Ординатура / Офтальмология / Английские материалы / Ocular Disease Mechanisms and Management_Levin, Albert_2010

Figure 82.3  Image of scleral hyaline plaque. They may be calcified or without calcification. They are of no pathological significance. (Reproduced with permission from Watson P et al (eds) Sclera and Systemic Disorders, 2nd edn. Butterworth and Heinemann, 2004.)

Treatment of infectious scleritis is directed at the underlying cause. Steroid should be avoided in the initial stage of therapy of a possible infection. In herpes zoster, the treatment of choice is aciclovir or valaciclovir acutely and this may be continued prophylactically.

Drugs used in scleritis

Nonimmunosuppressive drugs

Nonsteroidal anti-inflammatory drugs can be very effective therapy with full resolution of symptoms in about one-third of patients with scleritis.15

Immunosuppressives used in scleritis

Corticosteroids

•  Oral corticosteroids are highly effective at suppressing inflammation in the short term. Severe inflammation can be treated with 1 mg/kg at the outset with a subsequent tapering regimen. If chronic therapy with corticosteroids is required, a steroid-sparing agent should be considered.

•  Subconjunctival steroid depot may be successful for noninfectious cases of anterior, nonnecrotizing scleritis.16 This route should be chosen with caution due to a risk of inducing scleral necrosis.

Cyclophosphamide is an alkylating drug and is a potent immunosuppressant with a side-effect profile which includes a risk of malignancy, hemorrhagic cystitis, and neutropenia. It is the treatment of choice for scleritis associated with systemic vasculitides, such as Wegener’s granulomatosis or polyarteritis nodosa. It can also be used when scleritis is refractory to other forms of therapy.

Methotrexate, mycophenolate mofetil, and ciclosporin have been used successfully to treat scleritis.17-19

Biologic therapy for scleritis

Inhibitors of tumor necrosis factor-α (TNF-α) are increasingly used in the treatment of uveitis, although they have been less well studied in scleritis. Three agents are used in clinical practice: infliximab, humira, and etanercept. Etanercept is not as effective as others in treating eye disease.20 Small series and case reports demonstrate some success with infliximab in scleritis with and without associated systemic disease.21

Rituximab is a genetically engineered, chimeric, murine/ human monoclonal IgG1 antibody directed against the CD20 antigen found on the surface of pre-B and mature B cells. Rituximab has been shown to be successful in the treatment of ANCA-positive vasculitides and preliminary success has been reported in the treatment of scleritis.22

Prognosis

A diagnosis of necrotizing scleritis carries a 60% chance of developing ocular or systemic complications and up to 30% of patients have a loss in visual acuity.10,23

Studies of rheumatoid arthritis show that development of necrotizing scleritis, as well as other extra-articular manifestations, has been associated with reduced life expectancy and poor prognosis. The explanation is most likely to be that presence of extra-articular complications of rheumatoid arthritis reflects a more severe disease, and may accompany complications of therapy and other comorbidities such as cardiovascular health.24,25

Newer data suggest that the subset of patients who are either pANCAor cANCA-positive have a more aggressive course with increased risk of visual loss and ocular complications. They are also more likely to require immunosuppressive therapy.26

Complications of scleritis

About 60% of patients with scleritis develop complications10,23:

•  Roughly 15–30% of patients with scleritis develop visual loss.

•  Visual loss is more strongly associated with systemic disease.

•  Anterior uveitis occurs in approximately one-third of cases.

•  Peripheral ulcerative keratitis (PUK) occurs in up to 15% (Figure 82.5).

•  Cataract occurs in about 15% of cases.

•  Some fundus abnormalities are present in 6% overall.

