Janet L. Davis,
Gregory M. Fox,
Mark S. Blumenkranz
Initially described in Japan in 1971 by Urayama and colleagues and termed Kirisawa's uveitis, acute retinal necrosis (ARN) is a dramatic uveitic syndrome that presents with vitreous inflammation, retinal periarteritis, optic neuropathy, and confluent peripheral necrotizing retinal infiltrates.[1-7] This important clinical syndrome has since been documented to represent the consequences of acute infection of the retina and associated ocular tissues by certain types of Herpesvirus hominis.[8,9] In order to promote clarity of definition, the American Uveitis Society has suggested that the term acute retinal necrosis be used to designate only those cases that conform to a well-described clinical syndrome, characterized by peripheral retinal necrosis with discrete borders, rapid progression with circumferential spread in untreated eyes, occlusive vasculopathy with arteriolar involvement, and prominent inflammation in the vitreous and anterior chamber. Optic neuropathy or atrophy, scleritis, and pain are well-described features in some patients but are not necessary to make the diagnosis.[2,10]
The demonstration of a viral cause for this syndrome has led to the important development of specific pharmacologic therapies; however, late retinal detachment continues to be a serious complication.[11,12]Fortunately, modern vitreoretinal surgical techniques continue to improve the prognosis for retinal reattachment and for recovery of visual acuity.[14] Prompt treatment with antiviral agents and prophylactic retinal photocoagulation may also lessen the risk of disease in the fellow eye and the incidence of late retinal detachment in the initially involved eye.[15,16] Experimental animal studies have shed further light on the mode of viral transmission between the eye and the central nervous system and on the contribution of immunoregulatory events to the pathophysiology of this disease.[17,18] In selected cases in which optic neuropathy seems to be responsible for the large proportion of visual-field and visual-acuity loss, optic nerve sheath decompression has been reported to be worth considering.[19]
Since the original descriptions of ARN, atypical cases of herpetic retinitis have also been described that do not fit the classic syndrome, including more indolent forms of necrotizing retinitis in some patients with varicella.[20-22] The American Uveitis Society suggests that any cases of herpetic retinitis that do not fit the clinical syndrome of ARN be designated as necrotizing herpetic retinopathy. If the specific viral cause is known, the causative viral name can be added as a modifier.[10] Although typical features of ARN have been reported in patients with human immunodeficiency virus (HIV) infection, herpetic retinitis in patients with the acquired immunodeficiency syndrome (AIDS) frequently present with atypical features. An important devastating syndrome of necrotizing retinitis in patients with AIDS has been described by the term progressive outer retinal necrosis (PORN). Believed to be largely caused by retinal infection with varicella-zoster virus, PORN is characterized by the initial appearance of multifocal areas of outer retinal opacification (with little other intraocular inflammation), rapid progression of the lesions to confluence with full-thickness retinal necrosis, and poor response to antiviral therapy.[23,24]
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Terminology |
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EPIDEMIOLOGY
Initially described in Asia,[2] ARN has also been documented in both Europe[3,20-22] and North America.[4-9] Limited prevalence data are available for this disease, but the incidence does appear to be rising. There were no reported cases before 1971, although it now seems likely that previously cases either were not recognized or were misclassified as other forms of posterior uveitis. By 1982, there were 41 cases reported in the world literature,[6] and by 1996, more than 150 articles had been devoted to the syndrome. An epidemiologic study of uveitis in Switzerland found that cases of ARN represented 2.5% of cases of uveitis seen at the uveitis clinic of the Hospital Jules Gonin between January 1990 and March 1993. The incidence of ARN for the referral area studied was calculated to be 4.25 per 1 000 000 inhabitants per year.[25]
Men contract ARN more often than women, and more adults are affected than children. In one report, 63% of patients were male and 37% were female; none was younger than 13 years of age.[6] Since that report, an 11-year-old girl with HIV infection, acquired at birth from her infected mother developed an atypical case of necrotizing retinitis after contracting chickenpox.[26] The disease may affect one or both eyes, with the initial presentation being unilateral in approximately two-thirds of cases.[6,27] When the involvement is bilateral, there is generally a delay between involvement of the first and the second eyes, ranging from 1-6 weeks.[2,28] The timing of involvement of the second eye is consistent with the theories on the propagation and transfer of virus from one eye to another via the optic nerve and central nervous system. Delays as long as 30[28] and 34[29] years between involvement of the first and the second eye have been reported in patients not treated with acyclovir during involvement of the first eye. The risk of development of disease in the fellow eye in patients not treated with intravenous acyclovir has been estimated to be as high as 65% 2 years after the onset of the disease.[15]
The disease was initially described in otherwise healthy patients,[1-7] and immunocompetence has been judged to be one criterion for establishing the diagnosis.[13] This characteristic has distinguished ARN from other forms of opportunistic retinitis in patients with incompetent immune systems or in those with concurrent herpetic disease of the central nervous system.[30,31] Subsequent reports have documented that immunosuppressed patients may experience a clinical syndrome of ARN that is identical to that seen in immunocompetent patients and is readily distinguished from other types of opportunistic retinitis, including cytomegalovirus (CMV) retinitis.[32-34]
HOST FACTORS
Most cases of ARN probably represent primary infection of the retina with virus reactivated from dormant sites, including ganglionic tissue. Serum neutralizing antibodies to the herpes zoster varicella virus group are present in up to 95% of adults,[1,35] and it is likely that host factors predispose certain individuals to the development of the syndrome of ARN. For example, although in excess of 3 million persons each year experience chickenpox, to date there have been 10 patients reported with ARN as a short-term complication of varicella.[20,21,26,36] Similarly, although ARN has been reported to occur as an early complication of herpes zoster in a small number of patients, this is also believed to be an extremely infrequent problem in immunocompetent patients with cutaneous herpes zoster.[37,38] In one prospective randomized series of patients with herpes zoster ophthalmicus (HZO), none of the 71 patients treated with either acyclovir or placebo experienced ARN, although in another large series, 10-33% of patients with HZO demonstrated other forms of viral dissemination.[39] In contrast, the risk of a patient with HIV infection and HZO developing ARN is likely substantial. Sellitti and associates[40] cited an incidence of ARN in 17% of patients with HIV infection and HZO. The majority of these patients developed bilateral retinal necrosis, and all patients presented with retinal necrosis within 9 months of the onset of HZO.
It is likely that patients who experience ARN may have an underlying immunogenetic predisposition to the disease. Holland and colleagues[41] demonstrated a statistically significant increase in the frequency of human leukocyte antigen (HLA) -DQw7 in patients with ARN (55%) versus control patients (19%) (P < 0.0004; relative risk 5.2). In this study, the HLA phenotype Bw62, DR4 was also more frequent than in the controls (16% vs 2.6%; relative risk 7.49). Moreover, the HLA phenotypes of patients may have some effect on the severity of the clinical disease. Matsuo and Matsuo[42] measured an increased frequency of HLA-DR9 in their patients with fulminant ARN (50%) as compared with their patients with mild ARN (0%) (P< 0.05). However, the difference does not retain statistical significance after analysis in a chi-squared test with Yates correction for the number of HLA antigens that were tested.[42] Klok and associates[43] identified the presence of anticardiolipin antibodies in the sera of seven out of 24 patients with ARN versus 10% of healthy control patients. The importance of anticardiolipin antibodies in the pathogenesis of ARN in these patients is uncertain.
In addition to differences in underlying genetic predisposition, it is likely that other host factors and viral factors may play a role in the development of ARN and may influence the incidence of unfavorable clinical outcomes. Recent periocular trauma has been reported to precede the onset of ARN in a few patients.[44,45] Clinical signs such as diffuse arteritis, at the optic disc or beyond the area of retinitis, reduced electroretinographic a- and b-waves, elevated levels of circulating immune complexes, and larger zones of necrosis and exudation are associated with an especially poor prognosis, suggesting that the immunologic response to the virus or intrinsic factors may strongly affect the outcome.[46]
CLINICAL FEATURES
Although the most dramatic and visually devastating aspect of this disease is the confluent necrotizing retinitis from which the syndrome draws its name, most ocular tissues are concurrently affected. The disease can be divided into two different phases: (1) the acute herpetic phase, which lasts ~4-8 weeks; and (2) the late cicatricial phase, occurring after the onset of the disease and characterized by the organization of the vitreous and development of large retinal tears, retinal detachment, and proliferative vitreoretinopathy (PVR).
