Ординатура / Офтальмология / Учебные материалы / Uveitis Text and Imaging Text and Imaging Text and Imaging 2009

independent. The disease has been reported worldwide. In a recent survey from UK, the incidence of ARN seems to be approximately 1 case per 1.6 to 2.0 million population per year.5

PATHOPHYSIOLOGY

Animal models have been developed to define the main characteristics of viral retinitis.6,7 Human cytomegalovirus has a different pattern of replication than that of HSV and VZV. Pertinent permissive cell cultures, such as retinal glial cells or retinal pigment epithelial cells, have been used to study HCMV replication. Virus replicates slowly and progressively.6,8,9 In the era of highly active antiretroviral therapy, intraocular inflammation, like cystoid macular edema, vitritis or papillitis, have been reported in patients presenting with completely cicatricial retinitis. It was therefore of interest to analyze different pathways involving antiviral immune responses that might potentially play a role in these situations. The model of retinal pigment epithelial cells was used to analyze virus-host interactions. The occurrence of HCMV retinitis in the late phase of immunosuppression may be related to perturbation of cytokine production and secretion, associated with the progressive loss of the CD3+CD4+ cell subset. The effect of different cytokines such as IFN-γ, IFN-β, IL-1β, TGF-β and TNF-α, which are present in the eye under different immunopathological conditions, were studied to discover which of them play a role during HCMV replication in retinal pigment epithelial cells. IFN-γ and IL-1β appeared to be the major antiviral cytokines in this in vitro system.8 A lack of IFN-γ in the final stage of immunosuppression could play a role in the pathogenesis of HCMV retinitis. Immune reconstitution may be associated with the infiltration of retina with leukocytes that recognize resident cells expressing latent viral antigens. Immune activation induces immune recovery uveitis in the absence of active viral replication.

CLINICAL FEATURES

Intraocular herpetic infections can be divided into two major entities, anterior uveitis and viral retinopathies. Clinical manifestations have been relatively welldefined. However, it is still difficult to present strong

clinical and virological correlations without molecular analysis. Retinitis is usually unilateral with an acute onset.

VIRAL RETINOPATHIES

Necrotizing Herpetic Retinopathies

Necrotizing viral retinopathies have been described and largely characterized by electron microscopic studies, immunocytochemistry,10,11 viral culture from intraocular specimens, serologic analysis of serum and/or intraocular fluids,12-14 and, finally, by the polymerase chain reaction.15,16 They include acute retinal necrosis syndrome, progressive outer retinal necrosis syndrome and CMV retinitis.

Acute retinal necrosis (ARN)

In 1971 Urayama and associates reported the first 6 cases of presumed viral retinal necrosis and called it unilateral acute uveitis with retinal periarteritis and detachment.17 The disease is known in Japan as Kirisawa’s uveitis. Bilateral forms were described later by Western authors. Fisher et al used the term “acute retinal necrosis” for the first time in 1982.11 Later studies confirmed the role of VZV and HSV in the pathogenesis of ARN. In 1994, Holland and the American Uveitis Society unified the spectrum of presumed herpetic retinopathies and defined it as necrotizing herpetic retinopathies.18 The prevalence of ARN is nearly equal in both sexes. The majority of cases occur in the fifth to seventh decades of life. Viral retinitis may occur congenitally, in newborns or in young children. It is still not known why the disease was not reported before the 1970s. Both healthy and immunocompromised patients may develop ARN during either primary or recurrent herpes virus infection. However, clinical presentation may vary in severity.

