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

disease recognize human melanocyte antigens. Invest Ophthalmol Vis Sci 2006;47:2547–2554.

44.Amadi-Obi A, Yu CR, Liu X, et al. TH17 cells contribute to uveitis and scleritis and are expanded by IL-2 and inhibited by IL-27/STAT1. Nat Med 2007;13:711– 718.

47.Silver PB, Agarwal RK, Su SB, et al. Hydrodynamic vaccination with DNA encoding an immunologically privileged retinal antigen protects from autoimmunity through induction of

regulatory T cells. J Immunol 2007;179: 5146–5158.

55.Foxman EF, Zhang M, Hurst SD, et al. Inflammatory mediators in uveitis: differential induction of cytokines and chemokines in Th1versus Th2mediated ocular inflammation. J Immunol 2002;168:2483–2492.

70.Fine HF, Baffi J, Reed GF, et al. Aqueous humor and plasma vascular endothelial growth factor in uveitis-associated cystoid macular edema. Am J Ophthalmol 2001;132:794–796.

Key references

86.Jabs DA, Rosenbaum JT, Foster CS, et al. Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel.

Am J Ophthalmol 2000;130:492–513.

94.Galor A, Perez VL, Hammel JP, et al. Differential effectiveness of etanercept and infliximab in the treatment of ocular inflammation. Ophthalmology 2006;113:2317–2323.

Clinical background

Acute retinal necrosis (ARN), which was first reported by Urayama and colleagues, occurs rarely but is a potentially blinding disorder.1 Most cases of ARN are unilateral, although approximately one-third of patients develop bilateral disease which may occur either coincident with involvement of the presenting eye, or weeks, months, or years later.2 ARN is observed most commonly in the immunocompetent host but occasionally occurs when there is immunocompromise. Although varicella-zoster virus (VZV) was associated with the initial description of ARN, subsequently herpes simplex virus (HSV) type 1 (HSV-1), HSV type 2 (HSV-2), Epstein– Barr virus (EBV), and, very rarely, cytomegalovirus (CMV) were also implicated in its pathogenesis (Box 80.1).3–8 A member of the herpesvirus family is presumed to be the pathogenic agent in cases in which a close (usually) temporal relationship between clinical herpetic infection and the onset of the retinal infection is observed.

Patients with herpesvirus retinitis will commonly present with blurred vision caused by inflammatory debris in the vitreous humor. Some patients may also have ocular pain which is indicative of inflammation of the anterior segment of the eye. HSV retinitis is characterized by marked retinal edema, exudate, hemorrhage, and vascular occlusion (Figures 80.1 and 80.2). The disease may start in the posterior pole, equator, or periphery and is commonly associated with swelling of the optic disc and rhegmatogenous retinal detachment that usually occurs after a period of several weeks.9 Unless recognized quickly, retinitis may progress to ARN.

As defined by the American Uveitis Society (AUS), the features of ARN are not disease-specific or immune statusspecific but are rather determined by the clinical characteristics of the disease and its course. These features include:

(1) one or more discrete foci of necrosis in the periphery of the retina; (2) rapid progression in the absence of treatment;

(3) circumferential spread; (4) occlusive arteriolar vasculopathy; and (5) inflammation in the anterior chamber and/or in the vitreous (Box 80.2). Additional features may include optic neuropathy, scleritis, and pain.10 ARN is commonly seen in those with normal to mildly depressed immune status. Another syndrome involving herpesvirus infection of the retina is progressive outer retinal necrosis

Herpesvirus retinitis

Sally S Atherton and Mei Zheng

(PORN), which is characterized by decreased vision, floaters, and loss of peripheral vision. However, in contrast to ARN, there are cottonwool spots and multifocal areas of retinal whitening with confluent necrosis are observed, but retinal vasculitis and intraretinal hemorrhages are rare. PORN is usually observed in patients with moderate-to-severe immunosuppression, such as those with acquired immunodeficiency syndrome (AIDS).11 The original definition of ARN included the requirement that patients be immunocompetent; however, as noted above, the immune status of the patient is not an important clinical criterion, so ARN may also be observed in immunosuppressed patients.

