Sehu - Ophthalmic Pathology-2005

Toxocara

This infection results from a common parasitic intestinal roundworm (Toxocara canis) that resides in the dog.

Clinical presentation

Infection by Toxocara larvae is systemic and involves both the lung and liver (visceral larva migrans). The ocular manifestations include:

1 A solitary nodule which resembles a small retinoblastoma. The location may be in the posterior pole or in the periphery.

2Retinal detachment due to an inflammatory reaction in the peripheral retina and resultant vitreous traction.

3Endophthalmitis.

In the past, the globe of an infected child would be

enucleated if the eye was blind and there was a suspicion of a retinoblastoma.

Current diagnosis involves the use of ELISA titres for antitoxocara antibodies in serum or vitreous and may include ultrasonography.

Pathogenesis

Puppies are infected and the organisms are passed in the faeces in a cyst form. Humans are infected by direct ingestion of contaminated food or soil in the case of young children (pica). The cysts dissolve in gastric juice and the larvae (or microfilaria) pass through the intestinal wall into the blood-stream. The organism evades immune recognition by secretion of a surface coat that has the property of changing antigenicity. An inflammatory reaction only occurs when the organism dies.

Possible modes of treatment

The main damage occurs if the organisms are killed. The main therapy therefore is to modulate the inflammatory response in the form of corticosteroids. Antihelminthic therapy (for example thiabendazole) is only indicated in exceptional cases.

Vitrectomy is used for retinal complications such as traction detachment and folds. Surgical removal of a parasitised focus requires retinectomy. Argon photocoagulation is sometimes used if a mobile larva is identified.

Macroscopic

In the past, opportunities to observe Toxocara ocular infections came from enucleations for suspected retinoblastomas.

A fibrogranulomatous mass at the posterior pole can resemble a small endophytic retinoblastoma. A misdiagnosis of a retinoblastoma can also occur when a chronic infective focus at the retinal periphery leads to vitritis and the formation of vitreous traction bands (Figure 8.64). The inflammatory foci within the retina stimulate exudation and retinal detachment (Figure 8.65).

Currently a pathologist may be required to examine a retinectomy specimen for the presence of Toxocara larvae.

Secondary glaucoma can result from chronic inflammation.

Microscopic

When a Toxocara infection simulates a retinoblastoma, a large fibrotic inflammatory mass is located within the retina (Figure 8.66). More commonly, the enucleated eye will contain the following features: necrotic foci in the retinal periphery and detachment of the retina (tractional and exudative). Toxocara larvae are multicellular organisms which appear as rows of nuclei within a cuticle. It may not be possible to identify intact larvae within the microabscess but intact organisms may be observed in the adjacent tissue (Figure 8.67).

Special investigations/stains

Serial sections are required to demonstrate the sparsely distributed larvae. Toxocara antibody labels are also available.

Non-granulomatous uveitis

Pathological studies have so far failed to unravel the many causes of non-granulomatous uveitis. In clinical practice, these are divided according to anatomical location (anterior, intermediate, and posterior) and usually respond well to immunomodulatory therapy.

Rare infections

The reader should be aware that the above descriptions are restricted to the commoner entities encountered in pathological material in Europe. In other continents, a wider variety of fungal and protozoal parasitic infections commonly occur. The ophthalmologist should be aware of the possibility of exotic diseases as a consequence of international travel.

Inflammatory disease - Toxocara canis

inflammatory mass in vitreous

exudative retinal detachment

fibrous traction band on retina

infective focus in retina

Figure 8.64

Inflammatory disease - Toxocara canis

fibrous inflammatory mass penetrating macula

part of toxocaral larval form

Figure 8.66

Figure 8.64 This eye was enucleated for suspicion of retinoblastoma due to the presence of vitreous opacities. A necrotic focus in the retinal periphery in association with tractional bands suggests the diagnosis of Toxocara infection.

Figure 8.65 This archival specimen shows the end stage of a Toxocara infection with a complete retinal detachment and the suggestion of infective foci in the retinal periphery. The histology of this case is shown in Figure 8.67.

Figure 8.66 The first time that Toxocara was identified in the UK as a cause of a pseudo-retinoblastoma was when Professor Norman Ashton studied this case

Accidental and non-accidental trauma is common in ophthalmic practice and is the leading cause of blindness in young adults. Depending on the type of trauma, there may be specific patterns of tissue damage on both clinical and pathological examination.

Healing and repair in ocular tissues

Repair of damage to intraocular tissues often leads to fibrous proliferation within the ocular compartments, fibrous metaplasia in the lens epithelium, and proliferation of glial cells (gliosis) in the retina. The most important basic research on wound healing has been carried out on the cornea and this is described in detail below.