DISEASE TYPES
Increased awareness and recognition of ARN have enabled clinicians to make increasingly subtle distinctions between ARN, as defined by the American Uveitis Society,[10] and other variants of necrotizing retinitis. These variants include a 'mild form which is more indolent in character and not associated with retinal detachment',[46] and a severe, rapidly progressive syndrome of outer retinal necrosis associated with little vitritis, seen in patients with HIV infection, that is distinct from CMV retinitis.[23,24,34,47] Moreover, there is some evidence to suggest that the disease course and clinical profile of patients with ARN may differ, depending on whether the causative agent is herpes simplex virus (HSV) or the herpes varicella virus group.[22]
ACUTE HERPETIC PHASE
Presenting Symptoms
The onset of ARN is frequently heralded by the development of ocular pain, diminished vision, floaters, and external ocular injection. The patient may give a history of recent or remote herpes zoster or varicella infection in the majority of cases or may occasionally volunteer no history of prior herpetic infection.
Anterior Segment Examination
The conjunctiva is invariably injected with limbal flush, episcleritis, or scleritis. Anterior chamber cell and flare are frequent in conjunction with granulomatous keratinous precipitates (Fig. 164.1). Although a plasmoid aqueous or mild fibrin strands may be seen, iris nodules or hypopyon rare. One clinical feature that may assist in the differentiation of the early phase of ARN from other causes of acute granulomatous anterior uveitis is the frequent occurrence of ocular hypertension, which is also seen in herpes zoster keratouveitis. Herpetic corneal epithelial dendrites or disciform corneal lesions are not encountered, although some patients with concurrent HZO may demonstrate typical vesicular lesions in the distribution of the affected fifth dermatome. The lens is typically unaffected aside from the presence of inflammatory precipitates on its surfaces, which are responsive to steroid therapy. If untreated, posterior synechiae and pupillary seclusion may occur in addition to complicated cataract formation.
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FIGURE 164.1 Granulomatous keratic pzrecipitates are seen in a slit-lamp photomicrograph of a middle-aged man with the early phases of acute retinal necrosis (ARN). |
Vitreous Examination
Vitreous cellular infiltration and protein exudation are characteristic features of the acute phases of the syndrome. In the earliest stages, the inflammatory infiltrate in the vitreous may be relatively mild, increasing as cellular immunity to the virus develops. The vitreous cellular infiltrate is composed predominantly of mononuclear cells including lymphocytes and plasma cells, paralleling the infiltrates seen in other ocular tissues.[1] A viral cytopathic effect has been demonstrated from culture of vitreous specimens obtained at the time of enucleation during the acute phase of the disease.[8,74] Polyclonal anti-HSV antibodies have been identified from vitrectomy specimens in patients with the active phase of the disease.[13] Aqueous specimens from patients with the disease similarly demonstrate antibodies to either HSV-1 and the herpes zoster varicella virus group in ratios suggesting local intraocular antibody production.[8,13,14,70,72,90] High levels of cytokines such as interleukin (IL)-6 have also been found in the vitreous in patients with ARN.[48]
Retina Examination
Retina examination may reveal two characteristic features: confluent zones of opaque necrotizing retinitis predominantly involving the periphery and generalized retinal arteritis associated with capillary vasoocclusion.
Necrotizing retinitis
The earliest retinal lesions are subtle, isolated retinal opacities that may assume a patchy, granular or nummular configuration, depending on their stage of evolution. Although usually seen in the mid-periphery and preequatorial regions, small nummular lesions may also be seen in the posterior retina, generally sparing the macula (Fig. 164.2). In distinction to the granular white dots frequently associated with CMV inclusion disease of the retina, the earliest lesions of ARN are not prominently associated with venules or perivenous hemorrhage. With progression of the syndrome, the granular and nummular lesions increase in size and coalesce to form confluent zones of full-thickness retinal necrosis. These lesions, which are typically situated in the retinal periphery, may occupy as little as 1-2 clock hours or may extend to completely encircle the retina over 360° (Fig. 164.3). The mature lesions have a yellow to white homogeneous color with a somewhat jagged or dentate posterior border in portions extending more posteriorly (Fig. 164.4). They obstruct visualization of the underlying retinal pigment epithelium and choroid. The lesions end abruptly at the ora serrata anteriorly and do not appear to parallel or otherwise respect the retinal vasculature, as is frequently seen in CMV inclusion disease. The retinal lesions that are seen early in the disease arise abruptly and may progress in size and number over approximately a 2-week period in untreated patients. The lesions then begin a period of regression characterized by loss of retinal opacification, thinning, and pigmentary scarring (Fig. 164.5). The loss of opacification, which correlates with the resolution of the inflammatory and viral infiltration of the retina, may initially be seen as perivascular curvilinear lucencies within zones of confluent necrosis. This has been termed a Swiss-cheese appearance (Fig. 164.6). Over the course of several ensuing weeks, these zones of retinal lucency enlarge in conjunction with the development of pigmentary changes in the retinal pigment epithelium and neural retina.
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FIGURE 164.2 Nummular lesion of ARN superonasal and inferonasal to the optic nerve in a middle-aged man with associated herpes zoster involving the upper extremity. |
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FIGURE 164.3 Typical lesions of ARN involving the periphery. Note the confluent white-yellow appearance with an irregular scalloped posterior margin and a sharp transition between involved and uninvolved portions. |
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FIGURE 164.4 Area of confluent necrotizing retinitis with early depigmentation at the posterior margin signifies the beginning of the resolution phase. |
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FIGURE 164.5 The same region as shown in Figure 164.4, ~4 months later, demonstrates clearing of ocular media opacity and better visualization of retinal vascular detail. Note the atrophic pigmented zone corresponding to the area of prior necrosis with some fibroglial proliferative change overlying the center of scar. |
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FIGURE 164.6 Midresolution phase of ARN with the development of curvilinear perivascular lucencies within zones of necrosis before the development of late pigmentary changes (Swiss-cheese appearance). |
The pigmentary changes that characterize the convalescent phase of ARN are most prominent initially at the posterior margins of the lesions and progress outward in a centrifugal fashion coincident with the development of lucencies. The character of the pigmentary response associated with the resolution of ARN is similar to that associated with other forms of viral retinitis, including rubella and CMV, and is distinct from either the heavily pigmented hyperplastic response typical of toxoplasmosis or the atrophic scalloped appearance associated with ocular histoplasmosis. In zones in which there has been particularly severe retinal inflammation and underlying choroidal inflammation, the degree of postnecrotic thinning and retinal pigment epithelial atrophy may be prominent. In some patients in the convalescent phase, giant retinal pigment epithelial tears can develop, leaving large areas devoid of retinal pigment epithelium.[49] In other zones in which the necrotizing retinitis was more mild, it may be difficult to identify the original margins of involvement in the later phases of the disease. In some instances, the acute phase of the disease may be accompanied by the development of a peripheral exudative retinal detachment. This may be distinguished from a rhegmatogenous or complex detachment by the lack of retinal holes,its presence beneath areas of opaque retina, and the presence of shifting subretinal fluid or xanthochromia.
Retinal vasculitis
The second major feature of retinal involvement in this disorder is the development of severe vasoocclusive changes predominantly involving the arterial system. The presence of arteritis, rather than phlebitis, and the associated peripheral vasoocclusion seen in this disease help to distinguish it from CMV infection of the retina on ophthalmoscopic grounds. Although occasionally seen in ocular toxoplasmosis and syphilis, retinal arteritis is particularly striking and severe in ARN and was recognized to be a characteristic feature of herpes zoster infection of the retina even before the widespread recognition of the syndrome ARN in the English-language literature (Fig. 164.7).[50]
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FIGURE 164.7 Artist's representation of a patient with the classic features of ARN, including confluent necrotizing retinitis, posterior nummular infiltrates, and retinal arteritis (with involved vessels seen in yellow). |
Fluorescein angiographic and histopathologic studies on eyes with ARN confirm that the arteritis is not confined to the retinal vessels and may be seen in virtually all tissues studied, including the iris, ciliary body, choroid, and optic nerve. The ophthalmoscopic features of retinal periarteritis include opacification and refractile changes in the walls of the larger retinal arterioles; ophthalmoscopically visible nonperfusion and obliteration of the smaller, more distal ramifications; and retinal capillary nonperfusion best demonstrated by fluorescein angiography.