Posterior-segment complications tend to be associated with posterior scleritis. Exudative retinal detachments may cause visual loss. Cystoid macular edema may occur in posterior scleritis but rarely does so in necrotizing anterior scleritis. Vitritis rarely occurs in scleritis.5

Glaucoma occurs in roughly 9–13% of cases of scleritis.23,27 Raised intraocular pressure or glaucoma may be an acute presenting feature of anterior scleritis due to raised episcleral pressure reducing aqueous outflow or it may complicate scleritis chronically. In posterior scleritis, a large serous retinal detachment can be rarely complicated by angle closure glaucoma due to anterior displacement and rotation of the ciliary body.28

arteritis nodosa, and systemic lupus erythematosus.27,31 Approximately one-fourth of cases have an undiagnosed systemic disease at the time of presentation. The main differential diagnosis for PUK is microbial keratitis. The workup is otherwise identical to that for scleritis. Treatment is usually high-dose steroids and immunosuppression.

PUK can progress to a corneal melt syndrome where the stroma becomes involved, and ultimately corneal perforation. It may be painless in rheumatoid arthritis.

Etiology

Corneal complications of scleritis29 (Box 82.4)

Some corneal change has been found in 29% of patients with scleritis.

Corneal change in scleritis is described broadly as sclerokeratitis. Two main types of sclerokeratitis occur, infiltrative or destructive, and these are summarized in Table 82.6. Visual loss may occur when the optical axis is obscured by opacities or when destructive changes occur.

The presence of corneal thinning in sclerokeratitis is a sign of destruction of the cornea and frequently represents venoocclusive disease. Early detection of destructive keratitis in scleritis is important as some types can be rapidly visually threatening and may cause corneal perforation. Sometimes, peripheral corneal thinning or Terriens-like change can occur with little inflammation.

The presence of infiltrates in the cornea does not usually signify destructive vaso-occlusive disease.

Peripheral ulcerative keratitis

This is a visually threatening clinical presentation of a sclerokeratitis (Figure 82.5). It is very rare and has an estimated incidence of 3 per 1 million people per year.10,27,30 The systemic diseases associated with PUK include rheumatoid arthritis (34–42%), ANCA-associated vasculitides, poly­

Disease associations in scleritis

•  50% of patients with scleritis have an underlying systemic disease (Table 82.7).8

•  5–10% of these cases are associated with infection.

Figure 82.4  Dendritic cells in the peripheral cornea (cells labeled with fluorescent marker). (Courtesy of Dr. Ellen Lee, Casey Eye Institute.)

Figure 82.5  Peripheral ulcerative keratitis. Fluorescein stains the area of keratitis in this image.

Box 82.5  Special features of rheumatoid scleritis

Rheumatoid arthritis-associated scleritis is frequently bilateral and tends to appear after symptoms of rheumatoid arthritis have become established. The majority of cases of scleritis occur in the presence of seropositive rheumatoid arthritis with subcutaneous nodules (Box 82.5).32

The vasculitides constitute 7% of all scleritis cases.23 Although any vasculitis can cause a scleritis, Wegener’s granulomatosis is the most common. The majority of patients with a systemic etiology will present with symptoms of systemic disease that precede onset of scleritis, but vasculitis is frequently an exception to this rule.

Relapsing polychondritis is a rare disease which can present at any age. The hallmark of the disease is inflammation of cartilaginous structures such as the pinna of the ear, the cartilage of the nose, and the tracheal cartilage.

Inflammatory bowel disease is a relatively common group of systemic illnesses. A minority of patients with inflammatory bowel disease may present with ocular manifestations preceding systemic onset.33 Usually the patient will have symptoms of active bowel disease on history.

Systemic lupus erythematosus is a systemic autoimmune disease. It has a number of other ocular manifestations, including keratoconjuctivitis sicca and retinopathy, especially in the form of cottonwool spots.

Etiology

Table 82.7  Etiology of scleritis (where there is no frequency noted, the condition is rare and there are no representative data regarding frequency of occurrence)

*Associated with surgery/trauma.

†Usually associated with contact lens keratitis.

