: humans, rodents, fowl.

16. Toxoplasmosis Parasite invades retinal cells directly Focal retinitis with an overlying vitritis In this case presented with ARN (well recognised).

18. Toxoplasmosis Years later-reactivation can occur in areas of scars Congenital and acquired forms Congenital form-associated with encephalomyelitis, hepatosplenomegaly and retino-choroiditis

19. Histology of Toxoplasmosis Protozoa in 3 forms Free trophozoite-lives in intracellular vacuole. Free trophozoite-lives in intracellular vacuole. Pseudocyst form-many protozoa enclosed by retinal cell membrane. Pseudocyst form-many protozoa enclosed by retinal cell membrane. Bradyzoite surrounded by self-made membrane-becomes cyst and can be extruded from retinal cells. Cyst forms when environment hostile. Cyst can remain latent. Bradyzoite surrounded by self-made membrane-becomes cyst and can be extruded from retinal cells. Cyst forms when environment hostile. Cyst can remain latent.

20. Case 3 Red eye Patient just arrived from South- East Asia

22. Thickened iris Exudate in AC

24. Granulomatous inflammation

25. Pink, acid fast bacilli, stained with Ziehl-Neelsen stain. Other ways of detecting TB-Culture, PCR.

26. TB UVEITIS

27. TB AND THE EYE Direct innoculation, contiguous or blood- borne. Lids, conj, orbit, cornea, episclera and sclera, retina, optic nerve all involved. Cornea-immune mediated reaction (interstitial keratitis). Choroid vulnerable-rich blood supply

28. NON-INFECTIVE INFLAMMTION

29. 1

31. Non-caseating naked granulomas, in retina

33. SARCOID AND EYE IdiopathicAfro-caribbeans 30 % ocular involvement Uvea, retina, lacrimal gland Anterior uveitis, pars planitis, retinal periphlebitis Nodules on lids, conj, band keratopathy Non-necrotising granulomatous inflammation + fibrosis later on. Naked granulomas. Can undergo necrosis Diagnosis of exclusion.

34. 3

37. Iris expanded

38. Higher power shows diffuse population of small lymphocytes Mostly T cells (CD 3+).

39. UVEITIS EXOGENOUS-POST TRAUMA ENDOGENOUS-IDIOPATHIC and those with specific causes: Anterior (iritis), intermediate (cyclitis), posterior (choroiditis) Associations-juvenile RhA, ank spond (HLA B27) Reiter’s, uc, enteritis (salmonella, shigella, yersinnia), psoriatic, behcet’s Fuch’s uveitis syndrome, VKH. Causes-sarcoid, tb, leprosy, syphilis, parasites, fungi (candida, coccidio, histo, blasto), HSV, VZV, EBV,

40. Complications of uveitis Cornea-endothelial cell loss-BK, band keratopathy AC-scar formation-iris obliteration Iris-atrophy, necrosis, loss of muscle, PAS, rubeosis, ectropion uveae, immobile pupil, iris bombe Lens-posterior cataract secondary to lens epithelial migration.

41. Complications of uveitis Ciliary body-atrophy, cyclitic membrane Vitreous-vascularisation, condensation, PVD Choroid-atrophy, scarring, chorioretinal scar. Retina-perivasculitis, cmo, exudative detachment, rpe alterations. Glaucoma-clogging due to cells, PAS, pupil block, bombe, trabeculitis

42. 4

45. Diffuse chronic inflammation of sclera-brawny type

47. Chronic inflammatory cells

49. Palisaded granulomatous Inflammation of sclera with collagen degeneration (necrobiosis). This is seen in nodular variant scleritis Often see this pattern of inflammation in connective tissue disorder assoc. scleritis

50. Granulomatous inflammation again

51. SCLERITIS Diffuse chronic inflammation in diffuse form, Or : granulomatous inflammation with collagen degeneration (necrobiosis) in nodular form.

52. SCLERITIS Anterior-diffuse, nodular and necrotising with inflammation (brawny), necrotising without inflammation (scleromalacia perforans) Posterior-30% associated with systemic vasculitides, CTDs (rheumatoid, SLE, PAN, Wegener’s, relapsing polychondritis etc etc), lymphoma.

53. Complications of scleritis KeratitisCataractUveitisGlaucoma Perforation of sclera Retinal detachment

54. 5

55. Granulomatous (non-caseating) inflammation of uvea (choroid in this case), sparing the choriocapillaries Choriocapillaris intact

57. Dalen-Fuch’s nodule-sub RPE granuloma (arrow).

59. Reaction to uveal melanocytes….(current thinking) Histological differential: INFECTION, SARCOID,VKH

60. DIFFERENTIAL INFECTION, SARCOID,VKH

61. 6

62. DIABETES AND THE EYE Should be very familiar with this topic.

63. Pathogenesis Irreversible non-enzymatic glycation of proteins occurs, for example: of matrix proteins (platelet activator inhibitor -1); this affects cell migration/activation of calcium channels in pericytes (  responsiveness to endothelin-1-induced contractility) and thereby affecting function apoptosis has been linked to hyperglycemia and retinal pericyte death hyperglycemic states deplete intracellular glutathione (defense against peroxidation) hyperglycemic environments trigger upregulation of bax (apoptosis activator) and downregulation of bcl-2 (apoptosis inhibitor) eventually causing capillary pericyte and capillary endothelial cell death -glycosylated hemoglobin levels correspond to increased risk of retinopathy -growth factors that are considered to have a role in PDR include VEGF, Insulin like- GF I, Fibroblast GF; chemical mediators include IL-8 and interferon induced protein VEGF is associated with endothelial cell hypertrophy and capillary lumen obliteration -evidence of an intra-ocular rennin-angiotensin system with  vitreous pro-rennin in diabetic patients; intra-ocular angiotensin-II synthesis is elevated and may have a role in NVI in DR -abnormal platelets, abnormal red cell deformability (micro-displacement), altered leucocyte deformability and altered blood viscosity contribute to retinal vessel occlusion and ischemia -plasma lipids are associated with hard exudates -growth hormone is thought to support development and progression of DR