The ARN syndrome is characterized by acute primarily peripheral, necrotizing retinitis, retinal arteriolitis and mild to severe vitritis. The disease is usually unilateral and is known to be caused by VZV, HSV, but rarely by CMV. Recently, studies from the US and Japan pointed out the high frequency of VZV or HSV-2 infection in cases of acute retinal necrosis.15,19

The main clinical characteristics of ARN syndrome were defined by the American Uveitis Society and include: focal, well-demarcated areas of retinal necrosis

located in the peripheral retina, rapid, circumferential progression of necrosis, evidence of occlusive vasculopathy (Figure 1) and a prominent inflammatory reaction in the vitreous and anterior chamber.18 OCT seems to be an interesting tool for the evaluation of retinal lesions during the acute and resolution phases of the disease.20 Mild optic disc edema may be present early in the course of the disease and increases progressively. A granulomatous anterior uveitis with secondary glaucoma may be associated. Retinitis progresses rapidly in the absence of treatment, but classically spreads to the posterior pole. An exudative retinal detachment occasionally develops if inflammation is important and rhegmatogenous retinal detachment occurs frequently in the absence of antiviral, and sometimes anti-inflammatory, therapy

(Figure 2). Occasionally, retinitis remains limited defining low-spreading forms of retinal necrosis.

Progressive outer retinal necrosis

This variant of herpetic retinopathy was first described by Forster and associates.21 It usually occurs in immunocompromised patients and is characterized by a minimal nongranulomatous anterior uveitis without vitritis, associated with a fulgurant necrotizing retinitis starting at the posterior pole and spreading toward the peripheral retina. Foci of lesions become rapidly confluent and involve the entire retina (Figures 3 and 4). Unlike ARN syndrome, retinal vasculitis and optic neuritis are less common, but retinitis is often bilateral. The disease is quite severe and visual prognosis is usually poor due to resistance to antivirals and occurrence of retinal detachment.

Figure 2: Retinal detachment in a patient with HSV-1- associated acute retinal necrosis syndrome

Figure 3: Progressive outer retinal necrosis in an HIV-positive patient

Figure 4: Fluorescein angiography showing diffuse peripheral retinal ischemia and hemorrhages during progressive outer retinal necrosis syndrome

Cytomegalovirus retinitis

CMV is one of the most puzzling members of the Herpesviridae family. Ocular involvement has been reported during congenital infection and in patients with acquired immunodeficiency syndrome (AIDS).22,23 Before the use of highly active antiretroviral therapy (HAART) in AIDS patients, CMV disease was the major cause of blindness. CMV retinitis was observed late during the disease and the risk was significant when the level of CD4 lymphocytes dropped below 50-100/mm3. In a small percentage of patients, CMV retinitis may be the first clinical manifestation of AIDS. CMV retinitis is probably secondary to the passage of the virus across the blood retinal barrier, when local defense mechanisms are almost completely abolished. Viral progression into the retina seems to occur in a polarized manner. The internal blood-retinal barrier is initially disrupted after primary replication in endothelial cells, allowing viral particles to reach retinal glial cells. CMV then spreads towards the retinal pigment epithelium. The retinal site of HCMV latency is still under debate: retinal pigment epithelium or glial cells are two putative candidates. CMV retinitis occurs initially in the peripheral retina. Visual complaints remain rare for a long period of time. Systematic fundus examination should be performed every 3 months if CD4 lymphocytes counts are below 50/mm3. Interestingly, a few cases of CMV retinitis have been recently reported in immunocompetent patients after intravitreal injection of triamcinolone or after fluocinolone acetonide implant.24,25 Active CMV retinitis is usually diagnosed on ophthalmoscopic signs, such as white fluffy areas of necrotizing retinitis associated with hemorrhages and vascular sheating. Early CMV retinitis may begin with a small, white retinal infiltrate. The lesion may masquerade as a cotton-wool spot present in HIV-related microvasculopathy. Fundus examination must be controlled in order to confirm a putative CMV retinitis. Two distinct subtypes of CMV retinitis have been described. The fulminant or edematous variant is the classic appearance of disease. Dense, white confluent opacifications of the retina without any central atrophic lesion occur usually along vessels, associated with retinal hemorrhages and inflammatory vascular sheating. The indolent or granular variant of disease associates granular foci of retinal necrosis with a central atrophic