Rare associations with scleritis include Takayasu’s arteritis, cryoglobulinemic vasculitis (associated with hepatitis C), Churg–Strauss syndrome, giant cell arteritis, and Cogan’s disease, all of which are vasculitides. Behçet’s is another rare cause.

Other causes of scleritis

Infectious scleritis

Many infections can cause scleritis but varicella-zoster causing herpes zoster ophthalmicus is most common. Scleritis is a feature in 8% of cases of herpes zoster ophthalmicus.34,35

An infectious cause of scleritis should be suspected in cases that occur after trauma or surgery. Other features of bacterial or fungal infections in the sclera are an indolent course of scleral destruction and abscess formation or suppuration.

In bacterial or fungal cases (suppurative), surgical debridement as well as antimicrobial therapy is sometimes required as the penetration of systemic antimicrobials into the sclera is poor.

Surgically induced necrotizing scleritis (SINS)

SINS usually arises within 9 months of surgery but it can be activated long after.

Common precipitants of SINS are pterygial surgery, trabeculectomy, and cataract surgery. In rare cases treatment with an anti TNF-α agent (infliximab) has been used to control the necrotizing process but generally systemic steroids are adequate.36

Trauma/other injury

Trauma and chemical injury can cause a localized scleritis. Control of the inflammatory response is indicated for symptom relief and prevention of complications. Treatment is with an oral nonsteroidal anti-inflammatory or with oral/ topical corticosteroids.

Drug-induced scleritis

Two agents which have been described as causing scleritis are:

•  Mitomycin C, usually in glaucoma or pterygium surgery37

•  Bisphosphonates (Box 82.6).

The bisphosphonates are potent inhibitors of osteoclasts used in the prevention and treatment of osteoporosis.They cause scleritis, but so rarely that they can still be prescribed safely in people with ocular inflammatory disease.

Malignancy

Occasionally primary intraocular tumors and secondary tumors can precipitate an acute inflammatory scleritis.

Box 82.6  Episcleritis and Bisphosphonates

•  Episcleritis due to bisphosphonates does not require cessation of the drug. It can be treated with nonsteroidal antiinflammatories. In scleritis associated with bisphosphonates, the drug may have to be discontinued

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Sometimes a malignant deposit such as lymphomatous infiltration or a metastatic deposit such as that from squamous carcinoma can mimic a scleritis. Melanoma is the most reported intraocular malignancy associated with scleritis.38,39

Genetics

There is no recognized inheritance pattern for scleritis and most cases present de novo or in the context of systemic disease. There is no strong association with human leukocyte antigens (HLA) in scleritis.40,41

Pathology

Scleral structure

Scleral anatomy

The sclera forms the fibrous coat of the eye and has a white, opaque appearance due to the dense, irregular arrangement of collagen fibrils. The sclera provides a tough housing for intraocular contents and maintains the shape of the eye. The sclera comes to an end anteriorly where it attaches to the limbus of the cornea. Posteriorly the sclera fuses with the sheath of the optic nerve.

Types I, III, V, and VI collagen are present in sclera. Type I is found in the highest proportion. Elastic fibers constitute a small part of the fibrillar scaffold of the scleral substance. Collagen and elastic fibers confer mechanical properties, including viscoelasticity and limited distension of the sclera. The extracellular matrix of the sclera also consists of proteoglycan.

Episcleral anatomy

The episclera is a thin, highly vascular tissue which consists of a uniform arrangement of collagen bundles which are attached tightly to blood vessels. The episclera blends with the stroma of the sclera which lies underneath it.

Blood supply to the sclera and episclera

The sclera is relatively avascular and there is no direct blood supply to the scleral stroma. Blood vessels and nerves pass

Table 82.8  Cases of scleritis and episcleritis attributed to bisphosphonates reported until 2008 worldwide

No data at time of writing in 2008 for zolendronate, etidronate, tiludronate, or clodronate.

