Sehu - Ophthalmic Pathology-2005

Microscopic

At the earliest stages, focal granulomatous cellular infiltration occurs on the surface of the exposed lens matter (Figure 8.36). There may be evidence of rupture of the lens capsule. A zonal distribution of inflammatory cells is often evident. Neutrophils line the lens matter and are surrounded by macrophages (epithelioid and multinucleate giant cells), lymphocytes, and plasma cells (Figure 8.37). Eosinophils may also be identified – these cells are thought to be a critical component of anaphylaxis, hence the usage of the term “phacoanaphylaxis”. The capsule is also

eroded by inflammatory cells once the reaction is established (Figure 8.38).

The most vigorous reaction is encountered when the lens matter comes to rest against the ciliary body or is adherent to the iris. The iris often contains a dense lymphoplasmacytoid infiltrate.

Any reaction in the choroid should raise the suspicion of concomitant sympathetic ophthalmitis. Care should be taken to exclude the presence of a bacterial endophthalmitis by using a Gram stain.

retina

*

iris

ciliary body

granulomatous inflammatory reaction

Inflammatory disease - Lens induced uveitis

Phacoanaphylactic endophthalmitis

Figure 8.36

lens capsule

macrophages

giant cell

eosinophils lymphocytes

Inflammatory disease - Lens induced uveitis

Phacoanaphylactic endophthalmitis

Inflammatory disease - Lens induced uveitis Phacoanaphylactic endophthalmitis

lens fibres

neutrophils

epithelioid

macrophages

giant cells

chronic inflammatory cells

Figure 8.37

Figure 8.36 A granulomatous mass fuses the exposed lens matter to the iris and ciliary body epithelium. The inflammatory cells have cleaved a space between the capsule and lens matter. The iris stroma contains an inflammatory cell infiltrate. The angle is open and is filled by a hyphaema. The area marked with an asterix is magnified and shown in Figure 8.37.

Figure 8.37 The magnified area (marked with an asterix in Figure 8.36) shows erosion of lens matter by a giant cell granulomatous reaction consisting of epithelioid macrophages, neutrophils, and lymphocytes.

Figure 8.38 As a rarity, the lens capsule is consumed by the giant cell granulomatous process. In this example, the infiltrate contains eosinophils, hence the adoption of the term “phacoanaphylactic endophthalmitis”.

Scleritis

Destruction of the corneoscleral envelope by a granulomatous or non-granulomatous inflammatory process is the primary abnormality. The corneal manifestations are described in Chapter 4. A milder form of the disease, episcleritis, should be differentiated from anterior scleritis as the aetiology and management differ.

Scleritis is an idiopathic autoimmune disease either confined to the eye or associated with systemic disease. The most common association is rheumatoid disease, but the following conditions should be considered in the differential diagnosis:

•Wegener’s granulomatosis

•relapsing polychondritis

•polyarteritis nodosa

•inflammatory bowel disease (Crohn’s disease)

•sarcoidosis

•systemic lupus erythematosus

•ankylosing spondylitis

•Reiter’s syndrome

•psoriatic arthritis.

Scleritis is subgrouped to the following categories which

are very different both clinically and pathologically:

1Anterior scleritis: which may be non-necrotising (diffuse or nodular) or necrotising (with or without inflammation). Scleromalacia perforans is a rare non-inflammatory variant of the latter and is a specific painless necrotising condition in untreated rheumatoid disease (see below).

2Posterior scleritis: located behind the equator of the eye (brawny scleritis).

Clinical presentation

Scleritis is more common in females and is often bilateral. The onset of this condition is gradual and the main symptom is often a severe ocular ache along with visual loss.

1Anterior scleritis: the affected areas may be translucent revealing the underlying purplish choroid. Staphylomas may develop over previously necrotic areas. The cornea may be affected with sclerokeratitis and marginal keratolysis (see Chapter 4). It is common to find a concomitant anterior uveitis. It is important to emphasise that surgical interventions in the anterior segment (for example trabeculectomy, an intraocular procedure, and penetrating keratoplasty) may all be complicated by scleritis.

