TREAMENT
- CORTICOSTEROIDS -The inflammation responds to topical corticosteroids. It is advisable to withhold topical steroid therapy till the corneal epithelium has healed in cases an epithelial defect is present. The duration of treatment depends on individual response and ocular inflammation. Some patients require low dose topical steroids or low potency topical steroids for a longer duration. Patients with HZO often require tapering doses of topical steroids over months as well as anti glaucoma medications (17).
- CYCLOPLEGICS- Cycloplegics especially atropine sulphate and homatropine are recommended. They reduce pain by relieving ciliary spasm. They also break pre-existing synechia, prevent the formation of new synechia and stabilize the blood aqueous barrier. They may also assist fundal evaluation.
- ANTI VIRALS - treatment of choice in HSV keratouveitis is oral acyclovir 800 mg 5 times a day for 2 weeks followed by 800 mg/day. Long term maintenance therapy may be required for recurrent cases of herpetic uveitis. Anti virals must be continued throughout the entire course of steroid therapy (17).
The Herpetic eye disease study (HEDS), a prospective, randomized, double blind, placebo controlled multicentric study, assessed the effect of topical corticosteroids and oral acyclovir to conventional antiviral therapy in patients with HSV keratitis and iridocyclitis (18). The herpes simplex virus iridocyclitis, receiving topical steroids trial (HEDS-IRT) was carried out in HEDS 1. However, the trial was stopped because of low recruitment. Treatment failures occurred at a higher rate in the placebo group. This indicated a potential benefit to adding oral acyclovir to the regimen of topical steroid and an antiviral.
High dose oral acyclovir has been demonstrated to shorten the disease course in HZV infection (17). Gnann and Whitley (30) recommend that all patients with acute HZO must receive antiviral therapy for reducing ocular complications. They report that benefit of therapy started after 72 hours of is not established. Presence of vesicles correlates with viral replication and hence anti viral therapy may be of benefit even if started after 3 days as suggested by some authors.
Studies by Colin et al (31) and Tyring et al (32) have shown valaciclovir and famciclovir, prodrugs of acyclovir and penciclovir to be equivalent in HZO. Oral antiviral therapy does not reduce the complications of HZO but reduces the frequency of late ocular complications from about 50% in untreated to about 20-30% in treated patients. All the drugs are well tolerated with adjustment of dose required only in patients with renal insufficiency.
- ANTI GLAUCOMA MEDICATION -Anti glaucoma medications may be required in cases where the IOP has risen. Glaucoma filtering surgery with or without ant metabolites, seton placement or cyclophotocoagulation may be required in eyes with glaucomatous damage.
- NEWER MEDICATIONS -Mei et al (33) have recently shown the beneficial effect of tumour necrosis factor-alpha anti sense oligonucleotide (TNF-α ASON) on experimental HSV type 1 induced chorioretinitis of mouse eye. It reduced the content of TNF- α in mouse eyes, and this topical treatment decreased the inflammatory reaction.
SPECIFIC CONDITIONS:
Patients with HZO are at risk of corneal decompensation and they should be treated with topical lubricants and followed for development of bacterial infections. Observation for development of associated ocular conditions like conjunctivitis, episcleritis, scleritis, neurotrophic keratitis, cataract and optic neuritis is required (17).
The inflammation associated with EBV is usually self-limited and hence no treatment is required. Occasionally, topical steroids and cycloplegics with rarely systemic steroids may be used in iritis (34).
HTLV 1 associated anterior uveitis responds well to topical steroids and shows a good visual outcome (17).
ACUTE RETINAL NECROSIS SYNDROME
Necrotizing herpetic retinopathy (NHR) is a spectrum of posterior segment inflammation caused by herpes viruses mostly VZV. It presents as either acute retinal necrosis (ARN) or as progressive outer retinal necrosis (PORN). Former usually occurs in healthy persons and latter in severely immunocompromised.
ARN was first described in the Japanese literature by Urayama et al in 1971 and termed Kirisawa uveitis (35). The term BARN for bilateral acute retinal necrosis was first described by Young and Bird in 1978 (36). It is a form of vaso-occlusive retinitis with blinding potential.