Sources: World Health Organization adverse drug events database. World Health Organization Uppsala Monitoring Center, Uppsala, Sweden. Data with kind permission of National Registry of Drug-Induced Ocular Side Effects, USA.

Figure 82.6  Blood supply to the sclera and episclera. (Modified from Watson P et al (eds) Sclera and Systemic Disorders, 2nd edn. Butterworth and Heinemann, 2004.)

through the sclera, including the long and short posterior ciliary arteries, their associated nerves, and the vortex veins. The sclera derives its nutrition from choroidal and episcleral vascular networks.42

There are three main vascular layers of the episclera. It is the deeper plexus that is involved in scleritis.1

1.Conjunctival plexus: the most superficial plexus of fine vessels movable over underlying structures.

2.Superficial episcleral plexus: a radially arranged plexus lying in the episcleral tissues.

3.Deep episcleral plexus: a network which penetrates the sclera.

Nerve supply

The severe pain in scleritis may be explained by the fact that its sensory nerve supply is very rich. Pain arises due to direct stimulation of nerve roots or by distension of the scleral tissue when scleral edema occurs.

The sensory nerve supply arises from the branches of the nasociliary branch of the trigeminal nerve. The nerve supply to the anterior sclera is from the long posterior ciliary nerves and the posterior sclera is supplied from the short ciliary nerves.

Histopathology

It is widely accepted that noninfectious scleritis is an immune-mediated disease (Figure 82.4). In support of this, highly magnified dynamic images using intravital microscopy show the presence of numerous leukocytes involved in rolling and arresting in the endothelium of active scleritis43 (Figure 82.7).

Scleritis has been histopathologically divided into necrotizing and nonnecrotizing types of inflammation (Table 82.8). The necrotizing type has been further classified into three main groups, summarized in Table 82.3. There is an additional fourth group which consists of patients with sarcoidosis.

Pathophysiology

Figure 82.7  Leukocyte movement in scleral vessels. Large numbers of rolling and arrested leukocytes are evident along the wall of the vessels. (Image taken with Heidelberg confocal laser microscope; HRTII, Heidelberg Engineering, Heidelberg, Germany.) (Reproduced with permission from Lim LL, Hoang L, Wong T et al. Intravital microscopy of leukocyte-endothelial dynamics using the Heidelberg confocal laser microscope in scleritis and allergic conjunctivitis. Mol Vis 2006;12:1302–1305.)

1.Necrotizing scleritis consists of rheumatoid and rheumatoid-like necrotizing scleritis, including systemic vasculitides or connective tissue diseases.44

2.Postinfection scleral inflammation.

3.Idiopathic necrotizing scleral inflammation.

Pathophysiology

The pathophysiology of scleritis is incompletely understood and there are probably diverse mechanisms depending on the etiology of the scleritis. In autoimmune diseases, immune complexes circulate and can deposit in and around episcleral vessels, inciting an immune response. In many cases, however, there is no immune complex deposition and scleritis is thought to be T-cell-driven. Patients respond to different types of therapy, suggesting that differential response to treatment can further classify patients.

Immune response in scleritis

Understanding the pathogenesis of scleritis is daunting because: (1) the disease is relatively rare; (2) biopsy is rarely obtained; (3) the disease is clinically diverse; and (4) there are no ideal animal models. Much remains to be done to clarify the pathophysiology.

Role of T cells in scleritis

In studies of nodular scleritis the cellular infiltrate seems to be composed of macrophages, CD4+ T cells, and CD8+

Figure 82.8  Scleromalacia perforans. (Reproduced with permission from Watson P et al (eds) Sclera and Systemic Disorders, 2nd edn. Butterworth and Heinemann, 2004.)

T cells, indicating a dominant T-cell-mediated immune response.