ARN is rare. A study to assess the incidence of ARN in the UK revealed an incidence of approximately 1 case per 1.6– 2.0 million people per year (Box 80.3).12 Because of the small number of individuals who develop ARN, large-scale genetic studies to determine whether there are genetic predilections toward ARN have not been done. However, in a study of 27 patients with ARN, the frequency of the HLADQw7 antigen was significantly increased in ARN patients compared with controls (55% versus 19%) and the BW62, DR4 was also more common in ARN patients (16% versus 2.6%).13 In another study, HLA-DR9 was associated with more severe ARN and 50% of the patients with fulminant ARN had the HLA-DR9 genotypes compared with none of the patients with milder disease.14 It has also been suggested that impaired control of latent HSV-1 is attributable to defects in the ability of plasmacytoid dendritic cells to produce type 1 interferons in response to herpesvirus infection.15 Therefore, in addition to the possibility of increased risk of ARN in patients with certain HLA phenotypes, other non-HLA-associated factors such as the ability of certain cells to produce interferon may also play a role in predisposition to development of ARN and/or its severity.

There appears to be a difference in age distribution between ARN caused by HSV-1 or VZV and ARN caused by HSV-2, but this distribution is not absolute. A review of 28 patients (30 eyes) with ARN suggested that patients with ARN resulting from HSV-1 or VZV are usually older (median age 47 and 57 years, respectively) whereas those patients with ARN resulting from HSV-2 are often younger (median age, 20 years). ARN is occasionally observed in patients coincident with or following encephalitis or meningitis; in the former, ARN is usually due to HSV-1 while in the latter, ARN is usually caused by HSV-2.5,16,17

Figure 80.2  Photomicrograph of hematoxylin and eosin-stained section of a retinal biopsy from a human patient with acute retinal necrosis. There is loss of the retinal architecture and extensive inflammation. (Courtesy of the Department of Ophthalmology, Medical College of Georgia, Augusta, Georgia.)

Box 80.1  Causes of acute retinal necrosis

Diagnosis

The diagnosis of viral retinitis depends on the ocular and systemic manifestations as well as the clinical examination of the fundus of the eye. While comparison of local and systemic antiviral antibody titers as well as virus isolation

Box 80.2  Clinical characteristics of acute

retinal necrosis

Box 80.3  Patient-specific factors in development of

acute retinal necrosis

have been used to diagnose the disease, the current standard for diagnosis of viral infection of the retina is polymerase chain reaction (PCR) of aqueous humor and/or vitreous samples to detect viral DNA.18,19 PCR is exquisitely sensitive and specific; for example, the sensitivity and specificity of PCR for diagnosis of VZV infection are 100% and 97%, respectively.20

A number of diseases may result in retinitis and, even if viral, not all of these diseases are caused by a member of the herpesvirus family.21,22 The differential diagnosis of herpesvirus retinitis should include Behçet’s disease, CMV retinitis, HSV-1 and 2 retinitis, lymphocytic choriomeningitis virus

Section 10  Uveitis Chapter 80  Herpesvirus retinitis

Box 80.4  Differential diagnosis of acute

retinal necrosis

retinitis, primary intraocular lymphoma, sarcoidosis, syphilis, toxoplasmosis, and VZV-induced retinitis (Box 80.4). In infants with apparent congenital chorioretinitis, the diagnostic workup should include lymphocytic choriomeningitis virus serology, especially if antibody titers for Toxoplasma gondii, rubella virus, CMV, and HSV are negative.23

Treatment

The usual treatment of ARN is intravenous aciclovir, corticosteroids, and aspirin, followed by oral aciclovir. Intravitreal injections of foscarnet and oral aciclovir have been used in mild cases that have been detected early. VZV has also been successfully treated with brivuldine (not currently available in the USA) and valganciclovir.24–26 In general, retinal necrosis which progresses rapidly to the posterior pole is associated with a poor visual outcome. Eyes with less than grade II necrosis extension are good candidates for prophylactic peripheral retinal photocoagulation. Not surprisingly, early detection, prompt treatment with aciclovir, and rapid repair of retinal detachments seem to improve the final visual outcome.27 The issue of long-term prophylactic antiviral therapy to prevent ARN in an uninvolved fellow eye or to prevent ARN in a patient with a history of meningitis or encephalitis caused by a member of the herpesvirus family has not been resolved.28 However, since there is currently no way to predict who among patients with unilateral ARN will develop ARN in the fellow eye, long-term prophylactic antiviral therapy appears to be warranted.