2Posterior scleritis: the diagnosis presents many more difficulties than anterior scleritis. The patient may be asymptomatic, although pain and visual disturbance are still common. The sclera is usually thickened by inflammation resulting in exudative retinal and choroidal detachments, chorioretinal inflammation, and disc swelling. The severe thickening of the sclera and retro-ocular tissue can produce a proptosis. Ultrasound or CT imaging is required to confirm the thickened sclera.

With the high visual morbidity and mortality in many of the associated systemic conditions, it is common to have a protocol of investigations that would help to differentiate the many possible causes of scleritis.

Pathogenesis

The pathogenesis is commonly thought to be secondary to the formation of antigen–antibody complexes resulting in a vasculitis. In some cases of posterior scleritis, T cells have also been implicated in the inflammatory reaction.

Genetics

Genetics may have relevance depending on any underlying systemic disease.

Possible modes of treatment

Systemic non-steroidal anti-inflammatory medications, corticosteroids, and immunosuppressive therapy may be required. Topical steroids may be used to treat the anterior uveitis. Reinforcement of a weakened sclera may occasionally require patch grafting with sclera or fascia lata.

Macroscopic and microscopic

It is very rare to receive a scleral or corneal biopsy to confirm a scleritis due to the risk of perforation or stimulation of the disease process. Enucleations are performed for intractable symptoms, irretrievable damage after perforation, in misdiagnosis of malignancy, and for cosmesis.

1 Anterior scleritis: at a macroscopic level, the necrotic sclera has a creamy yellow appearance (Figure 8.39). On section, the normal white condensed scleral tissue is replaced by partially pigmented granular tissue (Figure 8.40). Corneoscleral collagenolysis with a predominant lymphocytic infiltrate is characteristic; giant cell granulomatous reactions are inconspicuous (Figures 8.41, 8.42). A dense lymphocytic infiltration may replace the normal sclera (Figure 8.43).

2Posterior scleritis: in contrast with the anterior variant, the progress of posterior scleritis is much more chronic

and the inflammatory cell infiltration is accompanied by massive reactionary fibrosis (Figure 8.44). When the process is diffuse, the term brawny scleritis is appropriate (Figures 8.45, 8.46).

The fibrous reaction can be so extreme that an episcleral mass causes a proptosis (Figures 8.47, 8.48). The mass may also extend into the globe and may simulate an intraocular melanoma (Figure 8.49).

Complications/secondary effects

Severe inflammation can result in scleral thinning with staphyloma formation as well as perforation. Bacterial superinfection may result.

normal sclera

macrophages

giant cell

CHOROIDAL SIDE

Figure 8.42

Figure 8.41 Anterior scleritis is characterised by a dense lymphocytic reaction in the region of the scleral disruption and destruction. It is frequently difficult to demonstrate giant cells and macrophages in such cases.

Figure 8.42 In some cases of scleritis, a granulomatous reaction with epithelioid macrophages and multinucleate giant cells can be demonstrated. Leakage of fibrin into the necrotic sclera gives the tissue a brick-red appearance.

Inflammatory disease - Necrotising scleritis

open angle

pupillary membrane

mild disc oedema

necrotising scleritis

(scleromalacia perforans)

closed angle

oedematous folds in retina

thickened sclera

thickened sclera

exudative

retinal detachment

shallow anterior

chamber

Inflammatory disease - Posterior scleritis

Figure 8.47

Inflammatory disease - Early posterior scleritis

Figure 8.44

Inflammatory disease - Posterior scleritis

optic nerve

Alizarin stain

Figure 8.46

Figure 8.43 A patient suffering from rheumatoid arthritis had intractable pain due to extensive anterior necrotising scleritis with imminent perforation. Enucleation was the only option available. Note the dense cellular infiltrate in the pars plana region with severe scleral thinning. Ocular hypotonia has resulted in retinal and optic disc oedema.

Figure 8.44 In the early stage of posterior scleritis, there is a lymphocytic infiltration within the sclera and this is accompanied by a fibrovascular proliferation in the episclera. Lymphocytic infiltration in the choroid interferes with the integrity of the choriocapillaris and retinal pigment epithelium, and the release of proteinaceous fluid detaches the retina. Note the involvement of the meninges.