The infiltrate in necrotizing scleritis has been reported to consist predominantly of CD4+ T cells, a mixture of plasma cells, some CD20-positive B cells and macrophages (Table 82.9). Unlike nonnecrotizing forms, in necrotizing scleritis activated macrophages organize themselves into granulomas. The T-cell infiltrate is often perivascular but has also been inconsistently seen within the vessel, supporting the theory that there is a vasculitic process underlying the pathogenesis.40,41

Recently a newly described Th17 subset of CD4+ T cells and its secreted product, the cytokine interleukin (IL)-17, have been localized to the eye in active scleritis and uveitis of humans.45 Antibodies to IL-17 also dampen inflammation of experimental autoimmune uveoretinitis (EAU). The Th17 subset has been recognized to play a role in diverse autoimmune diseases.46,47

Role of TNF-α

TNF-α is a potent cytokine which has a central role in the inflammation of chronic autoimmune diseases. TNF-α has been localized to tissue specimens of necrotizing scleritis.48,49 Blockade of TNF-α using infliximab, a humanized mouse,

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chimeric monoclonal antibody in patients with scleritis, both idiopathic and associated with underlying systemic disease, has proved very effective clinically.21

Role of B cells and autoantibodies in autoimmune scleritis

Scleritis has traditionally been considered a T-cell disease but there is probably a greater role for the B cell in the pathogenesis of scleritis than conventionally understood. There is also some evidence for a role for ANCA antibodies in mediating vasculitis.21,50 A heavy infiltrate of B cells may be seen in autoimmune scleritis.51 In autoimmune vasculitis, for example Wegener’s granulomatosis, the B cell has become a promising treatment target.52 There have also been early reports of the utility of rituximab, a potent B-cell-depleting agent, in scleritis.

Role of matrix metalloproteinases

Matrix metalloproteinases (MMPs) are important in normal connective tissue turnover, wound healing, and angiogenesis. There is overproduction of MMP-9, stromelysin and, to a lesser extent, tissue inhibitor of metalloproteinases-1 (TIMP-1) in biopsy specimens of necrotizing scleritis.48,53 MMPs degrade collagen and other extracellular matrix components. An imbalance of the local TIMP:MMP ratio results in scleral destruction.

Conclusion

Scleritis is a rare but serious and potentially vision-threaten- ing condition with a variety of ocular manifestations. The strong association with systemic disease means that the ophthalmologist needs to have an understanding of systemic disease, prognostic factors, and natural history in order to determine the diagnosis effectively and institute therapy. The prognosis for scleritis is good, with a wide range of immunosuppressives available for therapy.

The pathogenesis of scleritis is complex with multiple components of the immune response implicated in the evolution of scleritis. Advances in understanding of the immunology of autoimmune disease are also enabling us to understand ocular inflammation better. This increased knowledge is directly translated into clinical practice, as seen in the development of new, exciting therapies for scleritis.

1.Watson PG, Hayreh SS, Awdry PN. Episcleritis and scleritis. I. Br J Ophthalmol 1968;52:278–279.

5.McCluskey PJ, Watson PG, Lightman S, et al. Posterior scleritis: clinical features, systemic associations, and outcome in a large series of patients. Ophthalmology 1999;106:2380–2386.

7.Lin P, Bhullar SS, Tessler HH, et al. Immunologic markers as potential predictors of systemic autoimmune disease in patients with idiopathic scleritis. Am J Ophthalmol 2008;145:463–471.

8.Watson PG. The diagnosis and management of scleritis. Ophthalmology 1980;87:716–720.

9.Akpek EK, Thorne JE, Qazi FA, et al. Evaluation of patients with scleritis for

systemic disease. Ophthalmology 2004;111:501–506.

10.Sainz de la Maza M, Foster CS, Jabbur NS. Scleritis associated with systemic vasculitic diseases. Ophthalmology 1995;102:687–692.

19.Sen HN, Suhler EB, Al-Khatib SQ, et al. Mycophenolate mofetil for the treatment of scleritis. Ophthalmology 2003;110:1750–1755.