If the diagnosis of ARN is not made quickly or if appropriate antiviral and anti-inflammatory therapies are delayed, retinitis caused by any of the three neurotropic herpesviruses (i.e., HSV-1, HSV-2, VZV) will usually progress quickly to ARN. Therefore, the prognosis for many patients with herpesvirus infections of the retina is poor because of the rapid and destructive nature of the disease.29 Although there are several antiviral agents that can be administered intravenously, intraocularly, and/or orally, many patients still experience significant vision loss because of optic neuritis, necrosis of the retina in or near the macula, or rhegmatogenous retinal detachment.30,31 Therefore, preventing/reducing vision loss in patients with ARN requires early detection (usually by PCR of aqueous or vitreous samples) and prompt treatment with the appropriate therapeutic regimen.

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Pathology

The characteristics of ARN are focal, well-demarcated areas of retinal necrosis in the peripheral retina, circumferential progression of necrosis (which occurs rapidly in the absence of antiviral therapy), occlusive vasculopathy, and inflammation in both the anterior chamber and the vitreous humor. Optic neuritis and late retinal detachments are also observed in association with the disease, and, as noted above, even with treatment, severe visual impairment and/or blindness may result.5,29

Etiology

Although bacteria, fungi, and parasites may all infect the posterior segment of the eye, members of the herpesvirus family are among the most common causes of infection involving the eye. The ubiquitous nature of the human herpesviruses together with the permissiveness in the human neuronal system for herpesvirus infection and transmission have conspired to make several of the herpesviruses the most common agents of chorioretinitis. Five of the eight members of the human herpesvirus family have the ability to cause retinitis. The first herpesvirus virus to be identified as a cause of ARN was VZV, and this virus remains the most common cause of ARN (accounting for 50–80% of cases) followed by HSV-1 and HSV-2. Rare cases of ARN caused by EBV and CMV (in immunocompetent patients) have been reported. However, given the ubiquitous nature of the human herpesviruses and the constant development of increasingly sensitive identification methodology, perhaps it would not be too surprising if other members of the herpesviruses are also identified as causative agents of retinal infections.

In infants, herpes simplex retinitis can result from congenital infection or from acute infection acquired during passage through an infected birth canal. Congenital HSV retinitis is defined as disease transmitted during gestation, before initiation of labor and delivery. In most cases of congenital HSV retinitis, the mothers have a history of newly acquired genital herpes infection which usually occurs during the second trimester.32 Active genital infection in the mothers at delivery is extremely rare compared with the neonatal acquired herpes retinitis, but sometimes it is difficult to differentiate congenital HSV retinitis from neonatally acquired HSV retinitis. Neonatal ocular infection with HSV is usually bilateral and is observed in infants from 2 days to several weeks of age; however, retinal findings may not be apparent until 3 weeks of age or after. Most cases of neonatal HSV retinitis occur concomitantly with HSV infection of the central nervous system (CNS) with only about 20% of cases of HSV retinitis associated with HSV conjunctivitis, keratitis, or disseminated dermatitis. ARN has also been described in children, and HSV-2 is the most common cause of ARN in children.

In adults, herpesvirus retinitis may result from acute virus infection or from reactivation of latent virus. A history of neonatal herpes infection is a risk factor for HSV-2 retinitis, as is a history of viral meningitis. The fact that HSV-2 retinitis has been observed following triggering events such as neurosurgery, periocular trauma, and administration of

high-dose corticosteroids supports the idea that, at least for HSV-2 retinitis, most cases in adults are due to reactivation rather than acute infection.

In summary, ARN is most commonly caused by VZV, followed by HSV-1 and HSV-2 with only rare cases of ARN attributable to EBV or to CMV. Management of patients with ARN should include prompt diagnosis as well as prompt initiation of appropriate antiviral therapy. Prophylactic laser barrier treatment has been shown to lower the incidence of retinal detachment and administration of systemic corticosteroids (in addition to antiviral therapy) helps to limit damage caused by the severe inflammation associated with ARN. Retinal detachment may occur acutely or several months after onset of symptoms; vitrectomy and prompt repair of retinal detachments may result in improved acuity.