Figure 5: CMV retinitis in an AIDS patient

zone, fewer hemorrhages and less vascular sheating (Figure 5). The border of retinal necrosis is usually irregular in both variants, surrounded by satellite infiltrates. The optic disc is rarely infiltrated initially, but papillitis may be observed when retinitis progresses toward the posterior pole. Mild vitritis is associated with minor anterior segment inflammation. Despite slow progression of retinitis, destruction of the entire retina occurs within 3 to 6 months in the absence of anti-CMV therapy. Cicatricial lesions are atrophic retina with vessel rarefaction. Fluorescein angiography may be helpful in complex cases, when other differential diagnoses such as retinochoroidal toxoplasmosis, Candida endophthalmitis, syphilitic retinitis, herpes simplex and herpes-zoster retinitis are suspected. Visual prognosis depends on occurrence of complications and long-trem control of viral replication.26-29

The administration of HAART to AIDS patients has dramatically changed the course of CMV disease by improving the function of the immune system and increasing survival.30-33 If CD4 cell counts increase after HAART, a beneficial effect on viral recurrences may be observed and anti-CMV maintenance therapy can be discontinued.29 In patients presenting with previous areas of CMV retinitis before immune restitution under HAART, episodes of posterior uveitis, vitritis, retinal vasculitis, papillitis and macular edema have been reported.34-36 The pathophysiology of disease, known as immune recovery uveitis, remains controversial.37,38 However, personal data and results reported recently seem to exclude viral replication and highlight an immune reaction due to restoration of lymphocytes

Figure 6: Fluorescein angiography disclosing papillitis and macular edema in a case of nonnecrotizing HSV-1 associated retinopathy

recognizing chronically infected retinal cells expressing CMV antigens at their surface.

Non-necrotizing Herpetic Retinopathies (NNHR)

This entity was reported more recently.39,40 Molecular analysis applied to ocular fluids confirmed the presence of herpes virus DNA in patients presenting with different forms of chronic and atypical posterior uveitis, such as Behçet disease, retinal vasculitis and birdshot retinochoroidopathy. Non-necrotizing retinopathies associated with hemorrhages have been described (Figures 6 and 7). The disease is usually bilateral. It is important to emphasize that all patients

Figure 7: Fluorescein angiography showing papillitis, retinal vasculitis and cystoid macular edema in a case of HHV-8- associated nonnecrotic herpetic retinopathy

with NNHR are corticoresistant or corticodependent at a high level. The initiation of specific antiviral therapy improved ocular inflammation. Immunosuppressors were discontinued and steroids were significantly tapered. Evolution under therapy is close to that observed in herpetic keratouveitis and steroids cannot be interrupted definitely.

DIFFERENTIAL DIAGNOSIS

Despite the AUS criteria, a diagnosis of ARN may be difficult. Clinical presentations range from focal to extensive retinal necrosis and the clinical course ranges from mild to fulminating. Moreover, in some patients the clinical findings can be atypical and may not be clear enough to make a definitive diagnosis or to promptly initiate an antiviral agent. The delay in diagnosis can lead to loss of vision that could otherwise be prevented. In addition, similar necrotizing retinitis may also occur from nonviral infectious agents, including Toxoplasma gondii (Figure 8), bacteria, or fungi.41,42 Other disease entities (namely, retinal vasculitis, intraocular tumors, Behçet’s disease and sarcoidosis) can also present with retinitis that mimicks ARN. Thus, specific and sensitive laboratory tests are necessary to confirm a diagnosis of ARN or the nonviral retinopathies that present with features simulating ARN. Toxoplasmic retinochoroiditis is the most frequent disease simulating necrotizing viral retinopathies. When either a viral infection or ocular toxoplasmosis are suspected, aqueous humor analysis

Figure 8: A case of severe toxoplasmic retinochoroiditis masquerading as an acute retinal necrosis syndrome, with a large area of retinal necrosis, vascular occlusions and hemorrhages

by PCR and the use of the Goldmann-Witmer coefficient appear to be the best methods for a final diagnostic confirmation. Results may also be obtained within 72 hours. Both antiparasitic and antiviral regimens may be required until a final diagnosis is obtained.

