Disease Entities

See Part 2 package for further clinically-focussed exploration of the subjects in this chapter.

Sjogren’s syndrome

• Affects the lacrimal gland, accessory lacrimal apparatus (glands of Wolfring and Krause) and salivary glands

• Lymphocytic infiltrate affecting conjunctival, oral and lacrimal acinar glands and loss of conjunctival goblet cells

• Impaired secretion of saliva and tears: dry mouth and eyes
• anti-Rho and anti-La antibodies
• Associated with other connective tissue diseases such as RA

Rheumatoid eye disease

• T-cell and immune complex mediated vasculitis
• Features
• Necrotizing scleritis and scleromalacia perforans
• Peripheral corneal ulceration
• Corneal melt (due to MMP release)
• Macular oedema
• Posterior nodular scleritis (may mimic melanoma)

Behcet’s disease

• Systemic vasculitis
• HLA-B51
• Prevalent in east Asia and the Mediterranean
• Onset in the second to fourth decades
• Triad
• Oral aphthous ulcers (98-99% of patients)
• Genital ulcers (80-87%)
• Ocular disease (70%): panuveitis with hypopyon most commonly
• An aggressive, sudden onset panuveitis

• Non-granulomatous, necrotizing, obliterative vasculitis which can cause posterior segment complications: BRVO, CMO, vitritis, neovascularisation

Sympathetic ophthalmia

• Bilateral granulomatous inflammation of the uvea  (panuveitis) following injury to one eye typically involving uveal incarceration in the sclera

• Sensitisation of ocular antigens leads to uveitis mediated by MHC-class II CD4 T cells
• Uvea is thickened by infiltrate of macrophages

• Small granulomas accumulate in the RPE: Dalen-Fuchs nodules (small discrete yellowish infiltrates in the RPE)

Giant cell arteritis

• Local dendritic cells recruit and activate CD4 T cells

• These direct the activity of activated macrophages, giant cells, smooth muscle cells (vascular remodelling)

• Inflammatory infiltrate
• Macrophages and multinucleated giant cells
• Lymphocytes
• Plasma cells
• Giant cells near the fragmented internal elastic lamina
• Fibrin thrombus obstructs vessel lumen

• No antibodies have been detected in GCA

Granulomatosis with polyangiitis (aka Wegener’s)

• Granulomatous inflammation and necrosis
• Ocular manifestations
• Scleritis
• Corneoscleral ulceration
• Orbital mass

• c-ANCA (antineutrophil, anticytoplasmic antibody) positive in >90% of patients with generalised Wegener’s

Thyroid eye disease

• Immune-mediated condition of orbital fibroblasts with increased insulin-like growth factor 1 receptors

• TSH receptor antibodies (TRAbs) cross react with orbital fibroblast antigens resulting in inflammatory activation

• Anti-thyroid peroxidase (anti-TPO) and anti-thyroglobulin may also be detected
• Hashimoto’s thyroiditis has a weaker association with eye disease
• There is an extraocular muscle perivascular lymphocytic infiltration
• If untreated, the muscles eventually fibrose

• Extracellular matrix proliferation: accumulation of glycosaminoglycans
• Replacement fibrosis between muscle fibres
• Sight-threatening complications
• Dysthyroid optic neuropathy
• Corneal exposure (keratopathy)
• Adequate control of thyroid function can reduce the severity of the thyroid eye disease.

Homocystinuria

• Reduction in levels of cystathione beta-synthetase affecting methionine (amino acid)
• Autosomal recessive
• Features

• Thromboembolic risk: especially prone to these with general anaesthesia

• Inferonasal lens dislocation (cp Marfans): metabolic abnormality of the zonules with a thick band of PAS-positive material of the surface of the ciliary processes and pars plana.

• Myopia
• Glaucoma
• Optic atrophy
• Marfanoid habitus
• Management: high dose vitamin B6 (pyridoxine) and a low methionine diet

Cystinosis

• Autosomal recessive
• Forms: infantile (most common), adolescent, adult
• Abnormal membrane transport of cystine: accumulation of cystine crystals in multi-systems
• Ocular manifestations

• Cystine crystals in the cornea, retina, choroid, RPE (causing patchy depigmentation), retina, conjunctiva 

• Bi-refringent crystals
• Associated with severe renal impairment due to nephrotic syndrome and dwarfism
• Management: cysteamine, a cystine-depleting drug can be given orally and topically

Aging and degeneration

• Hyalinization: replacement of normal cells by an acellular, collagenous/glycoprotein matrix

• Fatty: eg. corneal arcus senilis.
• Plasma lipids leak from blood vessels and are deposited in the corneal stroma

• Xanthelasma are a feature of macrophages containing lipids collecting in the eyelid dermis

• Elastic fibre degeneration: associated with sun exposure.