Figure 8.45 The macroscopic appearance of posterior scleritis. The posterior sclera and episclera are diffusedly thickened. Involvement of the choroid has led to exudation in the retina which is thrown into folds. The vitreous is semiopaque and is detached posteriorly. The cataractous lens is unusually white – see Figure 8.46.

Figure 8.46 A low power photomicrograph of the specimen shown in Figure 8.45 reveals the extent of inflammatory cell infiltration in the choroid,

sclera, and episclera. The white macroscopic appearance of the lens is due to calcification. The inset is stained to demonstrate the presence of calcium in the lens (alizarin is a red stain which chelates calcium).

Figure 8.47 A patient presented with a proptosis. In this more advanced case, the fibrous proliferation extends internally into the globe and the secondary complications are exudative detachment and haemorrhage in the retina. Enucleation of such a deformed globe can be difficult, and in this case the surgeon did not excise the anterior part of the optic nerve with the globe.

episcleral mass

subretinal haemorrhage due to close excision

of optic nerve

optic canal

Inflammatory disease - Posterior scleritis

Figure 8.48

Figure 8.48 A section of the same globe illustrated in Figure 8.47 shows that there is massive inflammation and fibrosis throughout the posterior sclera. The haemorrhage around the optic nerve is a surgical artefact.

Inflammatory disease - Posterior scleritis simulating a melanoma Exenteration

extraocular muscle

Figure 8.49 The patient presented with a proptosis which appeared to be due to an intraocular mass with extension into the orbit. A diagnosis of an amelanotic melanoma with extraocular extension was made. The possibility of posterior scleritis was excluded as the changes were so localised and the remainder of the ocular tissues appeared normal. An exenteration was performed in view of the possibility of extraocular spread into the orbit.

Vogt–Koyanagi–Harada (VKH) syndrome

A systemic granulomatous condition characterised by bilateral panophthalmitis of unknown aetiology. It is more common in pigmented races and was formerly divided into two different groups according to systemic findings:

1Vogt–Koyanagi:

•skin: alopecia, poliosis, and vitiligo

•anterior uveitis.

2Harada:

•neurological: headache, encephalopathy, inner and middle ear symptoms (deafness, tinnitus, and vertigo), cerebrospinal fluid pleocytosis

•posterior uveitis: in conjunction with disc swelling and exudative retinal detachments.

VKH is now commonly thought of as being one condition with a wide spectrum of presentations, although bilateral ocular involvement occurs in every case.

Clinical presentation

Ophthalmic findings will depend on the stage of the disease:

1Prodromal stage: flu-like illness. Eye signs are non-specific with visual disturbance, photophobia, ocular pain, and conjunctivitis.

2Uveitic phase: bilateral uveitis, disc swelling, and exudative retinal detachment.

3Chronic phase: fundus depigmentation, subretinal and optic disc neovascularisation.

Investigations are extensive to exclude other causes. Fluorescein angiography demonstrates multiple retinal pigment epithelium (RPE) window defects.

An important differential diagnosis is sympathetic ophthalmitis and a history of penetrating trauma should be sought.

Pathogenesis

An autoimmune granulomatous reaction against melanocytes, melanin, and retinal pigment epithelium. A viral agent has been suggested although not proven.

Genetics

Females are more commonly affected. There is an association with HLA DR4.

Possible modes of treatment

Principles involve high dose systemic corticosteroids with a long tapering off period. Immunosuppressants may also be used.

Macroscopic and microscopic

The appearances within a globe are indistinguishable from sympathetic ophthalmitis (see above).

Immunohistochemistry

The infiltrating lymphocytes are of T-cell type (suppressorcytotoxic subsets).

Behçet’s syndrome

A systemic vasculitic condition that manifests itself in the eye as a panuveitis. It is most common in Japan and Turkey.

Clinical presentation

Diagnostic criteria is recurrent oral ulceration with any two of the following:

1Eye lesions: anterior and posterior uveitis.

2Recurrent genital ulcerations.