DIAGNOSIS

The diagnosis of herpetic intraocular inflammation is initially based on the analysis of clinical features. Laboratory tests can help the clinician confirm the disease. However, more than 75 percent of the population in developed countries is seropositive for herpes viruses (HSV-1, VZV and/or CMV). Therefore, routinely used serologic testing is of little interest unless it shows the presence of IgM and eventual seroconversion. Confirmation of intraocular viral inflammation with or without viral replication relies on molecular techniques such as PCR.43-45 In fact, it is quite difficult to isolate the viral agent from ocular fluids in cell culture. This can be done using ocular tissues but its success rate remains quite low. The other method to confirm disease is to ascertain intraocular antibody production against different herpes viruses. The amount of ocular fluids is a limiting factor to perform diagnostic tests in patients with a suspicion of viral intraocular inflammation.

OBTENTION OF OCULAR FLUIDS

Anterior Chamber Paracentesis (ACP)

ACP seems to be safe, but it should be considered a surgical procedure and be performed by an experienced ophthalmologist. It can be performed at the slit lamp or under a microscope in the operating room after instillation of topical antibiotic and anesthetic drops. Up to 0.2 ml can be obtained. In a retrospective study of 361 patients, Van der Lelij and Rothova reported no serious complication, such as cataract, keratitis or endophthalmitis after paracentesis.46 Hyphaema was reported in 7 cases. The same degree of safety was reported in another series.47

Vitreous Tap/Vitrectomy

Vitreous fluid analysis has to be considered in both inflammatory conditions that do not respond to treatment and in masquerade syndromes. Diagnostic

vitrectomy can be associated with therapeutic vitrectomy, especially with a hazy vitreous. This procedure is more complicated than ACP, but provides a larger amount of material for analysis. It is mostly performed in the operating room using a surgical microscope with subtenon or peribulbar anesthesia. During three-port vitrectomy, 0.5-1 ml of undiluted vitreous can be aspirated initially. Retinal detachment remains a possible complication of vitreous biopsy or vitrectomy, but the incidence is particularly low. Viruses are difficult to culture, especially when the amount of the inoculum is limited, as with ocular fluids. Moreover, standard shell vial culture is frequently negative after antiviral treatment. The sensitivity of PCR for detection of virus is superior to culture and to evaluation of specific intraocular antibody production.

MOLECULAR DIAGNOSIS

Acute retinal necrosis (ARN), progressive outer retinal necrosis (PORN) and cytomegalovirus retinitis are well-defined entities. Diagnosis is quite unequivocal when the clinical presentation is typical, but fundus examination can be difficult in the presence of cloudy media. Cunningham et al reported the first two cases of AIDS-associated herpetic retinitis, confirmed by PCR and restriction analysis of the vitreous biopsy.48 The amount of herpes virus DNA, detectable by PCR techniques in ocular fluids of patients without ocular inflammation in a control study published by Pendergast et al, appears to be quite low.49 Therefore, the authors suggest that a positive result obtained in a patient presenting with vitreoretinal inflammation should be regarded as significant. In 1991, Fox et al confirmed by PCR the presence of CMV genome in the AH, vitreous and subretinal fluid of patients with a clinical diagnosis of CMV retinitis.50 Ganatra et al used PCR to confirm the diagnosis of ARN in 30 eyes of 28 patients.15 Viral genome was identified in 96.5 percent of cases. Moreover, viral identification showed that VZV and HSV-1 retinitis are more common in patients over 25 years, whereas HSV-2 retinitis occurs in younger patients. HSV-2-associated ARN is highly prevalent in Japan.19 Serologic tests may be less specific than PCR to discriminate HSV-1 and HSV-2 retinitis. Results of other series show the importance of PCR in the diagnosis of atypical viral retinitis.51 PCR can be