• Macular degeneration: the scarring in disciform macular degeneration is due to fibrous metaplasia of RPE cells leading to collagen deposition

• This follows choroidal neovascular leakage and haemorrhage
• Associated with polymorphisms in the complement factor H gene

• The age-related eye disease study (AREDS) found that zinc, beta-carotene, vitamins C and E reduced the progression of AMD

• Latterly, lutein, zeaxanthin, B vitamins and omega-3 were found to reduce progression

Calcification

• Metastatic calcification (occurs in hypercalcaemia)
• Band keratopathy: calcium (and urate) deposited in Bowman’s layer
• Managed with ETDA (ethylenediaminetetraacetic acid) which chelates calcium
• Epithelium should be removed to expose calcium in Bowman’s layer
• Dystrophic calcification (occurs in damaged or degenerating tissues)
• Phthisis bulbi

Amyloid

• Insoluble fibrillar glycoprotein deposited around blood vessels and basement membranes as an extracellular eosinophilic hyaline material

• Stains pink (eosin) with H&E and is ‘apple’ green birefringent when examined under polarized light with Congo red

• Systemic

• Associated with monoclonal plasma cell proliferation eg myeloma, Waldenstrom’s macroglobulinaemia. Light-chain derived (AL)

• Associated with chronic inflammation eg RA. acute-phase reactant derived (serum AA protein)

• Derived from polypeptide hormones in thyroid carcinoma
• Derived from prealbumin in Alzheimer’s
• Familial Mediterranean fever 
• Localised
• Deposition in endocrine tumours
• Deposition in organs and joints of the elderly including in Alzheimers
• Component of drusen in AMD
• Deposited in the cornea in lattice dystrophy
• Ocular involving forms
• Mutations in transthyretin (TTR) gene
• Includes familial amyloid polyneuropathy types I and II

• Ocular manifestations: bilateral vitreous opacification (‘glass-wool’ appearance) with retinal haemorrhages, exudates, CWS, neovascularization, increased IOP

• Mutations in keratoepithelin (TGFBI) gene

• Includes corneal dystrophies associated with different mutations in TGFBI: Reis-Bucklers, Thiel-Behnke, granular dystrophy, lattice corneal dystrophy type 1, Avellino dystrophy

• Considered ‘primary localised amyloidosis’
• Mutations in gelsolin (GSN) gene
• Gelsolin type lattice dystrophy or Meretoja’s syndrome

• Systemic manifestations of amyloidosis: masked facies, dermatochalasis, lagophthalmos, dry skin, cranial/peripheral neuropathies

Microvascular changes

• Cotton wool spots: microinfarctions cause swollen axonal endings

• Hard exudates: underperfusion damages vascular endothelium leading to plasma leakage into the outer plexiform layer

• These are eosinophilic masses containing foamy macrophages

• Microaneurysms: pericyte necrosis secondary to ischaemia leads to weakening of the capillary wall and bulges

• Gradually are filled by basement membrane deposits and can disappear from FFA imaging
• Haemorrhage: red cell leakage can have numerous appearances
• Flame haemorrhages: arteriole rupture with blood in the nerve fibre layer
• Dot haemorrhages: capillary rupture within the outer plexiform layer
• Blot haemorrhages: capillary bleeding between the photoreceptors and RPE

• Neovascularisation: growth from the venous side of the capillary bed in response to ischaemia and leak on FFA

• Vaso-active factors diffuse through the vitreous, PC and AC to induce rubeosis iridis and neovascular glaucoma.

Diabetic retinopathy

• Loss of pericytes (contractile cells around capillaries)
• Thickening of the capillary basement membrane

• Degeneration of capillary endothelial cells and breakdown of the inner blood-retinal barrier with leakage

• Exudates
• Microaneurysms 

• Inner nuclear and outer plexiform layers are initially affected and then oedema spreads to create a cystoid appearance

• Cotton wool spots: nerve fibre ischaemia

• IRMA: irregular segmental growth and dilation of vessels from the venous end of the circulation into areas of retinal ischaemia

• Hyalinzation of vessels

Mucous membrane pemphigoid

• Autoimmune response against basement membrane components
• Linear deposition of IgG and C3
• Fibrinous scarring and symblepharon of lids
• Diagnosis: immunofluorescence