ETIOLOGY
Viruses implicated in causing ARN are mainly herpes group of viruses viz. HSV type 1 and 2, VZV, CMV (35) and EBV (37). Culbertson et al for the first time suggested that herpes viruses may be associated with ARN in 1982 (38). Ganatra et al (39) reported that VZV or HSV type 1 cause ARN in patients older than 25 years of age and HSV type 2 causes ARN in patients younger than 25 years. They also found that central nervous system (CNS) infection in a patient with ARN suggests that HSV is the probable viral cause. It is essentially a virus induced cytopathology (40, 41). The accompanying immune response is responsible for retinal necrosis (40, 42). T lymphocytes have been implicated to play a role in ARN (43).
ARN is equally common in males and females. It may present without a prodrome, years after primary infection, as well as following herpetic encephalitis. Genetic markers like HLA-DQw7 and Bw62, DR4 in Caucasian patients in US as well as HLA-Aw33, B44 and DRw6 among Japanese patients may be associated with a higher risk of ARN (44)
Animal experiments have shown that viruses migrate in a retrograde fashion through the parasympathetic fibers of the oculomotor nerve that serve the iris and ciliary body in the CNS (45). The viral replication is limited to the nucleus of visual system and suprachiasmatic area of the hypothalamus (46). From here, the virus can spread to the contralateral eye which is seen in BARN. Along the optic nerve, the virus has been observed in the retinal ganglion cells (47).
PATHOGENESIS
ARN as the name suggests, is a necrotizing retinitis of all retinal layers. The retinal vessels show fibrinoid necrosis of the vessel wall and vascular occlusion. The RPE shows focal necrosis and is separated from the Bruch’s membrane. The necrotic cells reach the vitreous cavity and induce inflammation. The necrosed retina is sharply demarcated from the adjacent healthy retina. Electron microscopy has shown virus particles in the retinal cells (10).
The surrounding choroid shows severe choroiditis with vascular occlusions. Optic neuritis and papillitis may also be seen. Inflammatory cells may also be seen in the anterior chamber and the angle. Both granulomatous and non granulomatous iridocylitis with perivasculitis have been reported (15, 38, 49).
Vascular occlusion leads to ischemia of the retina and choroids and cause necrosis. As a result, breakdown of blood retinal barrier occurs which releases protein in the vitreous cavity. This in turn causes proliferative effect on the RPE and fibroblasts which result in proliferative vitreoretinopathy (PVR). Atrophic retinal holes along with PVR contribute towards increases incidence of retinal detachment in these eyes (10).
CLINICAL FEATURES
Patients are typically healthy and not debilitated, although ARN has been reported in AIDS. It affects adolescents to older adults (37). The prominent complains are irritation, redness, photophobia, tearing, blurring of vision and pain which may be worse on moving the eye. Rarely the first presentation may be with severe visual loss because posterior retinitis, retinal detachment or optic nerve involvement is seen later in the disease course (49, 50, 51).
ARN presents within 2 weeks of symptoms with as a classic triad of peripheral retinitis, vitritis and occlusive retinal arteriolitis. In addition posterior retinitis may also be present.
ARN begins with sharply demarcated retinal necrosis in the periphery, which spreads rapidly. This is accompanied by occlusive vasculitis and severe inflammation in the anterior chamber and vitreous cavity. The retinal lesions tend to be round, polymorphous and yellowish white. They are located at the level of RPE or in the deep layers of retina. The lesions may be described as retinal exudates, retinitis, retinal infiltrates or as swollen retina. They are most commonly found between the mid periphery and the ora with scalloped borders. The retina may appear white with demarcated posterior border. The necrosis spreads circumferentially and posteriorly very rapidly. The macula is often spared.