23.Jabs DA, Mudun A, Dunn JP, et al. Episcleritis and scleritis: clinical features and treatment results. Am J Ophthalmol 2000;130:469–476.

24.Lachmann SM, Hazleman BL, Watson PG. Scleritis and associated disease. Br Med J 1978;1:88–90.

26.Hoang LT, Lim LL, Vaillant B, et al. Antineutrophil cytoplasmic antibody-

associated active scleritis. Arch Ophthalmol 2008;126:651–655.

27.Sainz de la Maza M, Foster CS, Jabbur NS, et al. Ocular characteristics and disease associations in scleritis-associated peripheral keratopathy. Arch Ophthalmol 2002;120:15–19.

30.McKibbin M, Isaacs JD, Morrell AJ. Incidence of corneal melting in association with systemic disease in the Yorkshire region, 1995–7. Br J Ophthalmol 1999;83:941–943.

61.Rao NA, Marak GE, Hidayat AA. Necrotizing scleritis. A clinico-pathologic study of 41 cases. Ophthalmology 1985;92:1542–1549.

Overview

Uveitis can be infectious or noninfectious in origin. Although the most common etiology of uveitis is considered to be immune-mediated in developed countries, there remain many cases of uveitis caused by infectious agents. Infectious uveitis can become latent, smoldering, and chronic and mimic autoimmune uveitis. While autoimmune uveitis responds to corticosteroids or immunosuppressive chemotherapy, such treatment may worsen infectious uveitis. It is, therefore, essential to identify cases of chronic uveitis caused by microbes in order to initiate specific and appropriate antimicrobial therapy. The diagnosis of infectious uveitis can be established in most cases based on patient demographics, mode of onset of and morphology of the lesions, and the association with other systemic infectious diseases. Laboratory testing and imaging techniques are important tools that help refine the diagnosis. In this chapter, some of the major bacterial, viral, and parasitic infections leading to uveitis are discussed.

Herpesviruses

Herpes group of viruses are ubiquitous in nature and can be found in nearly all animal species. Several different herpesviruses have been described so far and eight of them are found in humans: herpes simplex virus-1 (HSV-1), herpes simplex virus-2 (HSV-2), varicella-zoster virus (VZV), human cytomegalovirus (CMV), Epstein–Barr virus (EBV) and human herpesviruses 6, 7, and 8 (HHV-6, HHV-7, and HHV-8).1

Herpes simplex retinitis has been discussed in Chapter 80. This section therefore covers CMV, EBV, and VZV.

Cytomegalovirus

Clinical background

Key symptoms and signs

CMV retinitis commonly affects the peripheral retina and symptoms of early disease may be minimal or absent. Blur-

Infectious uveitis

Pooja Bhat, Allen Tony Jackson, and C Stephen Foster

ring, floaters and central scotomas may develop with the affection of the central retina.2

Historical development

CMV eye disease was first reported in 1947,3 being a rare clinical entity mostly seen in adults under medical immunosuppression. In the 1980s, with the acquired immunodeficiency syndrome (AIDS) pandemic, CMV became a frequent form of posterior uveitis.4 In the mid-1990s, before the introduction of highly active antiretroviral therapy (HAART), about 30% of patients with AIDS developed CMV retinitis during their lifetime. However, the introduction of HAART achieved a 75% reduction in the incidence of CMV retinitis.2

Epidemiology

About half of the normal population has antibodies against CMV.1 However, CMV infection in immunocompetent hosts does not usually produce symptomatic disease. The mode of transmission is by direct person-to-person contact and the virus is shed predominantly in urine, saliva, and semen. Most of the CMV retinitis cases result from reactivation of previously acquired disease. In patients with AIDS, CMV is one of the most common opportunistic infection. CMV retinitis usually presents in an advanced disease stage and is strongly associated with a low CD4+ T-cell count below 50 cells/mm3.2,5