Pathophysiology

The pathogenesis of ARN in humans remains unclear but, as with most viral infections in immunocompetent hosts, is likely to result from a combination of virus replication and factors of both the innate and adaptive immune responses. Uncertainty about the pathogenesis in humans is mainly because of the very few samples available for study and because many of the samples that have been available for study represent only the end-stage of the disease with little evidence of active viral replication and considerable amounts of necrotic/scarred retinal tissue. Furthermore, most of the clinical reports of ARN are focused on the etiology of the infection and the clinical presentation in order to guide treatment, rather than on the pathogenesis of the disease. Another drawback to deciphering the pathogenesis of ARN in human patients is that, in most cases, sequential samples of ocular fluids or of retina tissues are not available and extensive testing at nonocular sites is not usually performed (for example, imaging studies of the CNS).

Route of infection

There are three possible routes by which virus might enter the retina: (1) hematogenously; (2) direct spread from an infected anterior segment of the eye to the posterior segment; and (3) spread from the CNS to the retina. If the blood– retinal barrier is breached, free virus in the circulation (or circulating virus-infected cells) might enter and infect the retina. Since one phase of VZV infection involves systemic spread of the virus, this might occur in patients with VZV ARN. However, since HSV-1 and HSV-2 do not usually spread via the hematogenous route, hematogenous spread of these viruses to the retina appears to be unlikely. Since many patients with retinitis also have anterior uveitis, direct spread of virus from the front of the eye to the back of the eye is a possibility. However, even though ARN is caused by the same members of the herpesvirus family that also cause keratitis, association of herpetic keratitis/herpes uveitis with ARN syndrome in one eye is uncommon and there have been few reports of herpes keratitis immediately antecedent or coincident to ARN.

Although the route by which HSV spreads to the retina to cause ARN in human patients has not been elucidated, reports of encephalitis or meningitis preceding symptoms of

Pathophysiology

ARN in some human patients suggest that, at least in some cases, the virus spreads from the brain to the eye.30,31 The observation that several patients with ARN had optic neuropathy coincident with or immediately preceding their infection further suggests that, in humans, one route by which the neurotropic herpesviruses reach the retina is via the optic nerve.

Therefore with the caveat that animal models of disease generally do not have 100% fidelity to their human counterpart, animal models may provide a way to gain insight into the pathogenesis of ARN caused by the neurotropic herpesviruses. Acute retinitis which evolves to ARN that shares some clinical and histopathologic similarities with ARN in humans is observed in rabbits and euthymic mice following uniocular anterior-chamber inoculation of HSV- 1.33,34 In the mouse model, the retina of the uninoculated contralateral eye is virus-infected, and acute retinitis that progresses to necrosis is observed beginning around 7 days postinoculation and continuing thereafter (Figure 80.3). Although the route by which viruses gain access to the body may differ in animal models (HSV is injected to the anterior chamber of one eye) from those of human patients (skin, eye infection, encephalitis, meningitis, pharyngitis), the outcome is similar retinal pathology in both animal model and human patients.

Although virus tracing experiments cannot be performed in humans, a variety of methods can be used to trace the route of spread of neurotropic virus in animals. Using a LacZ-containing recombinant of HSV-1, Vann and Atherton showed that, in the mouse model of ARN, virus spreads from the anterior chamber of the injected eye to the retina of the uninoculated eye via synaptically connected neurons.35 Sequentially, this pathway involves the ipsilateral ciliary ganglion (day 2 postinoculation), the ipsilateral Edinger– Westphal nucleus (day 3 postinoculation), the ipsilateral suprachiasmatic nucleus (SCN) (day 5 postinoculation), and the contralateral optic nerve and retina (on and after day 6–7 postinoculation). Paradoxically, although the anterior segment of the injected eye is virus-infected and there is extensive inflammation, in immunocompetent mice, the retina of the injected eye does not become virus-infected. Also, although the contralateral SCN becomes infected with virus on day 7 postinoculation, virus does not spread from this site to infect the optic nerve and retina of the ipsilateral injected eye, suggesting that virus cannot spread to the retina of the injected eye either directly or indirectly (by retrograde spread from the CNS).