3Skin lesions: for example erythema nodosum.

4Positive pathergy test.

Pathogenesis and genetics

The aetiology is unknown. The geographical distribution of the disease follows that of the “silk road”. Association with HLA-B51 for ocular involvement is recognised.

Possible modes of treatment

Despite treatment, visual prognosis is poor with progression to blindness within 4 years of disease onset.

Macroscopic and microscopic

By the time enucleation is required, secondary pathology obscures the nature of the primary disorder.

Retinal haemorrhage, exudation, and detachment are the result of retinal vasculitis. The uveal tract is thickened by a non-granulomatous lymphocytic infiltrate with a prominent CD4 T-cell population.

Chorioretinitis

Many infective organisms can lead to chorioretinitis. As a rule of thumb, a viral infection results in a diffuse necrotising retinitis, while parasitic and fungal infections are focal (see section on microbiology under “Stains for microscopy” in Chapter 1).

Viral: herpes simplex virus (HSV), herpes zoster virus (HZV), and cytomegalovirus (CMV)

The clinical patterns of disease in viral infections vary and have become of great importance due to the increase in

incidence of AIDS and immunosuppression therapy. Thus it is convenient to consider viral retinitis in terms of the patient’s immune status.

Immunocompetent

Acute retinal necrosis (ARN)

In HSV and HZV infections, there is a unilateral necrotising retinitis, initially patchy and subsequently becoming confluent, accompanied by a non-granulomatous choroiditis – this is classified as acute retinal necrosis (ARN). Severe vitritis, vasculitis, and papillitis are important features of this condition. The emphasis for prompt antiviral treatment is to avoid bilateral involvement (BARN).

Macroscopic and microscopic

The likely specimen submitted to the pathologist would be an enucleation for end-stage ARN (Figure 8.50). Microscopic examination reveals total retinal infarction, vitreous exudation, and infiltration by inflammatory cells (Figure 8.51). A retinal biopsy may be taken at the earlier stages of the disease and it is possible to demonstrate intranuclear inclusions formed by proliferating herpes simplex viral particles (Figure 8.52). The ultrastructural characteristics of HSV are identical to those of CMV and consist of a central core surrounded by a capsid (Figure 8.53).

Inflammatory disease - ARN

sub-hyaloid space

inflammatory cells in vitreous

surviving RPE and

photoreceptors

Figure 8.51

Figure 8.51 In the higher power view of the area marked with an asterix in Figure 8.50, there is total destruction of the retinal cells which appear as smudgy pink structures. Some of the cells in the outer nuclear layer have survived (in contrast with progressive outer retinal necrosis). The vitreous is detached by a proteinaceous exudate and the vitreous gel contains an inflammatory cell infiltrate which would be minimal in an immunocompromised patient.

Figure 8.52 In the early stages of infection, herpes virus can be identified by intranuclear inclusions within the retinal pigment epithelium cells and macrophages. Compared with cytomegalovirus (CMV) inclusions, the parent cell in a herpetic infection is much smaller and similar in size to a macrophage. Degeneration and fragmentation is present in the photoreceptor layer. The choroid contains a dense lymphoplasmacytoid infiltrate and the choriocapillaris is obliterated.

Figure 8.53 This electron micrograph illustrates the architecture of viral particles within a retinal cell infected with herpes simplex virus (HSV). Note that the viral morphology is identical in HSV and CMV infections. The viral particles vary in appearance because replication requires migration into the cell nucleus for the formation of viral DNA. The envelope is derived from the nuclear membrane.

Herpes zoster ophthalmicus (HZO)

HZO involving the fifth cranial nerve (shingles) can cause a mild neuritis in the ciliary nerves and a non-granulomatous nodular choroiditis (Figure 8.54) which is evident on fundoscopy.

Immunocompromised

The hallmark feature of viral retinitis in the immunocompromised patient (for example when CD4 T cells are reduced below 50 cells/mm3 in peripheral blood) is an absence of the inflammatory response, particularly in the vitreous. It is important to note that it is not always possible to reliably differentiate clinically between the infections caused by herpes simplex virus (HSV), herpes zoster virus (HZV), cytomegalovirus (CMV), and toxoplasmosis. Simultaneous infections may also occur. Thus, it is important in biopsies to perform PCR for the entire herpes family to achieve a precise diagnosis, because the treatments can vary.