Diagnostic workup

The diagnosis is principally based clinically, with the typical clinical features in an immunocompromised patient. Detection of anti-CMV antibody from the vitreous and/or aqueous humor (and comparing it with the serum levels using the Goldmann–Witmer coefficient) can be helpful in selected cases. Viral culture and polymerase chain reaction (PCR) from ocular tissue (if other malignant entities are suspected) or fluid can demonstrate the existence of viral DNA, but it is important to remember that this does not directly confirm the diagnosis of CMV retinitis, because CMV can persist in the tissue without causing disease.1,2

Differential diagnosis

CMV retinitis must be differentiated from retinitis due to HSV or VZV, syphilitic retinitis, toxoplasma retinochoroiditis, intraocular lymphomas and fungal infections.1

Treatment

The first step is to improve, if possible, the immune status of the patient. In AIDS, HAART therapy has demonstrated immune reconstruction and is beneficial not only for prevention, but also for treating CMV retinitis.6 Systemic and local anti-CMV drugs are needed in almost all AIDS patients. The most common include ganciclovir, foscarnet, and cidofovir. Others approved for treatment include fomivirsen and valganciclovir. These drugs are usually administered systemically, but in patients with intolerance or progression, intravitreal (injections or implants) ganciclovir or foscarnet can also be considered. The size of the lesion will be the main sign to evaluate the response to the treatment. In chronic immunocompromised patients, the anti-CMV therapy must be maintained indefinitely.6–8

Prognosis and complications

Rhegmatogenous retinal detachment (RD) is a common complication of CMV retinitis. This is usually associated with retinal necrosis and multiple retinal breaks. A vitrectomy with silicone oil tamponade has been shown to be an effective treatment for patients who have an RD caused by CMV retinitis.9,10

The course of CMV retinitis in the HAART era shows that the rate of retinitis progression is decreased compared with the pre-HAART era, even among those with low CD4+ T-cell counts. The incidence of visual impairment during follow-up after CMV retinitis is substantially lower among patients who receive HAART, especially those observed to have immune recovery. However, among patients with CD4+ T-cell counts less than 50 cells/mm3, while on HAART, the rates were more similar to those from the pre-HAART era.6–8

Pathology

CMV retinitis is a slowly expanding lesion, usually beginning as a small, white, retinal infiltrate (Figure 83.1). Initially, it can simulate a cottonwool spot, commonly present in human immunodeficiency virus (HIV) retinopathy. The clinical features, representing distinct manifestations of the same entity, are mainly:

1.Granular, white, multifocal satellite lesions of patchy retinitis (may represent infection of a terminal vessel) with limited or no retinal hemorrhage. This variant often shows a central atrophic zone.

2.Arc-shaped solitary expanding patch of retinitis, usually concurrent with multiple retinal hemorrhages and no atrophic zone in the center of the lesion. This variant is normally referred to as “fulminant” retinitis and is probably caused by infection of the major vascular arcades.

Clinical background

Figure 83.1  Extensive perivascular retinitis with areas of retinal hemorrhages and whitening secondary to cytomegalovirus infection.

3.Sometimes, in CMV retinitis, the perivasculitis may be predominant with some retinal necrosis. This variant is called “frosted-branch angiitis CMV retinitis.” The degree of vitritis in these patients is typically low because of the extreme immunosuppression.1,2,6,7

Etiology

CMV, a human herpesvirus, is an omnipresent microbe in the general population, but it seldom causes clinically apparent disease in an immunocompetent individual. Neonates and immunocompromised patients are the main groups at risk for CMV retinitis, which is the most frequent cause of blindness among patients with AIDS.6,7

Pathophysiology

After primary infection, CMV remains in its host, establishing a latent infection typical for all herpesviruses. CMV generally reactivates from latency associated with T-cell impairment. In most cases, the retina is infected via hematogenous spread. Damage of capillary endothelial cells caused by HIV infection probably facilitates the passage of CMV-infected cells through the blood–retinal barrier.1,2