Role of the immune cells

In addition to identification of sites of virus infection and of sequential spread, a number of factors have been identified that play a role in the pathogenesis of the disease in the mouse that may be applicable to increasing our understanding of the infectious process in humans. In the mouse, virus does not spread directly from the anterior segment to the retina and in humans, direct spread from an infected anterior segment to the posterior segment is observed rarely, if at all. While the reason for this is not immediately apparent, especially since there is not a physical anatomic barrier to prevent such spread, studies using the mouse suggest that the early responders of the innate immune system (includ-

ing natural killer (NK) cells and polymorphonuclear leukocytes (PMN)) participate in limiting direct virus spread and, by extension, perhaps also in limiting virus replication.

NK cells have been identified in the aqueous of an ARN patient.36 In the mouse, NK cell activity is increased in the virus-infected eye compared with mock injected controls and depletion of NK cells correlates with spread of HSV-1 from the infected anterior segment to the retina.37 Additional studies in the mouse in which PMNs were depleted by treatment with Gr-1 antibody (specific for PMN) indicate that PMNs also play a role.38 The mechanism by which these cells either separately or together with NK cells (since NK cells are not depleted by Gr-1 antibody treatment) limit virus spread from the anterior segment of the eye to the posterior segment are currently being investigated and preliminary studies suggest that interferons are likely to be involved.

While limitation of virus spread from the anterior to the pos­terior part of the eye appears to be due to modulators of the innate immune response, results from studies using the mouse model together with those from human patients suggest that the contributors to destruction of a virus-infected retina are more complicated. Replicating virus is almost certainly required. In sequential studies in the mouse, a direct correlation was observed between the amount of virus and the extent of retinal destruction.39 However, since the pace of retinal destruction proceeds more slowly in athymic or in T-cell-depleted mice, it is likely that T cells along with other components of the innate and adaptive immune responses contribute to the process in mice and by extrapolation, most likely in humans.40

Involvement of T cells in human patients with ARN is supported by the studies of Verjans and colleagues who reported that intraocular T cells of patients with HSV-induced ARN recognize HSV tegument proteins VP11/12 and

632

VP13/14.41 However, although T cells may play a cytotoxic role and kill virus-infected retinal cells, they may also be protective and their presence may explain why so few of the many individuals who are seropositive for one or more of the neurotropic herpesviruses (HSV-1, HSV-2, VZV) develop ARN. In the mouse model of ARN, T cells play a role in limiting virus spread in the CNS and both CD4+and CD8+ T cells have been implicated in the prevention of retrograde virus spread from the contralateral SCN of the hypothalamus into the optic nerve and retina of the injected eye.42 Furthermore, the presence of T cells in the contralateral SCN correlates with protection of the ipsilateral retina.43 However, how T cells limit virus in the CNS and perhaps within the eye remains to be elucidated.

In addition to T cells, studies using the mouse model indicate that macrophages may also play a role in the pathogenesis of virus infection after uniocular anterior chamber or intravitreal inoculation.44,45 Systemic depletion of microphages by treatment with clodronate-containing liposomes correlated with increased titers of virus in the SCN following anterior-chamber inoculation of HSV-1. When the levels of tumor necrosis factor-α (TNF-α), a product of macrophages, were measured, the amount of TNF-α was significantly reduced in the SCN of macrophage-depleted mice. However, while these results implicate macrophages and TNF-α in protection, the mechanism by which such protection occurs has not been determined. Moreover, merely increasing the amount of TNF-α at sites of virus infection was not protective. When mice were infected with a recombinant of HSV-1 that produces TNF-α constitutively, neither the timing of virus spread nor the path of virus spread from the injected eye to the contralateral optic nerve and retina was affected. However, in the uninoculated eye, the titer of virus was significantly higher and the speed of retinal destruction was

more rapid.46 Thus, production of TNF-α and infiltration of macrophages seem to play an important role in limiting virus spread and/or virus replication in the CNS but whether the role of TNF-α during virus infection is protective, destructive, or both remains to be determined.

The response of different types of cells to virus infection is just beginning to be studied. For example, Toll-like receptors (TLR), an important component of the innate immune response to many pathogens, function by activation of NF-κB followed by production of proinflammatory cytokines.47 Expression of TLRs in the retina of the uninoculated eye in response to virus infection is dynamic and different TLRs are expressed on retinal cells at different times during the course of the infection. For example, expression of TLR3 is increased in the retina of the uninoculated eye shortly before the onset of acute retinitis and decreases gradually during the course of the infection. TLR7 increases steadily during the course of the infection, while TLR9 is maximal at the peak of the acute disease coincident with the highest titers of virus (Zheng and Atherton, unpublished data). Such temporal expression suggests that TLRs are involved in the infectious process but the mechanism of their involvement is not understood.