65. Lacey vacuolation of iris pigment epithelium-due to accumulation of glycogen-present in 40% of enucleated eyes from diabetics- DIABETIC IRIDOPATHY

66. Pink glycogen deposits, with PAS stain

67. Ectropion uveae, secondary to rubeosis

68. New vessels on anterior stromal surface

69. Normal pars plicata

70. Grossly thickened basement membrane of pars plicata

71. Normal retinal arteriole

72. Arteriolosclerosis-note thick wall-called hyalinisation. Hyalinisation due to accumulation of lipid and fibrin, from leaky vessel, due to pericyte death

73. Exudative maculopathy-pink exudate between RPE and fovea

74. Hard exudates-protein rich eosinophilic material settles in outer plexiform layer because this is watershed zone between retina’s 2 blood supplies. Therefore cannot drain away easily.

75. Hard exudates composed of lipid containing foamy macrophages

76. Ovoid eosinophilic bodies of varying size in optic fibre layer

77. Pink bodies in optic fibre layer-cotton wool spots or cytoid bodies. Indicate ischaemia and composed of swollen axons from disturbed axoplasmic flow-packed full of organelles.

78. Chronic ischaemia of retina. Note loss of inner 2/3 rd architecture (RGCs, INL, IPL), and replaced by gliosis-pink stuff. ONL remains with outer photoreceptor segments. gliosis

79. Proliferative diabetic retinopathy Note new-vessels, surrounded Fibrous tissue on retinal surface.

80. PRP SCAR

81. PRP SCAR-loss of RPE and choriocapillaris Retinochoroidal atrophy Retinal gliosis Gliotic retina in direct apposition to Bruch’s Loss of choriocapillaris Bruch’s Gliotic retina Loss of RPE

82. 7

83. Occluded branch venule. Note inflammation around vessel -attempts at organisation of thrombus

84. Perl’s stain picks up haemosiderin Stains it intense blue. This indicates previous intra-retinal haemorrhage from BRVO

85. CRVO/BRVO

86. 8

87. Hard druse. Pink, homogeneous nodular material Lies between RPE basement membrane and inner collagenous part of Bruch’s. Note overlying RPE arophy

88. Drusen Made up of: Alpha 1 antitrypsin Alzheiner amyloid beta protein Amyloid p protein Apolipoproteins B and E Cholesterol esters Clusterin Complement factors Complement receptor 1 Factor 10 Heparan sulfate proteoglycan HLA DR Immunoglubulins MHC class 2 antigens Peroxidized lipids Phospholipids TIMP-3 Transthyretin Ubiquitin vitronectin

89. Fluffier, more diffuse, soft drusen Thickened Bruch’s

90. Thick Bruch’s, hard drusen and complete loss of photoreceptors

91. Haemorrhage of CNVM. CNVM lies between neural retina And RPE Eventual organisation of haemorrhage Will lead to disciform scar. CNVM RPE choroid RETINA

92. CNVM Vessel of CNVM RPE choroid

93. ARMD dry and wet

94. ARMD…. Commonest cause of legal blindness in developed world. Elderly Caucasian Hallmarks=drusen, RPE atrophy, CNV

95. Pathogenesis ? Defects in RPE-Bruch’s-choriocapillaris complex Collection of heterogeneous disorders associated with multiple genetic and environmental factors

96. ARMD pathogenesis ? Bruch’s accumulates lipids, non-collagenous proteins, extracellular matrix + collagen and elastin changes. This occurs with aging. Then…second phase…accumulation of basal linear deposit (between RPE cell and its basement membrane) and basal laminar deposit (between RPE basement membrane and inner collagen layer of Bruch’s membrane). Lipofuscin accumulates in RPE. Resultant increase in thickness of Bruch’s and impaired molecular transport through Bruch’s and RPE……photoreceptor cell death…..AMD.

97. Drusen=sign of sick RPE. Thickening of Bruch’s thought to lead to metabolic changes and hypoxia. This is a stimulus for angiogenic factor release from RPE cells. Basal laminar deposits associated with neovascularisation. Choroidal neovascularisation leads to-exudative AMD- haemorrhage-disciform scarring

98. Some AMD facts Wet and dry forms Risk factors: age (older), sex (women?), race (white caucasian),light exposure (controversial), cardiovascular (atheroma), diet (lipids, AREDS study-zinc and anti-oxidants), smoking+ Complement factor H gene strongly associated with AMD (up to 50% of cases). Single nucleotide polymorphism (Tyr402-His). Thought to lead to inappropriate inflammatory response of which drusen is a product. Leads to death of RPE and photoreceptors.