There is vascular sheathing and attenuation of arterioles. Sheathing of venules is less conspicuous. Often, vascular non perfusion may be found especially in the periphery which may result in retinal neovasculariztion (10). Simultaneously, dense vitritis is seen (10)
Sometimes, a triangular retinal involvement is seen within a quadrant with a point towards the optic nerve. Simultaneously, retinal vasculitis and optic nerve head swelling may develop. Multiple small intraretinal hemorrhages can also be seen (10). Accordingly, color vision abnormalities and an afferent papillary defect may be seen. ARN may also present with a scleritis picture, and hence dilated fundus examination of such patients is necessary (44).
Regression of ARN begins from the outer edge, especially near the venules where a ‘Swiss cheese’ pattern is seen. This leads to retinal atrophy with salt-and-pepper retinal pigmentation with a demarcation line between the healthy and atrophic retina. Membranes develop in the vitreous cavity with posterior vitreous detachment (PVD) and sometimes (PVR) (10). Optic atrophy frequently develops in patients who had optic disc edema earlier in the disease course (44).
Bodaghi et al (52) reported 5 cases of non necrotizing herpetic vasculitis (NNHR) masquerading as severe posterior uveitis. All the cases were PCR proven cases of herpes virus infection. Clinical presentations included birdshot-like chorioretinopathy, occlusive bilateral vasculitis and cystoid macular edema.
Jalali et al (53) recently described a case of bilateral ARN proven to be caused by HSV 1 in a child who initially presented with extensive hemorrhagic retinopathy in one eye. The other eye also had associated retinal venous engorgement. Both eyes did not have occlusive vasculitis as is described for ARN. The patient promptly responded to antiviral therapy
De Boer et al (54) have shown using PCR and local antibody production that VZV infection is two times more common that HSV as a cause for ARN. Similar results were found by Ganatra et al (39) in 30 eyes with clinically diagnosed ARN. 15 eyes were positive for VZV, 7 eyes for HSV 1, 6 eyes with HSV 2 and 1 eye with CMV.
In AIDS, 59-70% patients may have bilateral disease (55). Retrobulbar optic neuritis can cause visual loss which is out of proportion to the macular involvement and it has been reported to precede the clinical appearance of both forms of NHR (55).
DIAGNOSIS
ARN and NHR can be diagnosed on the basis of characteristic fundus picture. The clinical criteria for diagnosis of ARN were published by the American Uveitis Society in the year 1994 (51). It includes presence of one or more foci of retinal necrosis with discrete borders located in the peripheral retina (primarily involving the area adjacent to, or outside of, the major temporal arcades), a rapid progression of the disease in the absence of treatment, circumferential spread, evidence of occlusive vasculopathy with arteriolar involvement and a prominent inflammatory reaction in the vitreous and anterior chamber. Other characteristics that support the diagnosis are optic neuropathy, scleritis and pain.
Fluorescein angiography shows dye leakage from retinal vessels and sometimes from the optic disc. In the affected retina, vascular occlusions are seen especially affecting the venules and the capillaries. Associated retinal neovascularisation may be observed. Healed ARN shows RPE atrophy, damaged choriocapillaries and retinal non perfusion (10).
Herpes virus has been demonstrated in the retinal lesion sand vitreous body by culture, histology, electron microscopy, immunohistochemistry or PCR (10). Antibody analysis of intraocular fluid and serum has further implicated HSV type 1 and 2, VZV and rarely CMV infections (35).
PCR has been used for the etiological diagnosis in uveitis and described in literature (56). Ganatra et al (39) have suggested using PCR based assays in situations in which the cause of uveitis may not be obvious. Pendergast et al (57) suggest that detection of herpes virus DNA on PCR of ocular fluids in a patient with vitreoretinal inflammation should be regarded significant. However, very low levels of viral DNA may persist from prior infection producing a false positive result, which may be misinterpreted as active infection (44). Itoh et al (58) conclude that negative pre existing anti HSV 1 antibody may play an important role in ARN syndrome associated with HSV 2.
Intraocular fluid analysis is indicated in patients with atypical presentation. Negative tests still do not rule out ARN (10). In cases where PCR is negative and there is a high suspicion of ARN, a retinochoroidal biopsy may provide additional information (44).