Since many cases of ARN in human patients result from infection from reactivated virus, these individuals will have virus-specific immune cells, including memory T cells as well as antibody to the virus (Box 80.5). The role of antiviral antibody in ARN has not been explored but such antibody could facilitate destruction of the virus-infected retinal cells by antibody-dependent cellular cytotoxicity or it could help to limit virus by neutralizing extracellular virus.

Following uniocular anterior-chamber injection of HSV-1, mice develop anterior-chamber associated immune deviation which is characterized by downregulation of virusspecific delayed-type hypersensitivity with preservation of virus-specific antibody responsiveness.48 Results of studies by Kezuka and colleagues have suggested that a similar downregulation of VZV-specific T-cell immunity occurs in some ARN patients.49,50 Therefore, it may be postulated that a failure of T-cell immunity to control virus spread from a site of virus reactivation into neurons synaptically connected to the optic nerve and retina, and/or within the retina may play a role in the pathogenesis of ARN.

Key references

Box 80.5  Contributors to the pathogenesis of acute

retinal necrosis

Summary

Observations and laboratory studies of human patients together with virologic and immunologic studies using the mouse model underscore the idea that the pathogenesis of ARN caused by neurotropic members of the herpesvirus family is complex. While virus infection must occur, the roles of virus type-specific factors and of viral genetics have not yet been investigated. It is likely that both innate and adaptive immune responses play a role in the destruction of virus-infected retinal cells. However, irrespective of how these factors contribute, given the usually poor visual outcome in human patients with ARN, the most important question to be addressed is whether there are specific parameters that can be used to predict who among the very large number of individuals who are seropositive for one or more of the neurotropic herpesviruses is at the highest risk of developing viral retinitis and ARN and to monitor and treat these individuals appropriately. Until this question is answered, early identification of the infection along with prompt initiation of antiviral therapy remain the best options for preservation of sight.

1.Urayama A, Yamada N, Sasaki T, et al. Unilateral acute uveitis with retinal periarteritis and detachment. Jpn J Clin Ophthalmol 1971;25:607–619.

10.Holland GN. Standard diagnostic criteria for the acute retinal necrosis syndrome. Executive Committee of the American Uveitis Society. Am J Ophthalmol 1994;117:663–667.

11.Holland GN. The progressive outer retinal necrosis syndrome. Int Ophthalmol 1994;18:163–165.

13.Holland GN, Cornell PJ, Park MS, et al. An association between acute retinal necrosis syndrome and HLADQw7 and phenotype Bw62, DR4. Am J Ophthalmol 1989;108:370– 374.

15.Kittan NA, Bergua A, Haupt S, et al. Impaired plasmacytoid dendritic cell innate immune responses in patients with herpes virus-associated acute retinal necrosis. J Immunol 2007;179:4219– 4230.

20.Knox CM, Chandler D, Short GA, et al. Polymerase chain reaction-based assays of vitreous samples for the diagnosis of viral retinitis. Use in diagnostic dilemmas. Ophthalmology 1998;105:37– 44.

23.Balansard B, Bodaghi B, Cassoux N, et al. Necrotising retinopathies simulating acute retinal necrosis syndrome. Br J Ophthalmol 2005;89:96–101.

25.Aizman A, Johnson MW, Elner SG. Treatment of acute retinal necrosis

simplex virus-mediated acute retinal necrosis. J Infect Dis 1998;178:27–33.

49.Kezuka T, Sakai J, Minoda H, et al. A relationship between varicella-zoster virus-specific delayed hypersensitivity and varicella-zoster virus-induced anterior uveitis. Arch Ophthalmol 2002;120:1183–1188.

Box 81.1  Posterior-segment findings in sympathetic

ophthalmia

•  Vitritis •  Papillitis

•  Choroiditis

•  Exudative retinal detachment •  Dalen–Fuchs nodules

wise have been enucleated in the past. In 1982, Gass reported an incidence of 0.06% after vitrectomy and 0.01% incidence when vitrectomy was the only operative procedure causing the penetrating wound.7

Chan et al, in their retrospective study from 1982 to 1992, reported that 28% of patients with SO developed it following intraocular surgical procedures.8 Kilmartin et al reported in 2000 that ocular surgery, especially retinal surgery, accounted for 56% of all cases of SO.6 A report by Su and Chee stated that the proportion of SO caused by ocular surgery is 70%.9 All of these studies indicate that ocular surgery as a precipitating factor is gaining importance.