The retinal opacification seen in this syndrome is distinct from the cloudy swelling commonly associated with retinal arteriolar obstruction, although the latter may contribute to this phenomenon in addition to the cellular infiltration seen histopathologically. Despite the presence of peripheral retinal capillary nonperfusion, retinal, optic nerve, and iris neovascularization are distinctly uncommon in this disease, as contrasted with other forms of vasoocclusive retinopathies.[51,52] The reasons for this observation are unknown but may reflect the concurrent development of retinal and retinal pigment epithelial necrosis in conjunction with nonperfusion, resulting in decreased production of intraocular angiogenic factors. Although large zones of intraretinal hemorrhage are not a characteristic feature of ARN, they may occur in patients in association with zones of phlebitis or frank venous occlusion. Rarely, the fundus appearance may be that of a combined central retinal artery and vein occlusion when there has been severe involvement of the optic nerve and associated vasculature (Fig. 164.8).
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FIGURE 164.8 Patient with confirmed herpes zoster infection of the retina producing ARN. Note the prominent hemorrhagic component suggestive of concomitant retinal venous obstruction. |
Choroidal Involvement
The choroidal vasculature is actively involved in this syndrome. Before the development of opaque confluent retinal lesions, it is possible to identify more subtle opacifications in the outer retina and underlying choroid and pigment epithelium. Early frame angiograms document the presence of focal areas of choroidal hypoperfusion with intense late staining suggestive of infiltration and ischemia (Fig. 164.9). These frequently presage overlying zones of necrotizing retinitis. In histopathologic specimens, the choroidal thickness may be increased three- to fourfold in conjunction with diffuse plasma cell, macrophagic, and lymphocytic stromal infiltrates and perivascular cuffing(Fig. 164.10). To date, despite the early marked inflammatory changes seen in the choroid, herpesvirus particles have been identified only within the choriocapillaris and choroid by in situ DNA hybridization and immunohistochemical stains in a blind eye with burned-out disease.[53] Thus, the majority of early choroidal changes are likely immunocytopathologic rather than the effect of direct viral infection.
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FIGURE 164.9 Fluorescein angiogram of a patient with ARN. |
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FIGURE 164.10 Histopathologic specimen demonstrates marked choroidal stromal thickening and lymphocytic infiltration including larger choroidal vessels. H & E×100. |
Optic Nerve Examination
Optic neuropathy is a frequent and serious complication of ARN. Some degree of optic disk swelling is seen in most cases and may be associated with engorgement of the disk capillaries, swelling of the neural tissue, and distention of the optic nerve sheath (Fig. 164.11).[19,54] In some instances, this may result in profound vision loss. The mechanism of vision loss associated with optic neuropathy in ARN remains somewhat uncertain. It may reflect one of multiple causes, including direct viral infection of the optic nerve,[8,17,19] optic nerve ischemia secondary to vasooclusion,[8] or the result of compression by distention of the nerve sheath.[19] Optic nerve sheath fenestration has been proposed as a method of therapy for patients who demonstrate optic nerve sheath distention by neuroradiologic imaging studies. This has been associated with dramatic visual improvement in some instances. In one clinical series, 47% of eyes in patients with ARN demonstrated neuropathy severe enough to warrant consideration of surgical intervention.[54] Optic neuropathy in ARN that is sufficiently severe to warrant consideration of surgical optic sheath decompression has been defined as (1) the presence of an afferent pupillary defect not consistent with retinal findings, (2) poor correlation between retinal findings and visual acuity and visual field, and (3) sudden deterioration of visual acuity not corresponding to retinal changes.
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FIGURE 164.11 Photographs of severe optic nerve involvement in a patient with ARN. Visual acuity is reduced to light perception despite the lack of obvious macular involvement. Media opacity secondary to vitritis is not consistent with the level of vision dysfunction. |
CICATRICIAL PHASE
With or without therapy, ARN appears to be a self-limited disease, with resolution of the acute inflammatory changes occurring over the course of 1-3 months, depending on the severity of the initial infection and other factors. After resolution of the active phase of the disease, secondary cicatricial changes occur, which frequently lead to the development of late retinal tears, retinal detachment, and loss of useful visual function.
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Key Features: Signs and Symptoms of Acute Phase of ARN |
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The phase of active viral replication is believed to be controlled by normal host humoral and cellular immune mechanisms. In patients not treated with oral acyclovir, corticosteroids, or other pharmacologic agents, the time course for resolution of the active phase may be 6-12 weeks. In patients treated with oral acyclovir, this time phase may be shortened to 4-6 weeks, although to date no prospective studies confirming this have been performed. It is believed that the breakdown in the blood-ocular barrier and secondary cellular and humoral infiltration of the vitreous contribute to the development of late organizational changes in the vitreous body. Collagenous and cellular membranes develop, composed of pigment epithelial cells and fibroblastic elements develop (Fig. 164.12).[28,55] Additionally, secondary growth of pigment epithelial, glial, and fibroblastic membranes on the surface of the retina and continuous with the organized vitreal membranes occurs in the periphery. The concurrence of peripheral retinal thinning, membrane formation, and vitreous contraction contributes to the development of severe PVR frequently seen in patients in the cicatricial stages of ARN (Figs 164.13 and 164.14). Irrespective of acyclovir therapy, late retinal detachment occurs in 75-86% of eyes with ARN.[7,11]
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FIGURE 164.12 Zone of retinal pigment epithelial proliferation and migration underlying thinned necrotic peripheral retina. Note the presence of the nonpigmented epiretinal membrane on the surface of the necrotic retina. H & E×250. |
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FIGURE 164.13 Large tear in the inferior posterior retina of a patient with ARN. |
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FIGURE 164.14 Retinal folds in stage C2 proliferative vitreoretinopathy associated with ARN. Note the pigmented epiretinal membranes in the lower left corner. |
Prophylactic photocoagulation during the acute phase of the disease may reduce the risk of late retinal detachment in some patients.[13,14,17] Although retinal detachment in this condition has been associated with a generally unfavorable prognosis,[2,14] vitreoretinal surgical therapy has improved the outlook (see section on Management of Retinal Detachment). Other late cicatricial complications of the syndrome include iris atrophy, cataract, ciliary body fibrosis and hyposecretion, visually significant vitreous opacities, macular pucker, and giant tears of the retinal pigment epithelium.[49]
OTHER TYPES OF NECROTIZING RETINITIS
Necrotizing Herpetic Retinopathy, Varicella Associated
In addition to the classic form of ARN, patients may exhibit both more benign and more fulminant degrees of ocular involvement in retinal infections caused by the varicella-zoster group. Matsuo and co-workers[46] described six patients with isolated mid-peripheral nonconfluent retinal infiltrates and serologic evidence of herpes zoster varicella infection in whom the ocular involvement did not progress to retinal detachment. In these patients, the role of early acyclovir treatment in the prevention of more severe phases of the disease is unclear. More indolent manifestations of retinal involvement have also been reported in other patients with varicella.[20,21,56-58] Necrotizing herpetic retinopathy associated with varicella appears to be limited predominantly to adults rather than children who contract the disease despite more than 90% of all cases of varicella occuring between the ages of 1 and 14 years.[58] Necrotizing herpetic retinopathy associated with varicella occurs within 3 months of the onset of primary infection (ranging from 5 to 40 days) and is believed to be limited primarily to adults, to involve fewer quadrants, to have less vitritis, and infrequently to lead to retinal detachment.[21]
Acute Retinal Necrosis Associated with Cutaneous Herpes Zoster
Typical ARN has also been associated with cutaneous herpes zoster, reflecting reactivation of latent virus rather than primary infection as in varicella. In contrast to necrotizing herpetic retinopathy associated with varicella, patients with ARN and cutaneous herpes zoster demonstrate typical features including confluent peripheral necrosis, severe vitritis, optic nerve involvement, and late retinal detachment.[37-40]The time interval between cutaneous eruption and ARN ranges from 5 days to 3 months and has been unilateral in eight of nine cases reported in immunologically competent patients to date. Slightly less than half of the cases reported to date have involved cranial nerve V or VII, with the remainder of sites being remote from the eye. However, in patients with AIDS, five cases have been reported of ARN in patients with AIDS and history of prior HZO. The time interval between cutaneous eruption and ARN in these patients has ranged between 0 and 9 months, and four out of five patients developed bilateral ARN.[40] Patients with AIDS and cutaneous zoster remote from the eye have also been reported to develop typical ARN.[59]