the first step for molecular epidemiology of viral retinitis. About 25 per cent of VZV strains in Japan carry a mutation lacking the PstI recognition site. Kumano et al have detected a VZV genome with a PstI site from the AH of a Japanese patient with ARN.52 There is a putative polymorphism among VZV strains in patients with ARN. More recently, Mochizuki et al showed that there is no clinical difference related to the presence of the PstI recognition site.53 Viral amplification and subsequent sequencing are promising in defining correlations based on molecular virology and polymorphism. VZV seems to be the principal agent of atypical necrotizing herpetic retinopathies.54 Despite aggressive antiviral therapy, the clinical course of NHR is variable and complications can lead to blindness. Viral analysis of ocular fluids allows determination of risk factors. Abe et al estimated the number of VZV copies in the AH and vitreous of patients with ARN by PCR and semi-nested PCR. The number of virus copies seems to be higher in elderly or immunocompromised patients.55 Severity of retinal necrosis may be due to the implication of different viral strains.56 Antiviral treatment is less efficient in these cases and the visual outcome remains poor. The same group has shown that different VZV strains participate in ARN. Analysis of the R1 variable region of VZV may help determine the viral strains associated with more fulminant types of ARN. Multiple viral infections may occur in immunodeficient patients, mimicking leukemic infiltration of the eye.57 Viral identification may show point-mutations in the UL97 gene of CMV amplified after vitreous biopsy in patients with ganciclovir-resistant retinitis. Results can be compared with extraocular CMV isolates.58,59 In 1999, Smith et al showed that CMV retinitis activity is interestingly evaluated by the level of CMV DNA obtained by quantitative PCR applied to ocular fluids.60

Prospective studies to evaluate PCR results, clinical evolution, and treatment are needed to corroborate the real value of PCR in the diagnostic and therapeutic management of viral retinitis.

PCR may often be negative due to prior antiviral treatment. Thus, alternative techniques have been developed, amongst which analysis of the coefficient of immunological burden is most frequently applied. Theoretically, one should associate both methods.13

SEARCH FOR ANTIVIRAL ANTIBODIES

This type of analysis was the method of choice in numerous institutes until the advent of techniques of molecular biology. Serology by immunoenzymatic (ELISA) and radioimmunological techniques allow assessing antibodies in 40 to 50 microliters of aqueous humor or vitreous. However, the presence of intraocular specific antibodies does not necessarily correspond to a local synthesis, but may also reflect passive antibody passage across the blood-ocular barrier ruptured by inflammation. In order to confirm local synthesis, a coeffcient of immune burden must be evaluated by comparing ocular and serum antibody levels. This is the Witmer-Goldman C coefficient also used for the diagnosis of ocular toxoplasmosis.14 This remains a laborious technique. Several groups use a variant of the C coefficient by calculating the ratio of antibody for a given virus in aqueous humor and serum. This ratio is then compared to that of another virus to which the patient is immune, but which is not responsible for the ocular disease. The measles virus is regularly used for this purpose.

TREATMENT

The therapeutic strategy of viral ocular inflammatory disorders includes associations of antiviral, antiinflammatory and antiglaucomatous medications. All antiherpes virus drugs available today are virostatic and cannot sterilize retinal cells. Relapses may occur especially in the absence of antiviral prophylaxis.

VIRAL RETINOPATHIES

Necrotizing retinopathies represent a diagnostic and therapeutic challenge. In such cases, ARN is usually suspected, since it carries a poor visual outcome and a high rate of complications, such as rhegmatogenous retinal detachment.2,61

Acute Retinal Necrosis

Antivirals represent the major tools in the treatment of viral retinopathies. Any delay in the initiation of antiviral therapy may be dangerous for the visual outcome of the patient. Despite a few reports on the good penetration of oral acyclovir and the clinical efficacy of oral valacyclovir, intravenous adminis-

tration of acyclovir remains the classical approach. It is effective against HSV and VZV. Close monitoring of the retina is necessary in order to confirm antiviral efficacy. Lesions must be stabilized after a mean period of 48 hours. In resistant cases, more aggressive antiviral therapy should be initiated based on intravenous foscarnet or ganciclovir. Associations are recommended and intravitreal injections of ganciclovir seem to be efficient,62 especially in immunocompromised patients. A case of macular infarction after intravitreal ganciclovir injection has been recently reported.63 Intravenous antiviral therapy must be proposed for a period of 14-21 days, after which, 4 g daily acyclovir or 3 g daily valacyclovir is necessary for an additional period of 1 to 3 months before regular tapering. The total duration of antiviral therapy is controversial but long-term therapy is the only possible way to avoid further relapses, especially in patients with monophthalmus status. After antiviral therapy, infection of the fellow eye is reduced from 70 percent to 13 percent in the first year.64