Cytomegaloviral (CMV) retinitis

Small areas of retinal necrosis increasing in size, with or without haemorrhage, in any region of the retina are characteristic (Figure 8.55). As the infection progresses, the retina becomes thickened and linear perivascular infiltrates extend laterally from the vessel (frosted branch angiitis – Figure 8.56). Untreated, the condition is progressively destructive to the whole retina resulting in blindness with the further complication of retinal detachment.

Destruction of the neurones in the retina by the virus leaves a relatively thin strand of tissue containing inflammatory cells and scattered surviving neurones (Figure 8.57). Extremely large infected cells, diagnostic for CMV infection, may contain obvious viral inclusion bodies within the nuclei (Figure 8.58).

Progressive outer retinal necrosis (PORN)

This is the result of HSV/HZV retinitis in the absence of an active immune response. The lack of vitritis, vasculitis, and papillitis are important differentiating features from ARN.

The condition is characterised by extensive destruction of the outer retina (compared with ARN), which can be located in any region of the fundus. The clinical appearance is characteristic: it begins with a blanching of the fundus which later progresses to extensive destruction of the outer retina. The histological features are similar to ARN, but the destruction of the outer retina predominates. There is also relative sparing of the retina adjacent to retinal vessels.

Human immunodeficiency virus (HIV)

Infection by HIV alters the immune system by selective destruction of the CD4 helper and inducer cells with an increased incidence of secondary infections apart from those described above. An awareness of the complexities which occur in the management of AIDS patients will be apparent from the following list of ocular opportunistic infections and malignancies (refer to relevant chapters):

•Toxoplasma gondii (see below)

•fungal chorioretinitis (Histoplasma capsulatum, Coccidioides immitis, Pneumocystis carinii, Candida sp.)

•endogenous bacterial endophthalmitis (Mycobacterium intracellulare and M. avium)

•molluscum contagiosum

•Kaposi’s sarcoma

•lymphomas.

NB: HIV causes a specific microvasculopathy which is manifest in early cases as retinal microinfarcts due to viral parasitisation of vascular endothelial cells.

Parasites

Toxoplasma

Toxoplasma gondii is the commonest protozoal parasite to infect the eye. This organism is neurotrophic and infection is limited to the neural retina and the brain. Whereas it was previously thought that toxoplasma retinochoroiditis was due to reactivation of congenital infections, there is growing evidence for acquired disease.

Clinical presentation

Congenital In this category, acute infection of the mother during pregnancy proceeds to transplacental infection of the fetus. If infection occurs during the first trimester, stillbirth usually results. The fetus can survive a later infection but often the triad of convulsions, cerebral calcifications, and chorioretinitis are clinical manifestations after birth. With this potential outcome, mothers who have toxoplasma chorioretinitis during pregnancy may choose to have an elective termination of pregnancy.

Reactivation or acquired infection in adulthood The patient presents with reduced vision and floaters. Examination reveals a moderate to severe vitritis with underlying single or multiple patches of necrotising retinitis. A pre-existing chorioretinal scar is evident in cases of reactivation of infection – “headlight in the fog” appearance. Satellite lesions are common. The parasitisation is usually situated in the inner retina leading to retinal oedema.

The surrounding inflammation may be severe enough to affect other regions producing choroiditis, scleritis, and anterior uveitis of differing severity.

Pathogenesis: life cycle of Toxoplasma gondii

The cat is the definitive host in which the organism undergoes sexual reproduction (Figure 8.59). Oocysts are passed in cat faeces which may be directly ingested by domestic animals. Human infection occurs either from direct ingestion of oocysts in contaminated soil or from uncooked meat of infected animals. The organism can exist in a free form (trophozoites) or an encysted form (bradyzoites). Parasitisation within neural cells provides protection from the immune system. Multiplication within intermediate hosts is by asexual reproduction.