Progressive Outer Retinal Necrosis
Although typical ARN has been reported in immunocompromised patients, including those with AIDS,[33-35] a subgroup of patients experience a more fulminant, rapidly progressive necrotizing retinopathy, distinct from either CMV retinitis or typical ARN and consistent with herpes zoster infection of the retina. Early disease in PORN syndrome is characterized by multifocal deep retinal opacifications. These lesions quickly coalesce and progress to total full-thickness retinal necrosis over a short period, and early retinal detachment develops in the majority of patients. In patients with PORN, little or no inflammatory reaction is seen in the vitreous and the anterior chamber, and occlusive vasculitis is generally not seen. Fluorescein angiography demonstrates full-thickness retinochoroiditis with associated choroidal leakage, pruning of the retinal vasculature and zones of frank nonperfusion.[60]
PORN can be easily distinguished from CMV retinitis. CMV retinopathy is characterized by slow progression, and the visual loss associated with CMV corresponds directly with the area of retina involved with the infection or with direct optic nerve involvement. In contrast, the lesions in PORN are rapidly progressive and are multifocal in presentation, and the retinal dysfunction in PORN syndrome is widespread, leading to severe visual loss. The role of varicella-zoster virus group in patients with PORN is strongly suggested by the frequent history of cutaneous herpes zoster infection in affected patients. In one report, antecedent cutaneous zoster occurred in 67% of patients for whom a history was available, and oral acyclovir was being taken by 32% for active cutaneous disease or for antiviral prophylaxis at the time PORN was diagnosed.[61] DNA amplification using the polymerase chain reaction of a paraffin-embedded transscleral eyewall biopsy specimen and an enucleation specimen from a patient with PORN has successfully identified herpes zoster virus DNA, and histologic studies showed intranuclear inclusion in choroidal cells consistent with viral particles.[62] Despite the apparently clear viral cause of this syndrome, potent antiviral medications have failed to preserve visual acuity for most of these patients. Some case reports have described success in treatment of patients with PORN syndrome using several combinations of antiviral medications, including intravenous ganciclovir and oral acyclovir,[63] intravitreal ganciclovir and oral sorivudine,[64] lifelong high-dose intravenous foscarnet alone,[65] or intravenous foscarnet and ganciclovir.[66] Overall, the visual prognosis is poor. Unlike other patients with ARN and like patients with CMV retinitis, patients with PORN often develop disease reactivation along edges of previous retinal infection, even in those who show some initial response to antiviral medications.[67] Laser prophylaxis may be of some benefit.[68] The overall poor visual prognosis for patients with PORN is attributable to a variety of factors, including frequent total necrosis of the retina, retinal detachments, and optic neuropathy. Intravitreal administration of antiviral medication may improve prognosis.[80]
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Key Features: Signs and Symptoms of the Cicatricial Phase of ARN |
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PATHOPHYSIOLOGY
VIRAL CAUSE
Although initial reports noted the similarities between the clinical findings of ARN and those of both Behçet's disease and certain viral infections, the viral cause of this syndrome was not definitively established until 1982.[8] Several lines of evidence implicate the Herpesvirus hominis class of viral infection as the cause of this syndrome. These data include direct viral culture,[7,59,69,74] detection of viral antigens in intraocular fluid specimens by direct or indirect immunofluorescence,[34,65] elevated or serially increasing intraocular or serum antibody titers to herpesviruses,[70-72] immunocytochemical staining of viral antigens in fixed tissue from biopsy or enucleation specimens,[8,23,72,73,74] Herpesvirus hominis particles in gluteraldehyde-fixed retinal tissue,[8,12,24,25,75] herpesvirus DNA amplified by polymerase chain reaction,[25] and clinical disease coincident with or immediately following herpes infection in other sites.[21-23,39] Several members of the Herpesvirus hominis family have been implicated in the pathogenesis of this disease, including the herpes zoster varicella virus group,[1,24,69,76] herpes simplex, types 1 and 2,[1,44,47,70] and CMV in several, rare, single case reports.[75-78] The herpes zoster varicella virus group is believed to account for the majority of cases and the typical syndrome.
Herpesvirus hominis organisms, although exhibiting different immunocytochemical staining characteristics, appear morphologically similar by electron microscopy. The herpes zoster varicella viruses are relatively large, measuring ~150-200 nm when fully enveloped by an outer lipid coat with a central core of double-stranded DNA measuring ~100 nm. The central core is covered by an icosahedral capsid composed of 162 tubular capsomers, which, in turn, are covered by the lipid bilayered envelope (Figs 164.15 and 164.16). The DNA contains ~125 000 bp and weighs 80 MDa. At least five families of varicella-zoster virus glycoproteins have been identified by immunohistochemical studies that represent the primary markers for both humoral and cell-mediated immunity. The varicella-zoster group is highly cell associated and spreads from cell to cell by direct contact. These viruses are fastidious and are difficult to culture, having been successfully transferred from ocular specimens to human embryonal lung fibroblasts and human embryonal kidney cells in vitro.[1,36,79]
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FIGURE 164.15 Transmission electron micrograph of viral particles in the necrotic retina of a middle-aged man with ARN. Note the complete and incomplete viral particles, including the central nucleocapsid and outer lipid envelope. ×87 000. |
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FIGURE 164.16 Another portion of the retina seen in Figure 164.15 demonstrates a large number of tightly packed viral particles in varying stages of assembly. ×30 000. |
HSV-1 and -2 are responsible for oral and genital ulcerations in humans. The virus is also transmitted by direct contact between skin surfaces and mucous membranes. The virus consists of four major components, a centrally located core surrounded by three concentric structures; capsid, tegumen, and envelope. The fully enveloped particle has an approximate diameter of 150-200 nm, with the envelope composed of lipid and protein components conveying the antigenicity of the virus and thereby dictating the host immunologic responses.
Both the herpes zoster varicella virus group and the HSVs code for two unique herpes-specific enzymes, an isofunctional deoxynucleoside kinase (herpes-specific thymidine kinase) and a herpes-specific DNA polymerase. These enzymes are coded by the herpesvirus genome and are not normally encountered in mammalian cells.[80] Acyclovir (9(2-hydroxy-ethoxy)methylguanine) is selectively phosphorylated by the herpes-coded thymidine kinase to its monophosphate form. Mammalian cellular enzymes are then capable of converting acyclovir monophosphate to acyclovir triphosphate. This represents the active antiviral form of the drug, which becomes a selective substrate and inhibitor of herpesviral DNA polymerase. As a result, acyclovir inhibits viral replication in two ways: first, by prevention of the incorporation of deoxynucleotide triphosphates into herpesvirus DNA and, second, by the incorporation of altered nucleotide analogs (Fig. 164.17). Since uninfected mammalian cells do not contain the virus-specific enzyme that converts acyclovir to its monophosphate form, this sequence of inhibitory events is not initiated in nonvirally infected cells, and the drug is therefore relatively nontoxic contrasted with other antiviral agents such as adenine arabinoside.[107]
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FIGURE 164.17 Structural formula of acyclovir, a substituted purine nucleoside that is active against various members of the Herpesvirus hominis family. |
HISTOPATHOLOGY
Histopathologic studies in the acute phases of ARN have been performed on a relatively small number of eyes, either after enucleation or on retinal biopsy specimens taken during vitrectomy.[1,24,35,76,77]Initial reports based on eyes undergoing either vitrectomy for late retinal detachment or enucleation for intractable pain with chronic retinal detachment demonstrated extensive atrophy and degeneration of the outer retinal layers and pigment epithelium, occlusion of the retinal blood vessels, and massive choroidal lymphocytic infiltration and engorgement. Membranes associated with PVR demonstrated a prominent pigment epithelial component with intraretinal and subretinal cysts and subretinal ossification. No viral particles were identified.[28,55]
Eyes in the acute phases of the disease show widespread profound changes in virtually all ocular structures. Granulomatous, keratic precipitates line the corneal endothelium, and chronic and acute inflammatory cells infiltrate the iris and ciliary body, in which perivascular lymphocytic cuffing is evident in conjunction with focal edema of the iris root and adjacent ciliary muscle. Chronic inflammatory cells are seen infiltrating the sclera, accounting for the pain and scleral injection commonly seen clinically. The histopathologic hallmarks of ARN are (1) retinal vasoocclusion, (2) sharply demarcated zones of necrotizing retinitis, (3) choroidal lymphocytic infiltration and thickening, and (4) optic neuropathy.
