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)

Vasculitis

Vasculitis
Large vessel	Takayasu’s arteritisGiant cell arteritis
Medium vessel	Polyarteritis nodosaKawasaki disease
Small vessel	Wegener’sChurg-StraussHenoch-Schonlein purpura

## 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

Retinal arterioles are NOT affected as they do not possess an elastic layer. The CRA, ophthalmic artery and cerebral arteries may be affected

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

On MRI, there is uniform swelling of the extraocular muscles and the tendons are spared. Orbital fat density is hyperdense compared to normal patients.

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

Erdheim-Chester disease is a rare systemic disease associated with xanthelasma and lipoid granulomas elsewhere

Elastic fibre degeneration: associated with sun exposure.

Pinguecula and pterygium represent elastic material deposition within the conjunctiva leading to bulbar nodules (pinguecula) and at the limbus (pterygium) which can encroach on the cornea

Thickening and hyalinization of the conjunctival stroma with deposition of degenerating elastin
Pterygium is most common within the interpalpebral fissure

Basophils predominate (basophilic degeneration)
Absent cystic spaces
Stromal elastosis
Fibroblastic proliferation
Stocker’s line: a line of iron at the advancing edge
Destroys Bowman’s layer as it advances over the cornea, leading to scarring
Conjunctival autografts and topical MMC can be used

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

Systemic associations with uveitis

Uveitis
Idiopathic	37%
Seronegative arthropathies	21%
Juvenile idiopathic arthritis	10%
Herpes virus	9%
Sarcoidosis	6%
SLE	3%

## Mucous membrane pemphigoid

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