Epstein–Barr virus

Clinical background

Key symptoms and signs

EBV may affect the eye in many different ways, usually as conjunctivitis or uveitis, and often occurs in primary infec-

tions in the context of infectious mononucleosis. Follicular conjunctivitis is the most frequent ocular feature. Severe bilateral iritis and iridocyclitis have also been reported. Almost all structures of the posterior segment can be affected. Macular edema, retinal hemorrhages, punctate outer retinitis with secondary subretinal neovascularization, and subretinal fibrosis may occur. Multifocal choroiditis and other posterior-segment pathologies are uncommon and have been described in patients with infectious mononucleosis and, more recently, in patients suffering from X-linked lymphoproliferative disorder, AIDS, or even in otherwise healthy individuals.11–14

tion. Visual prognosis is usually poor in patients with chronic smoldering chorioretinitis leading to subretinal neovascularization or cystoid macular edema.1,16

Pathophysiology

EBV shows B-cell tropism. However, the precise role of this virus in associated diseases is not well understood, but defective immunosurveillance against the virus may permit an uncontrolled proliferation of EBV-infected cells.1

EBV belongs to the gamma herpesvirus family.

Historical development

EBV was first isolated in 1964 from a cultured Burkitt’s lymphoma cell line. During recent decades, EBV has been implicated in a broad spectrum of human diseases like infectious mononucleosis, anaplastic nasopharyngeal carcinoma, and B-cell lymphomas, among others.15

Epidemiology

EBV infection is distributed worldwide. Antibodies against EBV can be detected in approximately 90% of the population but only a few suffer from ocular disease.1,16

Transmission requires contact with body fluids, primarily saliva, but also through blood transfusions. Primary infection is usually subclinical or leads to mild symptoms typical of a nonspecific viral illness, but in some cases it takes the clinical picture of infectious mononucleosis, especially when it affects adolescents.16,17

Diagnostic workup

Serum antibody titers against EBV may be helpful, especially if the initial high levels are followed by a subsequent decrease coinciding with the resolution of the acute phase. Other techniques like PCR or biopsy of the affected tissues may also be helpful in selected cases.13,14

Varicella-zoster virus

Clinical background

Key symptoms and signs

Systemic manifestations

Systemic manifestations consist of general malaise, fever, and headache. Subsequently, the characteristic papules, macules, vesicles, and, later, crusting occur with VZV.

Ocular manifestations

Ocular manifestations include trabeculitis, iridocyclitis, acute retinal necrosis (Figure 83.2), and variants of necrotizing herpetic retinopathy. Inflammation of the endothelium occurs relatively early in the course of disease and leads to stromal and epithelial edema. Endotheliitis is typically accompanied by signs of mild anterior-chamber inflammation. Keratic precipitates often appear under affected regions of the cornea and they can be either small or large (mutton fat). Iridocyclitis tends to occur within 1–2 weeks of disease onset, but can appear many months later. Later, inflammation is mediated by an immune reaction against persistent viral antigen presence in the corneal stroma. Sectoral occlu-

Differential diagnosis

Posterior-segment findings may appear similar to those caused by tuberculosis, syphilis, or sarcoidosis. Retinal and choroidal infiltrations may be confused with acute phases of toxoplasmosis, histoplasmosis, or white-dot syndromes.1

Treatment

Ocular disease is commonly self-limiting and no treatment is indicated. Uveitis sometimes requires corticosteroid therapy. Severe cases, especially those rare instances where the posterior segment is affected, may require similar antiviral agents as those used in acute retinal necrosis syndrome: intravenous aciclovir, ganciclovir, brivudine, valganciclovir, and foscarnet.16

Prognosis and complications

The panuveitis and choroiditis in patients with EBV infection can be complicated by macular edema and cataract forma-

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Figure 83.2  Foci of retinitis in acute retinal necrosis. Note the perivascular infiltrates along the arteries.