RETINAL VASOOCCLUSION
Both large- and small-caliber arterioles demonstrate perivascular cuffing, endothelial cell swelling, and fibrinoid or thrombotic occlusion to varying degrees.[1] In some instances, the lumina may be nearly or totally occluded through a combination of endothelial swelling, red blood cell and platelet thrombi, and fibrin (Figs 164.18 and 164.19). Despite the fact that the retinal and choroidal vascular changes are a conspicuous feature of the disease, to date no viral particles or antigen has been detected within retinal vessel walls, suggesting that the changes seen are immunologically mediated.
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FIGURE 164.18 Histophathologic specimen of thrombotic vascular occlusion in ARN. Note engorgement of the underlying choroidal vessel as well as severe perivascular cuffing and occlusion of the lumen in the vessel by erythrocytes. H & E×25. |
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FIGURE 164.19 Cowdry's A intranuclear eosinophilic nuclear inclusions in the retina in a zone of severe necrosis. Note the marked swelling of endothelial cells and the encroachment on lumen by fibrinoid change seen adjacent to a zone of inclusion bodies. H & E ×400. |
CONFLUENT NECROTIZING RETINITIS
Another characteristic feature of ARN is the abrupt demarcation of necrotic and normal retina. Areas of relatively well preserved retina containing inflammatory infiltrates and hemorrhages in the inner and outer layers may be immediately adjacent to other zones of full-thickness necrosis with partial or complete obliteration of the normal retinal architecture. High-power views disclose the presence of eosinophilic intranuclear inclusion bodies in infected retinal cells characteristic of herpes infection. These changes, termed Cowdry A inclusions, contain complete and incomplete viral particles and marginally displace the host nuclear chromatin, which is basophilic in H & E-stained sections. The pigment epithelial proliferation and migration from the normal monolayer through necrotic retina and onto the surface are frequently associated with reactive gliosis and epiretinal membrane formation. These represent the sites of future retinal tears in response to contracting preretinal and transvitreal membranes. Pigmented macrophages are commonly encountered, and cytomegaly is not a conspicuous feature.
CHOROIDAL THICKENING AND LYMPHOCYTIC INFILTRATION
Another feature that differentiates ARN from CMV retinitis histologically is the relatively severe thickening and lymphocytic infiltration of the choroid seen in the former condition. The infiltrate is mononuclear, consisting predominantly of lymphocytes and plasma cells with associated occlusion of the choriocapillaris and, to a lesser extent, the larger choroidal vessels. Areas of granulomatous inflammation may be seen as well. In a blind eye with ARN, varicella-zoster virus DNA was detected in the choroid and choriocapillaris by in situ hybridization and by immunohistochemical stains in mononuclear cells with eosinophilic inclusions.[53]
OPTIC NEUROPATHY
Involvement of the optic nerve is variable, ranging from patchy areas of chronic inflammation along the pia to broad zones of neuronal necrosis, plasma cell infiltration, and vascular occlusion (Fig. 164.20). To date, viral particles have not been identified in the optic nerves available for study, although there is experimental evidence to suggest that transmission from one eye to another in bilateral cases may occur via the optic nerve.[17,18]
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FIGURE 164.20 Cross-section of the optic nerve from a patient with ARN. Note the central zone of necrosis. H & E× 100. |
ELECTRON MICROSCOPIC AND IMMUNOCYTOLOGIC FEATURES
Viral particles found within individual retinal cells demonstrate nucleocapsids of 80-100 nm, which can be seen undergoing assembly within retinal cell nuclei to form poorly enveloped virus. These measure 150-200 nm in diameter and are adherent to retinal cell membranes (Figs 164.15 and 164.16). The virus appears most abundant in the inner retinal layers and in the transition zone between necrotic and preserved retina. In areas of greatest cytopathic effect, there is marked disruption of retinal tissue, with bare nuclei and fragmented cell membranes present. Viral antigens have been identified by immunocytochemical techniques employing a variety of murine monoclonal antibodies and avidin-biotin-peroxidase methods specific for the major GP98/GP62 varicella-zoster glycoprotein complex. Viral antigens have been detected in transitional zones between normal and necrotic retina, retinal pigment epithelial cells, and inner and outer retinal cells, but not in retinal vascular endothelium, ciliary body, or optic nerve. However, immunoglobulins G and M, fibrinogen, and complement component C3c have been detected in retinal arteriolar walls and in surrounding retinal tissue adjacent to zones of zoster antigens.[76]
EXPERIMENTAL ACUTE RETINAL NECROSIS IN AN ANIMAL MODEL
Although it is well established that the primary pathogenetic event of ARN is Herpesvirus hominis infection of the retina, a number of issues remain unresolved, including the route of transmission to the eye, the mechanism of bilateral disease in some patients, and the underlying mechanisms responsible for the variability and severity of the disease. The development of a murine model of herpes simplex retinitis has provided some insights into these questions.[17,18,81,82]
It has been shown that intracameral injection of HSV-1 (KOS strain) in BALB/c mice produces the picture of acute hemorrhagic necrotizing retinitis. Interestingly, the retinitis does not occur in the injected eye but rather in the contralateral (noninjected) eye 9-10 days after injection and is completed over the course of 12-48 h.[82,83] ARN develops only in immunocompetent animals and only when viral titers in the contralateral eye exceed a threshold level (4 log10 plaque-forming units). This confirms that viral infection is essential for the development of this syndrome. After injection into the anterior chamber of one eye, HSV reaches the contralateral eye in two waves. The first, which fails to replicate, arrives within 24 h. The second arrives within 5-7 days and reaches the eye after retrograde spread down the optic nerve from the brain. Within 24-48 h of the arrival of the second wave of replicating virus, the characteristic picture of hemorrhagic and necrotizing retinitis develops.[83]
In this murine model, in addition to viral infection, immunologic factors play an important role in the development of ARN. It is known that, paradoxically, immunocompetence is a prerequisite for the development of ARN in several different regards. First, immunoincompetent mice (athymic) do not develop the characteristic fundus picture of ARN, although viral replication takes place in the contralateral eye at a comparable time and in similar quantity to immunocompetent animals. Second, ARN does not develop unless there is suppression of virus-specific delayed hypersensitivity. This phenomenon is termed anterior chamber-associated immune deviation and is genetically determined in certain strains of mice in which humoral antiviral antibody production remains unaffected. These findings are consistent with a report on a patient with ARN caused by HSV who had documented evidence of bilateral high-intensity optic tract lesions involving the lateral geniculate ganglia, temporal lobes, and midbrain seen on magnetic resonance imaging (MRI). This, along with concurrent generalized malaise and fever, suggests a neural route of spread.[1]
The requirement for immunocompetence appears to be based on the participation of precursor cytotoxic T cells in the development of retinal necrosis. T cells harvested from lymph nodes ipsilateral to the injected eye and from the contralateral eye proliferate in vitro when exposed to viral antigens and are believed to mediate the destruction of retinal cells infected by HSV.[18] It has also been shown that HSV-specific effector T cells, when promptly injected into the contralateral eye of animals undergoing intracameral injection of HSV, will prevent the development of ARN, although injection of effector cells delayed by more than 1 day after virus injection will not. Moreover, HSV-1-specific immune effector cells restimulated with virus in vitro are more effective in producing cytotoxicity to HSV-1-infected target cells than are HSV-1-specific immune effector cells that are not restimulated.[83]
DIFFERENTIAL DIAGNOSIS
OPHTHALMOSCOPY
Because of its characteristic fundus appearance, the diagnosis of ARN can be established in the healthy immunocompetent patient on ophthalmoscopic grounds, which include (1) the presence of granulomatous anterior uveitis, (2) vitreous cellular reaction, (3) retinal arteritis, (4) multiple patchy or confluent areas of necrotizing retinitis with or without associated hemorrhage predominantly located in the retina periphery, and (5) optic disk swelling of variable degree.