The normal anatomy of the conjunctiva and cornea is described in Chapters 3 and 4 respectively.

Cornea

Epithelium

Normal turnover

In the normal process of “wear and tear”, there is a constant turnover of corneal surface epithelium with complete replacement of the surface epithelium every 7 days. The maintenance of the corneal epithelium depends upon a slow centripetal migration from the basal stem cells located in the corneal limbus. As the cells migrate, cell division occurs with increasing epithelial differentiation from the basal layer.

Trauma

Any form of trauma disrupting the surface of the epithelium will prompt an increase in the rate of migration to re-establish the epithelial surface. Studies have shown that complex cell-signalling interactions exist between the damaged corneal epithelium, the limbal stem cells, and the underlying stroma.

The stem cell source of corneal epithelium is located at the limbus. The limbus also acts as a barrier against conjunctival migration onto the cornea. Exhaustion of limbal stem cell supply through trauma (for example alkali burn, see below) may lead to “conjunctivalisation” in which the surface layer has the appearance of conjunctival epithelium.

Stroma

Normal turnover

The normal corneal stroma is less metabolically active compared with the epithelium – the keratocytes maintain

stromal lamellar collagen and the glycosaminoglycans in the extracellular matrix. Transparency is achieved via a relative state of dehydration of the stroma which is maintained by an intact overlying epithelium via evaporation and active transport of fluid by the endothelial cells.

Summary of corneal stromal healing

1Trauma with apoptosis of keratocytes at wound edges. The proposed signalling is via multiple cytokine pathways (for example Fas-ligand and interleukin 1 (IL-1)) from damaged epithelial cells to underlying keratocytes.

2Replacement of apoptosed keratocytes by proliferation and migration of remaining adjacent keratocytes.

3Metaplasia of stromal keratocytes to myofibroblasts, which in turn restore collagen, glycosaminoglycans, and other matrix constituents. Note that collagen in the normal cornea is principally type I with lesser amounts of types III, V, and VI. Replacement collagen, however, is primarily type III.

4Myofibroblasts also produce hepatocyte growth factor (HGF), keratinocyte growth factors (KGFs), and other cytokines. HGF promotes epithelial hyperplasia.

5Cross linking of collagen reinstates the mechanical strength

of the cornea but only rarely is complete transparency restored.

NB: Bowman’s layer of the corneal stroma is formed in embryogenesis – any disruption or loss of this tissue is an indication of previous corneal damage, including surgery, for example in the case of photorefractive keratectomy (PRK) or penetrating keratoplasty.

Matrix metalloproteinases (MMPs)

MMPs are a group of degradative enzymes that play a very significant role in the healing responses in the corneoscleral envelope. Overactivity of these enzymes is also of great importance in disorders such as rheumatoid eye disease and is responsible for severe collagenolysis. The characteristics of these enzymes are as follows:

1 Degradation of at least one component of the extracellular matrix.

2Each member of the group possesses significant amino acid homology.

3Optimal activity at neutral pH.

4Zinc is a co-factor; calcium ions are required for stability. Hence the terminology “metalloproteinase”.

5They are secreted in an inactive state and activation is achieved by cleavage of a small amino peptide.

6Tissue inhibitors of metalloproteinases (TIMPs) exist within the corneal tissues.

A complex interplay of cytokines and matrix metalloproteinases is present with the main MMPs being:

1Collagenases (for example MMP-1, type I collagenase): cleave collagen types I, II, and III and is sourced mainly from keratocytes. PMNLs also have a similar enzyme (MMP-8).

2Gelatinase: acts on basement membranes and denatured collagen (gelatin, collagen types IV, V, and VII). There are two main subtypes of gelatinases:

(a)Gelatinase A (MMP-2) is produced by keratocytes and is available in large amounts in inactivated form in the cornea.

(b)Gelatinase B (MMP-9) is produced in the corneal epithelium and also in monocytes, stromal keratocytes, and PMNLs acting against gelatin and collagen types IV and V. An inhibitor is produced by the corneal epithelium, and is thought to be involved in the resynthesis of basement membrane in repair.

3Stromelysin (for example MMP-3, type IV collagenase): has broad proteolytic activity (for example fibronectin, proteoglycans, laminin, and type IV collagen of basement membrane).

4Membrane-type MMPs: differ by an additional transmembrane domain and a cytoplasmic tail which

anchors the enzyme to the extracellular side of the cell membrane.

Abnormalities of MMP activity have been implicated in many ocular and systemic diseases. The main ocular disorders are corneal wound healing, pterygium, keratoconus, and glaucoma. Current research is directed toward modification of MMP activity in relation to altering the outcome of the disease processes.