Possible modes of treatment

Infections are usually self limiting and treatment is conservative. The indications for treatment are:

1Sight threatening: involving macula, papillomacular bundle, and optic disc.

2Vasculitis: overlying a major retinal vessel.

3Persistence: more than a month.

4Severity: severe vitritis leading to significant visual loss.

5Immunosuppression.

Treatment involves multiple drug combinations:

1Folic acid antagonists – sulfadiazine and pyrimethamine: the Toxoplasma organism has an inability to transport folate which is an essential component for DNA synthesis, and antagonists inhibit synthesis in the active trophozoite. Folinic acid supplement is added to prevent patient folate deficiency.

2Clindamycin, azithromycin, and atavaquone: although many of these agents are found to have cysticidal properties in vitro, recurrence of infection has been known to occur following treatment.

3Corticosteroids: introduced systemically at a later stage to modulate the inflammation and secondary damage.

4Other treatment modalities: these include argon laser ablation, cryotherapy, and vitrectomy.

The difficulty in management lies in the treatment resis-

tance of the parasite when it is in an encysted form.

Macroscopic

Acute Most cases of acute disease are observed in autopsy material obtained from aborted fetuses or stillborn infants.

Chronic or healed Sites of previous infection may be observed as an unrelated finding in an enucleated eye (Figure 8.60). This has the appearance of an irregular white chorioretinal scar with clumps of pigmentation usually in the periphery.

The associated uveitis may lead to secondary glaucoma.

Microscopic

Acute In the centre of the infected sector in the retina, there is a thickened strip of hypocellular pink-staining tissue. Adjacent to this, there is a more cellular zone containing inflammatory cells. The adjacent recognisable retina is thickened by oedema and contains a scattered infiltrate of inflammatory cells – lymphoplasmacytoid cells and macrophages (Figure 8.61). Bradyzoite cysts are most commonly identified at the edge of the surviving retina: freeform trophozoites are identified less easily (Figure 8.62). The complex morphology of Toxoplasma gondii is best appreciated at the ultrastructural level (Figure 8.63).

Chronic A healed scar consists of a thin strip of gliotic retina separated by clumps of retinal pigment epithelium from a fibrotic choroid.

Immunohistochemistry

Labelled antitoxoplasma antibodies identify the organisms (Figure 8.62). PCR may also be used.

Inflammation - Toxoplasmosis

Life cycle

vertical transmission of tachyzoites

through placenta

Figure 8.61

Inflammatory disease - Toxoplasma gondii

Transmission electron microscopy

organisms cut in

longitudinal section organisms cut in transverse section

Figure 8.63

Inflammatory disease - Adult toxoplasmosis

Healed chorioretinal scar

proliferation of retinal pigment epithelium

chorioretinal scar

optic disc

Figure 8.60

Inflammatory disease -

Toxoplasma gondii

free forms

(trophozoites)_ encysted organisms (bradyzoites)

encysted organisms (bradyzoites)

Figure 8.62

Figure 8.59 Diagram to show the lifecycle of Toxoplasma gondii. (Courtesy of Dr Fiona Roberts.)

Figure 8.60 This globe was enucleated for angle closure glaucoma secondary to recurrent anterior uveitis. A typical chorioretinal scar is identified in the midperiphery. It was not possible to histologically identify Toxoplasma cysts in the retina adjacent to the scar, and this is often the case in healed disease.

Figure 8.61 An eye from a stillborn infant was found to contain an area of acute retinal necrosis associated with dense choroiditis. Toxoplasma cysts are found at the edge of the necrotic area outlined by a box. An exudative retinal detachment is evident.

Figure 8.62 Identification of Toxoplasma organisms requires the high magnification of an oil immersion lens. Free forms or trophozoites (top left) are identified by a basophilic spot within an elongated eosinophilic tail. Most commonly the organisms are identified within cystic structures containing blue or purple dots (bradyzoites – top right and bottom left). The organisms can also be identified with antitoxoplasma antibody immunolabel (bottom right).

Figure 8.63 Electron microscopy demonstrates the complex structure of

Toxoplasma organisms within a retinal cyst. The organisms are cut in different planes.