The conditions to be considered in the differential diagnosis of ARN are listed in Table 164.1. The clinical syndromes most commonly misdiagnosed as ARN in healthy patients are syphilitic neuroretinitis and acute multifocal hemorrhagic retinal vasculitis.[51,84] The former can be distinguished on the basis of appropriate serologic testing, and the latter by the presence of a greater degree of retinal hemorrhages, initial venous involvement, and a subsequent clinical course that includes a failure to respond to acyclovir, a failure to develop retinal detachment, and the likelihood of ocular neovascularization. In some instances, the differentiation between ARN and CMV retinitis or toxoplasmic retinochoroiditis may be problematic in immunocompromised patients. PORN can be readily distinguished from ARN syndrome because of the absence of vitritis and anterior chamber inflammation, the extremely rapid progression from multifocal areas of deep retinal opacification to complete retinal necrosis, and the commonly very poor response to antiviral therapies seen in patients with PORN. Sarcoidosis, Candida albicans endophthalmitis, and Behçet's disease can generally be distinguished from ARN by the clinical history. It has been recognized that some patients with intraocular lymphoblastic lymphoma may present with retinal hemorrhages, pseudovasculitis, and infiltrates mimicking ARN.[85-87] Bilateral retinal necrosis has also been described as a complication of X-linked lymphoproliferative disease, and Epstein-Barr virus genomic DNA within the eye was shown by the polymerase chain reaction.[88]
TABLE 164.1 -- Differential Diagnosis of Acute Retinal Necrosis
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Syphilitic neuroretinitis |
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Cytomegalovirus retinitis |
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Epstein-Barr virus retinitis |
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Toxoplasmic retinochoroiditis |
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Candida albicans endophthalmitis |
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Acute multifocal hemorrhagic retinal vasculitis |
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Behçet's disease |
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Sarcoidosis |
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Progressive outer retinal necrosis |
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Primary intraocular lymphoma |
LABORATORY EVALUATION
Baseline laboratory examination of patients with suspected ARN can help establish the diagnosis and facilitate treatment. Suggested studies are outlined Key Features: Diagnosis. Patients should have a complete blood count, sedimentation rate determination, and basic serologic studies, including a Venereal Disease Research Laboratory (VDRL) test, fluorescent treponemal antibody absorption test, and rheumatoid factor and antinuclear antibody determinations to exclude systemic vasculitis or coagulopathy. Consideration should be given to serologic testing for HIV infection. Abnormal platelet hyperaggregation in response to adenosine diphosphate administration has been detected in patients with ARN.[89] Quantitative antibody level testing for herpesvirus in acute and chronic sera from patients with ARN is relatively unhelpful in determining a specific causative diagnosis in this syndrome. In one study, only 39% of cases had a diagnostic increase or decrease in herpes group viral antibody levels on serial sampling.[90] Serum creatinine, blood urea nitrogen determinations, as well as urinalysis, should be performed to determine the patient's suitability for acyclovir administration, and a chest radiograph study and a purified protein derivative test should be performed to exclude tuberculous disease, which could contraindicate oral corticosteroid therapy.
Optional studies should be performed in specialized circumstances, including a computed tomography (CT) scan or MRI study in patients with clinical evidence of severe optic nerve dysfunction or central nervous system symptoms such as headache, meningismus, or altered mental status. MRI evidence of optic nerve tract, ganglionic, or cerebral disease may have an impact on the dosage and duration of acyclovir therapy. Consideration should be given to lumbar puncture in patients with either neurologic symptoms or an abnormal neuroradiologic imaging study. Appropriate cerebrospinal fluid cultures, antibody testing, and cytologic studies should be performed only in rare instances to exclude other causes of central nervous system disease and retinal infiltration such as syphilis or lymphoblastic lymphoma.
Anterior chamber or vitreous specimens have been obtained in patients with ARN that helped to determine the causative viral agent. Assays are used to detect viral antibody levels in the intraocular fluids with appropriate recalculations for serum antibody levels by the Goldmann-Wittmer coefficient.[23,70,71,91-95] In one study, the rate of identifying viral cause in ARN via intraocular antibody production determinations was 89%.[96] However, the detection of multiple positive quotients for antibodies within a single eye can make interpretation problematic.[96] The detection of herpesviral DNA in specimens from eyes with ARN and eyes with PORN has also been reported utilizing the polymerase chain reaction to amplify minute quantities of viral DNA from specimens as small as 50 ?L.[63,97-101] When available and when intraocular surgery is otherwise warranted, these tests on intraocular fluids are certainly indicated. Rarely, in complex cases - such as in patients with underlying immunocompromise or atypical findings, or in those refractory to antiviral therapy - diagnostic vitrectomy or retinal biopsy, or both, may be indicated. In addition to conclusively establishing the diagnosis, this may permit testing for antiviral sensitivities.[1,24,48,70,73,102] Diagnostic vitrectomy has been combined with infusion of intravitreal acyclovir in a concentration of 10-40 ?g/mL.[12]
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CURRENT THERAPY
Current management of ARN consists of five primary components in the acute phase of the disease, in addition to treatment of retinal detachment if it occurs in the cicatricial phase of the disease. These five components are (1) antiviral therapy, (2) antiinflammatory therapy, (3) antithrombotic therapy, (4) retinal detachment prophylaxis, and (5) possible optic nerve therapy.
ANTIVIRAL THERAPY
The demonstration of herpesvirus particles in eyes with ARN facilitated the development of specific treatment regimens. Both intravitreal[12,80] and intravenous acyclovir[12,16] have been reported to be of benefit in the treatment of this disorder.
Acyclovir
Acyclovir remains the drug of choice for the initial treatment of ARN and has selective advantages over other purine and pyrimidine nucleoside antimetabolites with antiviral activity in vitro, including phosphonoformate, bromovinyldeoxyuridine, and fluoroiodoaracytosine.[69] Because of the relative sensitivity of HSV (ED50 of 0.1-1.6 ?M) and, to a lesser extent, the herpes zoster varicella group (ED50 of 3-4 ?M) to acyclovir, the drug theoretically is effective in ARN associated with either agent.[104] Because ARN is generally not believed to be caused by strains of CMV, which is typically more resistant to acyclovir (ED50 of 200 ?M), more toxic agents, including vidarabine[104] and ganciclovir[104] or foscarnet,[105] are not generally required, unless there is evidence of drug resistance or associated HIV infection.
After intravenous administration of 5 mg/kg of acyclovir in humans, peak plasma levels of 30-40 ?M are reached with a half-life of 2-4 h. These levels contrast with a peak concentration of 8.7 ?M in the serum and 3.3 ?M in the aqueous humor after five oral 400-mg doses in volunteers undergoing cataract extraction.[106,107] Because there is a significant correlation between plasma and aqueous concentrations of the drug, it can be inferred that intraocular concentrations of acyclovir are considerably higher after intravenous administration than after oral administration. At present, initial therapy with intravenous acyclovir for a minimum of 1 week is recommended. Because active viral particles have been identified in eyes with ARN subsequent to intravenous acyclovir therapy,[11] and the greatest period of risk for involvement of the fellow eye is within the first 6 weeks after presentation of the first eye, oral acyclovir should be administered at a dosage of 2-4 g daily for 4-12 weeks after completion of intravenous acyclovir as a precautionary measure. The role of oral acyclovir in higher dose ranges (4 g daily) as an alternative treatment to intravenous acyclovir remains unsettled and awaits further study.