Anti-inflammatory molecules are still under discussion in ARN syndrome. Vitritis and retinal vasculitis are due to secondary inflammation and not to cytopathic effects. The use of antivirals without the management of secondary inflammation may control viral replication with irreversible inflammatory macular or optic nerve damages. However, ophthalmologists should be aware of a possible activation of virus by corticosteroids leading to increased viral replication and further ocular complications. Corticosteroids should not be administered in the absence of antivirals. Steroids have been used in different atypical cases of ARN syndrome when the diagnosis was unknown for a few days or weeks, inducing major complications leading to blindness despite further aggressive antiviral therapy. This highlights the importance of a rapid confirmation of a viral agent and initiation of antiviral therapy. Steroids may be initiated at 1 mg/kg/d with progressive tapering. In some cases, intravenous pulses of methylprednisolone are administered during the first 3 days, then relayed with high dose oral prednisone. Steroids are not indicated in immunocompromised patients. The effects of anticoagulants and aspirin on occlusive vasculopathy and vasculitis remain controversial. Their influence on the course of the disease is not clear. Anti-

inflammatory treatment of anterior segment uveitis is usually effective.

Retinal detachment may occur in patients with viral retinitis.61,65 Rapidly initiated antiviral and antiinflammatory strategies may avoid retinal detachment in the majority of cases. Retinal detachment occurs in more than 75 percent of untreated cases within a period of 12 weeks from the onset of retinitis. Scleral buckling, pars plana vitrectomy and long-term internal tamponade with silicone oil allow good anatomic success but visual function remains impaired after macular detachment or optic neuropathy. Retinal detachment prophylaxis has been evaluated.66 Laser photocoagulation may be efficient in the presence of peripheral retinal tears. Anti-inflammatory therapy before photocoagulation is important for reducing vitreoretinal tractions. Prophylactic vitrectomy has been evaluated in ARN syndrome but it remains controversial.67

Viral replication is more difficult to stop in patients with PORN syndrome. Therefore, aggressive antiviral therapy based on intravenous foscarnet or ganciclovir and intravitreous ganciclovir are the mainstay treatment.68 Corticosteroids must be avoided in the majority of cases in order to prevent major complications due to viral replication.

Immune Recovery Uveitis

Inflammation plays a major role in the development of IRU. Systemic or periocular injections of steroids are the main therapeutic strategies to reduce ocular inflammation but must be administered under clinical control of HIV load and CD4+ cell counts.35,36,69

Non-necrotizing Herpetic Retinopathies

Atypical forms of posterior uveitis may be associated with viral replication. High dose steroids and conventional immunosuppressors fail to control ocular inflammation. After viral confirmation, the use of intravenous acyclovir or oral valacyclovir reduces inflammation and allow discontinuing immunosuppressors. However, low-dose oral prednisone is necessary in the majority of cases. Alpha interferon may be proposed in severe cases.39

KEY POINTS

•Herpes viruses are highly adapted opportunistic agents, which have evolved several means of evading the immune system and of establishing latency.

•The status of the host’s immune system largely defines the outcome of herpetic ocular infections and their complications.

•One of the major characteristics of herpetic ocular infections is the dual occurrence of a replicative lytic reaction followed or accompanied by subsequent ocular inflammation.

•The prevalence of seropositivity for herpes viruses increases with age and varies geographically.

•The diagnosis of herpetic intraocular inflammation is initially based on the analysis of clinical features. Confirmation of intraocular viral inflammation with or without viral replication relies on molecular techniques such as PCR applied to ocular fluids.

•The other method to confirm viral disease is to ascertain intraocular antibody production against different herpes viruses. However, the amount of ocular fluids is a limiting factor to perform diagnostic tests in patients with a suspicion of viral intraocular inflammation.

•Systemic antiviral drugs should be proposed rapidly in order to control viral replication before the use of corticosteroids.

•All antiherpes virus drugs available today are virostatic. Therefore, relapses may occur especially in the absence of antiviral prophylaxis.

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