This area of knowledge is rapidly evolving and the interested reader should pursue the latest journals on new developments. The main reference used here was: Wong TL et al. (2002) Matrix metalloproteinases in disease and repair processes of the anterior segment. Surv Ophthalmol 47:239–56.

Endothelium

Normal turnover

The human corneal endothelium has a very limited capacity to divide. Throughout life there is a gradual decline in the total population and depletion is compensated by widening of adjacent endothelial cells.

Trauma

Endothelial cells are delicate and any trauma of sufficient energy (including intraocular surgery) is capable of destroying substantial areas of the monolayer, which are compensated by the spreading of adjacent cells. As these

cells have a limited covering capacity, once a declining limit is reached, corneal decompensation ensues from overhydration of the stroma with resultant opacification (see Chapter 4).

Relevance to laser refractive surgery and differences between photorefractive keratectomy (PRK) and laser-assisted in situ keratomileusis (LASIK)

Keratocyte apoptosis has been shown to occur in the wound interfaces of both PRK and LASIK procedures. It has been theorised that the resultant epithelial hyperplasia (stage 4 of “Summary of corneal stromal healing” above) could be a factor in the regression of refraction being more significant in PRK (being closer to the epithelium) as compared with LASIK, especially in deep stromal ablations. Experimentally, the epithelial hyperplasia in PRK is lessened with transepithelial PRK (without initial scrape) which may disrupt the amount of cytokine induced apoptosis. There is currently much investigation of agents which may decrease the initial apoptotic response.

Trauma

Mechanical

Most types of mechanical trauma are civil.

Terminology

There has been a confusing array of terminologies to describe mechanical injury to the eye (Table 9.1).

Blunt trauma

Closed globe injury

Severe compression of the corneoscleral envelope and elastic rebound leads to disruption of the intraocular contents.

Conjunctival epithelium

Subconjunctival haemorrhages are located within the stroma.

Corneal epithelium

A corneal abrasion usually heals within days. Recurrent erosions are due to epithelial instability and may be followed by separation of the entire epithelium after minor trauma. Treatment is usually conservative with topical lubrication, although further intervention in the form of debridement or anterior stromal puncture may be required.

Anterior segment damage

This can be subdivided into the following types:

1 Iris sphincter/root tear (iridodialysis): may result in hyphaema if a major blood vessel is torn (Figure 9.3, left). Most clinical cases are microor macrohyphaemas (with a visible fluid level) which clear spontaneously. A massive bleed, however, can fill the entire anterior chamber (“8-ball” hyphaema: Figure 9.3, right). There is a high risk of rebleeding after surgical evacuation of the anterior chamber. Fibrosis does not occur in the iris after a tear or a surgical wound because the aqueous contains fibrinolysins.

2Angle recession: refers to a tear forming a cleft in the anterior face of the ciliary body. This predisposes to secondary open angle glaucoma (see Chapter 7).

3Iridocyclodialysis: partial or total separation of the iris and ciliary body from the sclera (Figure 9.4). This has a poor prognosis with a tendency to hypotony and phthisis due to ciliary body shutdown and a reduction in aqueous inflow.

Inflammation – traumatic iridocyclitis

Anterior uveitis is due to release of inflammatory mediators.

Lens subluxation/dislocation

Disruption of the zonular fibres may result in displacement of the lens into the anterior chamber (Figure 9.5) or into the vitreous.

Blunt trauma of sufficient force may also rupture the lens capsule and create a lens induced uveitis secondary to sensitisation of the immune system by lens antigens.

Vitreous haemorrhage

Traumatic rupture/tear of retinal vessels results in bleeding into the vitreous.

Ghost cell glaucoma occurs at a much later stage due to movement of lysed red cells from the vitreous into the anterior chamber and angle (see Chapter 7).

Trauma - Laceration/penetration

full thickness laceration involving cornea and sclera

Figure 9.1

Trauma - Blunt

Iris tear/Hyphaema

blood in vitreous

Figure 9.5

Retina

Commotio retinae describes localised retinal oedema (Figure 9.6) which appears clinically as pale grey swollen areas. Spot haemorrhages are occasionally observed. The condition resolves spontaneously and is only seen by the pathologist in conjunction with more severe injuries.

Retinal tear/dialysis results from oscillations of the vitreous following blunt trauma. The location of the tear occurs where the vitreous is strongly adherent (vitreous base, peripapillary, macula, and over vessels). Rhegmatogenous retinal detachment is the resultant complication. In severe trauma, these tears can extend beyond 90 degrees to form a giant retinal tear (Figure 9.7).