Intravenous acyclovir is generally administered at a total dosage of 1500 mg m?2 day?1 based on calculation of the body index in square meters from the height and weight; 500 mg m?2 day?1 is administered every 8 h. Oral acyclovir is available in either 200-mg or 800-mg strength, which is administered five times daily in dosages ranging from 1000 mg to 4 g daily, depending on the severity of the disease process and the age and weight of the patient. Studies of antiviral sensitivities of the herpes zoster varicella virus group isolated from the vitreous of a patient with ARN indicated in vitro susceptibility of the isolate to both acyclovir (ED50 of 5.3 ?M) and dehydroxyphenylglycol (ED50 of 4.7 ?M).
Acyclovir has a large therapeutic index, and complications reported to date have been relatively minor. They include local irritation at the intravenous entry site and, rarely, reversible elevation of serum creatinine concentration, presumably through crystallization. Central nervous system toxic reactions, including delirium, tremors, abnormal electroencephalograms, as well as elevation of liver transaminase levels, have been reported, although also rarely and in complex cases in which a causal relationship has not been clearly established. To date, acyclovir has not been found to be carcinogenic, mutagenic, or teratogenic.[107]
In one clinical series, treatment of patients with ARN with 1500 mg m?2 day?1 of acyclovir in conjunction with aspirin and corticosteroids resulted in regression of active retinal lesions of presumed viral origin beginning, on average, 3.9 days after initiation of therapy. Lesions completely regressed on an average of 32.5 days after initiation of therapy, and no eye developed new retinal lesions or progressive optic nerve involvement 48 h or more after initiation of therapy. Acyclovir treatment does not appear to ameliorate vitritis or retard the rate of retinal detachment in advanced cases, although it may do so in cases treated at an earlier time, before the development of severe confluent lesions.[11,46] Retrospective analysis of patients treated both before the era of acyclovir therapy and subsequent to the induction of acyclovir suggests a benefit of treatment with regard to prevention of new lesions in the fellow eye. Of 31 patients treated with acyclovir, 87.1% were disease- free in the fellow eye at the time of last examination, in contrast to only 30.4% of fellow eyes in patients not treated with acyclovir. Two years after treatment using multivariate methods, the cumulative proportion of patients who remained disease-free in the fellow eye was 75.3% for the group treated with acyclovir and 35.1% for the group not treated with acyclovir.[15] Since the patients involved in this study were evaluated retrospectively and treated at different times and at multiple different institutions, these data should be interpreted with appropriate caution (Figs 164.21 and 164.22).
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FIGURE 164.21 Life table analysis of lesions treated with and without acyclovir and the resultant cumulative risk of disease development in the fellow eye. The broken line represents untreated patients with unilateral disease over time. The group of patients treated with acyclovir is less likely than the group not treated to develop ARN in the fellow eye (P = 0.0013). |
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FIGURE 164.22 The same region as shown in Figure 164.2 after 10 days of intravenous administration of acyclovir. Note the nearly complete resolution of nummular lesions nasal to the optic nerve. |
In patients who are unable to tolerate acyclovir or who demonstrate clinical disease progression suggestive of acyclovir drug resistance, consideration may be given to administration of intravenous ganciclovir as an alternative form of therapy. Recommended guidelines for treatment with ganciclovir at present are 5 mg/kg every 12 h for 7 to 14 days by intravenous infusion. Patients undergoing ganciclovir administration should have a twice-weekly complete blood count with differential and platelet count to identify early signs of hematopoietic suppression. The dosage of ganciclovir should be reduced in patients with evidence of impaired creatinine clearance, and the drug should be discontinued on signs of severe leukopenia (<1000 cells/?L) or thrombocytopenia.[78,104,108]
In addition to oral and intravenous routes, acyclovir may also be administered as an intravitreal infusate during the course of vitrectomy. Concentrations of 10-40 ?g/mL have been reported to be safe.[12,108]This form of treatment may be effective as an adjunct to oral and intravenous therapy in patients requiring vitrectomy during the acute phase of viral replication within the eye. Direct intravitreal injection of ganciclovir 2 mg or foscarnet 2.4 mg during the acute phases of the disease appears to improve outcome compared to treatment with systemic medication only.[80]
Other Antiviral Agents
Famciclovir
Recently, congeners of acyclovir have been developed that have more favorable pharmacokinetic parameters after oral administration. Famciclovir is a synthetic acyclic guanine derivative prodrug that is metabolized to penciclovir after oral administration. Penciclovir is active against HSV and herpes zoster virus and has been used successfully in immunocompetent patients with shingles and recurrent genital infection (Fig. 164.23).[109]
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FIGURE 164.23 Structural formula of famciclovir and its active metabolite penciclovir. |
Valacyclovir
Valacyclovir is the L-valyl ester of acyclovir, which is given as an oral prodrug that undergoes rapid first-pass metabolism to yield acyclovir and L-valine. Its principal advantage over oral acyclovir is its greater bioavailability (Fig. 164.24). Three daily 1000-mg doses of valacyclovir are believed to be as effective as five daily 800-mg doses of acyclovir in the treatment of cutaneous herpes zoster infection.[110] There remain few published data on the effectiveness of either famciclovir or valacyclovir in the treatment of ARN, but anecdotal data seem promising.
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FIGURE 164.24 Structural formula of valacyclovir, a prodrug converted to acyclovir and L-valine by hydrolase. |
ANTIINFLAMMATORY THERAPY
Inflammatory cells, including cytotoxic lymphocytes, are believed to play a major role in both the primary phases of the syndrome, when they may contribute to both retinal necrosis and vasculitis,[17,18,111-114]and secondarily, when vitreous cellular infiltrates contribute to organization of the vitreous that predisposes to late retinal detachment.[1-9] As a result, antiinflammatory therapy is an important component of treatment for this disease. Administration of oral prednisone or equivalent corticosteroids in doses of 0.5-1.5 mg kg?1 day?1 is recommended in the acute phases of the syndrome during the period of greatest intraocular inflammation. Because steroids are known to enhance viral replication under selected conditions, the initiation of steroid therapy should be delayed 24-48 h after administration of intravenous acyclovir. However, in cases in which the severity of intraocular inflammation is great, particularly with optic nerve involvement, consideration may be given to earlier institution and increase of the dosage to 2 mg kg?1 day?1 of steroid therapy. The exact duration of steroid therapy is dictated by the severity of the intraocular inflammation and any associated complications of therapy. In patients in whom there is no contraindication to steroid therapy, treatment with prednisone should continue for 6-8 weeks, with gradual tapering of the dose in order to reduce both the anterior and the posterior segment intraocular inflammation. At present, no other form of antiinflammatory therapy, including cyclosporine or various antimetabolites, has been shown to be of benefit in this syndrome. Topical treatment with prednisolone in conjunction with cycloplegic agents should also be given with dosage dictated by the severity of anterior segment inflammation. No benefit has been demonstrated for the use of topical acyclovir in this syndrome.
ANTITHROMBOTIC THERAPY
Periarteritis and intraluminal narrowing are conspicuous features of ARN on both clinical and histopathologic studies. Viral particles have not been demonstrated in the retinal vascular endothelial cells, although the cells themselves may bemarkedly swollen, nearly obliterating the vascular lumina in some patients.[1,76] These events are believed to be secondary to humoral and cell-mediated mechanisms and contribute to stasis and vascular thrombosis in patients with ARN. This may result in vision loss from both optic nerve dysfunction and retinal infarction. In addition to treatment with antiinflammatory agents, both antiplatelet agents and anticoagulation have been previously recommended.[11,115] Platelet hyperaggregation has been detected in patients with ARN and may be treated with aspirin, 500-650 mg daily. The benefits of more aggressive forms of anticoagulation, including both heparin and warfarin, do not at present appear to warrant the use of such forms.