Previous studies indicate that SO is more prevalent in males and in children.2,10 But recent reports show no gender predominance and a smaller number of cases occurring in children.6 Elderly patients appear to be at an increased risk, probably because of the increased frequency in ocular surgery performed in this age group.6

Diagnostic workup

The clinical diagnosis of SO is based on history and clinical examination. There are no specific laboratory studies to establish the diagnosis. However, fluorescein angiography (FA) and indocyanine green (ICG) angiography are helpful in supporting the diagnosis.

The characteristic features of SO as seen on FA are multiple tiny foci of leakage at the level of retinal pigment epithelium (RPE) with late coalescence if there are areas of exudative detachment. Another, less common, angiographic appearance is similar to that seen in acute posterior multifocal placoid pigment epitheliopathy. Here the lesions appear as early focal obscuration of background choroidal fluorescence with late staining.11

Since the disease predominantly involves the choroid, use of ICG could help support the diagnosis of SO.12 Two ICG patterns have been observed. In the first type, the hypofluorescent dark dot appearing during the intermediate phase persisted throughout the late phase; in the second type, the dots faded away during late phase. The first pattern was thought to represent chorioretinal atropic areas, and the second was thought to correspond to active choroidal spaceoccupying lesions. Hence, some believe that ICG provides additional information about choroidal involvement and subsequent evolution of the lesion.12 However, the enucleated SO globes reveal no histopathologic evidence of chorio­ retinal atropy. Moreover, the retina is typically spared from the inflammatory cell infiltration.

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Box 81.2  Differential diagnosis of sympathetic

ophthalmia

•  Vogt–Koyanagi–Harada disease •  Phacoanaphylaxis

•  Sarcoidosis

•  Posterior scleritis

•  Uveal lymphoid infiltration

Ultrasound scans help to establish choroidal thickening, predominantly in the posterior choroid, and optical coherence tomography is believed to aid in monitoring the therapeutic response in patients with shallow retinal detachment.

Differential diagnosis

When considering the differential diagnosis of SO, it is important to rule out intraocular infections that could cause severe endophthalmitis. Posttraumatic iridocyclitis may also cause an inflammatory reaction, but neither endophthalmitis nor iridocyclitis involves the fellow eye.

The differential diagnosis also includes any other cause of granulomatous uveitis, especially phacoanaphylaxis, Vogt– Koyanagi–Harada disease (VKH), sarcoidosis, or posterior scleritis (Box 81.2).

Phacoanaphylaxis is a chronic granulomatous inflammation that occurs following traumatic or surgical lens capsule disruption and could closely simulate the clinical signs of SO. It typically manifests as a granulomatous anterior uveitis. The choroid, retina, and optic nerve are not usually involved in the disease process. Studies have shown that phacoanaphylaxis can coexist with SO (4–25%), and even though phacoanaphylaxis is normally a unilateral inflammation, bilateral occurrence has been reported in the absence of SO changes.13 In such cases, the posterior choroid is not thickened with inflammatory cellular infiltration, as seen in SO, and thus, no evidence of a thickened choroid is shown by ultrasonography. In bilateral phacoanaphylaxis, the first eye involved is usually quiet by the time the inflammation begins in the second eye. In contrast, in SO the exciting eye is usually severely inflamed at the time the sympathizing eye becomes involved.

VKH disease is a bilateral, diffuse, granulomatous uveitis with clinical, histopathological, immunohistochemical, and FA manifestations that are strikingly similar to those of SO. These associations suggest that the two conditions may involve closely related antigens and similar immune mechanisms. Shindo et al reported similar genetic backgrounds in patients with SO and VKH.14 Moorthy et al showed virtually identical histopathological changes in SO and VKH, including preservation of the choriocapillaris in acute VKH cases.15 Both entities have been associated with headache, tinnitus, alopecia, poliosis, and vitiligo.16 In most instances, a history of penetrating trauma would be the most helpful factor in making the diagnosis of SO.

Ocular sarcoidosis is another disease with a clinical resemblance to SO. However, systemic manifestations of