Post-traumatic pseudoretinitis pigmentosa appears as a unilateral pigmentary retinopathy following severe blunt trauma. The aetiology is unknown but is thought to be the result of photoreceptor damage. The clinical and pathological features (Figure 9.8) are indistinguishable from hereditary retinitis pigmentosa (which is a bilateral condition – see Chapter 10).

Choroidal tear

Blunt trauma of sufficient force can cause semicircular tears in the choroid around the optic disc and this exposes the underlying sclera. The retinal pigment epithelium (RPE) proliferates at the edge of the defect (Figure 9.5). A rupture in Bruch’s membrane predisposes to subretinal neovascularisation.

Optic nerve

Traumatic optic neuropathy may result from direct or indirect trauma to the head. Depending on the type of trauma, theories of indirect optic nerve damage range from

avulsion of nutrient vessels to direct transmitted energy to the optic canal. The treatment is variable depending on the institution, and controversial ranging from decompression of the optic canal to high dose systemic steroid therapy.

Avulsion of the optic nerve secondary to severe head injury occurs at the level of the optic foramen.

Miscellaneous

Haemosiderosis bulbi (also found in open globe injuries) occurs after longstanding haemorrhage with breakdown of haemoglobin. Iron salts can be identified in the following tissues: cornea, iris stroma, lens epithelium, ciliary epithelium, and retina. In the retina the metabolic consequences are the most serious due to the toxic effects of iron salts on neurones (Figure 9.9).

Phthisis bulbi occurs from any cause of ciliary body “shut down” resulting in hypotony and a decrease in globe size with shrinkage of the corneoscleral envelope.

Rupture of the corneoscleral envelope

When a blunt impact is extreme, for example by an iron bar, the force is sufficient to burst the corneoscleral envelope.

Most commonly, ruptures occur at the limbus or in the sclera just behind the insertion of the recti muscles where it is thinnest. The sudden hypotony may be followed by massive expulsive choroidal haemorrhage and extrusion of the intraocular contents:

1Limbal: associated with prolapse of anterior uveal tissue and loss of an intact lens or lens matter should the capsule rupture (Figure 9.10).

2Scleral: rupture is complicated by prolapse of uvea, retina, and vitreous (Figure 9.11).

Figure 9.6 At the histological level in commotio retinae, the accumulation of fluid within the substance of the retina creates a folding effect in the outer layers. The inset shows the macroscopic appearance of retinal oedema in a globe after fixation. NFL nerve fibre layer.

Figure 9.7 After severe blunt trauma, a tear in the retinal periphery may extend 360 degrees. In this case, treatment was not carried out immediately and the detached retina collapsed to form a folded mass on the optic disc. The trauma has also resulted in lens subluxation and a tear in the iris. This specimen was photographed after both calottes were removed, hence the background of the container is seen in the vitreous space.

Figure 9.8 The retina may not be detached after blunt trauma but the outer layers may be damaged and become atrophic and gliotic. The retinal pigment epithelium (RPE) proliferates within the retina, particularly around blood vessels, giving macroscopic (top left) and microscopic (top right and bottom) appearances very similar to retinitis pigmentosa. INL inner nuclear layer.

Figure 9.9 Prolonged haemorrhage within the globe leads to deposition of iron salts in the retina. In an H&E section (upper), the iron salts appear dark blue and are most striking around the walls of the blood vessels. This abnormality is best

demonstrated by the Prussian blue reaction (lower). There is also diffuse staining of the retinal tissue but the subretinal exudate is negative (pink staining on H&E).

Figure 9.10 This patient was hit in the eye by a golf club. A rupture is situated at the limbus and is partially blocked by iris tissue, which prevents lens extrusion. The retina is detached by a gelatinous exudate and is prolapsed towards the limbal wound. A similar exudate is present in the anterior chamber and a recent haemorrhage is located in the posterior chamber. The scleral thickening suggests prolonged hypotony prior to enucleation.

Figure 9.11 For comparison with Figure 9.10, this figure shows a rupture in the sclera just behind the insertion of the medial rectus muscle, which emphasises the importance of careful surgical exploration of this area where the sclera is thinnest. The patient was an elderly gentleman who, in an inebriated state, fell onto a wooden clothes horse! The lens and anterior segment tissues are intact, although there is haemorrhage into the ciliary body. The haemorrhagic vitreous is detached from the disc and has prolapsed into the wound. The retina

is detached by a choroidal haemorrhage and a subretinal haemorrhagic exudate.

oedematous areas

Figure 9.6

Trauma - Blunt / Pseudoretinitis pigmentosa

Figure 9.8

conjunctiva

iris

exudate in anterior chamber

rupture at limbus, plugged with iris

retina

prolapsing towards wound

torn detached

retina subluxed cataractous lens

torn iris

H & E

iron impregnation of blood vessels