RETINAL DETACHMENT PROPHYLAXIS
Retinal detachment continues to be the most serious late complication of ARN, even with the prompt administration of acyclovir and steroid therapy. Peripheral argon laser photocoagulation to demarcate zones of retinitis during the acute phase of the disease has been recommended as a potentially effective prophylactic measure if the media will permit such treatment.[16,68] In one retrospective clinical series,[16] 12 eyes in 10 patients underwent prophylactic laser photocoagulation and two (17%) retinal detachments developed. During the same time, four of six (66%) patients not receiving photocoagulation experienced retinal detachment as a complication of ARN. Because it is likely that eyes with less severe forms of ARN have the clearest media and are therefore more likely to be able to undergo prophylactic photocoagulation when compared with more severely affected eyes, it cannot be definitively concluded that the difference in these two rates is solely the result of photocoagulation. Nonetheless, it seems likely that photoco agulation does have some prophylactic value against the development of retinal detachment and it should be administered in all patients at the earliest possible stage. Recommended treatment guidelines at present include the placement of three rows of argon, krypton, or dye laser at the junctional zones demarcating peripheral confluent necrosis from normal retina. When possible, photocoagulation should be extended into zones of necrosis, in which the retina tears usually occur. The benefit of photocoagulation in isolated thumbprint lesions in the posterior segment is less certain. In some instances, longer wavelengths and retrobulbar anesthesia may be helpful in permitting successful applications in eyes with media opacities. Despite photocoagulation, it can be estimated that up to 50% of eyes with ARN will develop retinal detachment.
One alternative strategy for retinal detachment prophylaxis has been the use of vitrectomy combined with endophotocoagulation and scleral buckling.[12,14,114] One difficulty encountered in the performance of a vitrectomy in such eyes is the tight adherence between the nondetached vitreous gel and the atrophic, necrotic peripheral retina. Additionally, eyes with ARN-associated severe intraocular inflammation may develop severe postoperative ocular hypertension, fibrin response, and choroidal detachment after vitrectomy and scleral buckling.[115] The prophylactic benefit of combined vitrectomy and scleral buckling with endolaser remains uncertain.[12,14,117,118] In one series, three of four eyes undergoing such prophylactic surgery experienced retinal detachment despite this therapy and appeared to have a more unfavorable course than eyes not undergoing prophylactic vitrectomy and photocoagulation.[118]
TREATMENT OF ACUTE OPTIC NEUROPATHY
In addition to the zones of frank neural necrosis seen histopathologically,[19,54] it has been suggested that in some instances optic nerve sheath distention and compression of the optic nerve may contribute to the visual dysfunction associated with ARN. In one series, eight eyes in six patients with optic neuropathy believed to be secondary to ARN underwent optic nerve sheath decompression in addition to intravenous acyclovir therapy. These patients had a more favorable long-term visual prognosis than did patients with lesser degrees of neuropathy not undergoing decompression.[54] Clinical experience with this form of therapy remains limited, but it appears to be a potentially useful way to reduce visual disability in this condition in conjunction with appropriate antiviral, antiinflammatory, and antithrombotic therapy. This diagnosis may be established on the basis of CT or MRI scanning in patients with clinical or visual evidence of optic neuropathy in association with ARN.
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* Case series support use. |
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? Case reports support use. |
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? Recommended in patients who are immunocompromised. |
MANAGEMENT OF RETINAL DETACHMENT
Retinal detachment continues to be a difficult problem in patients with late-stage ARN. In initial series of patients treated appropriately with acyclovir, corticosteroids, and aspirin, 11 of 13 eyes experienced retinal detachment (84.6%).[11] This is comparable to a 75% rate of retinal detachment seen before the introduction of acyclovir therapy.[7]
Retinal detachment complicating ARN is particularly severe. The majority of retinal detachments occur within 3 months of the onset of symptoms. In one review, 41 of 55 eyes (75%) affected by the virus experienced retinal detachment. The time interval ranged from 1 to 10 months, with only four of 41 eyes experiencing a retinal detachment more than 3 months after the onset of the syndrome.[9] In a series of 12 patients (13 eyes) treated with intravenous acyclovir, 83.6% of eyes experienced retinal detachment an average of 59 days after initiation of therapy, with a range of 30-145 days.[11] Eyes with retinal detachment complicating ARN have a more unfavorable visual and anatomic prognosis for several reasons. The retinal breaks contributing to the rhegmatogenous components of these detachments are often multiple, large, and posteriorly located, either in necrotic retina or at the junction between normal and necrotic retina (Figs 164.25 and 164.13). PVR is frequent, and eyes that demonstrate severe preexisting intraocular inflammation and vascular compromise are predisposed to fibrin response, choroidal detachment, and ocular hypertension (Fig. 164.14).[5,15,118]
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FIGURE 164.25 Artist's representation of retinal detachment in a patient with ARN, including a large superior retinal tear at the junction of involved and noninvolved retina as well as multiple smaller pinpoint defects in areas of postnecrotic zones. Note the presence of fixed folds radiating through the posterior pole from the periphery |
PVR is a frequent occurrence in eyes with ARN that experience retinal detachment. In one series, 72.7% of eyes with retinal detachment demonstrated stage C1 or greater PVR.[12] The high frequency with which PVR occurs in this group of patients can be understood in view of the pathophysiology of the disease, including marked thinning of the peripheral retina and migration of pigment epithelial cells through necrotic retina onto the retina surface associated with metaplasia and epiretinal membrane formation. These changes occur in conjunction with cellular infiltration and secondary fibrotic changes in the vitreous, including adherence to the peripheral retina. It is known that the breakdown of the blood-ocular barrier encountered in patients with uveitis contributes to the development of PVR, through liberation of serum-derived growth factors within the eye.[119] It is also known that fibrin, which is known to be more common in eyes undergoing retinal reattachment surgery for ARN,[118] is capable of producing mesenchymal transformation of pigment epithelial cells, which may further contribute to the development of PVR.[120] As a result of these factors, retinal detachment repair in patients with ARN has been more difficult than other forms of retinal reattachment, although success rates appear to be improving with improved vitreoretinal surgical techniques.
Before 1982, retinal reattachment was attempted in only 18 of 41 eyes, with only four of 18 procedures being successful (22%).[7] Employing a combination of scleral buckling and vitrectomy in selected instances, Clarkson and colleagues[118] reported an improved success rate, with 13 of 16 eyes that experienced retinal detachment from ARN requiring operation and seven retinas remaining reattached (53.8%). Similar results have been reported by other authors employing a combination of vitreoretinal surgery and scleral buckling.[121]
Other reports suggest that a combination of vitrectomy, lensectomy, internal fluid-gas exchange, and endolaser treatment without scleral buckling may provide a more favorable anatomic and visual outcome in eyes with retinal detachment complicating ARN (Fig. 164.26).[14] In one series, eyes undergoing this procedure were compared with eyes undergoing conventional scleral buckling in association with vitrectomy. Overall, a combined final success rate of 93.8% (15 of 16 eyes) was reported. Complete retinal reattachment with one operation was achieved for all eyes not previously subjected to a prophylactic procedure.[14,118] In this series of patients, perioperative complications, including ocular hypertension (75%), fibrin response (87.5%), and choroidal detachment (62.5%), were common in patients undergoing scleral buckling (Fig. 164.27). Without scleral buckling and cryotherapy, only one of eight eyes (12.5%) experienced fibrin response and none had choroidal detachment or ocular hypertension (intraocular pressure greater than 35 mm Hg). The rate of reoperation and the final visual-acuity rate also appeared to be more favorable in those patients undergoing vitrectomy without scleral buckling, with 87.5% of patients achieving a visual acuity of 20/200 or better and 62.5% achieving a visual acuity of 20/70 or better. These visual-acuity results contrasted with only 25% of patients undergoing scleral buckling combined with vitrectomy achieving a visual acuity of 20/200 or better. This may be related to the higher rate of need for retinal reoperation and use of silicone oil in this group.[118] Silicone oil, or other tamponades, and retinotomy may be required in some eyes with severe proliferative retinopathy. However, the use of silicone oil in primary retinal detachment associated with ARN does not seem necessary in the majority of cases.
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FIGURE 164.26 Artist's representation of peripheral demarcating photocoagulation, after vitrectomy and fluid-gas exchange in a patient with retinal holes and detachment secondary to ARN, seen in Figure 164.25. |
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FIGURE 164.27 Slit-lamp photograph of a pupillary fibrin response in a patient who underwent lensectomy, vitrectomy, scleral buckling, and endolaser treatment for an ARN-related retinal detachment. |
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