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VIRAL UVEITIS

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Correspondance: Shri Ganapati Netralaya, Jalna

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Viral uveitis has myriad presentations. They may present as anterior uveitis, intermediate uveitis, acute retinal necrosis (ARN), progressive outer retinal necrosis (PORN) and neuroretinitis. The causative viruses mainly include herpes group of viruses and human immunodeficiency virus (HIV). Other DNA viruses which cause uveitis are poxviruses, adenoviruses especially those that produce epidemic keratoconjunctivitis and pharyngoconjunctival fever. RNA viruses isolated are influenza virus, mumps virus, measles virus, rubella virus, rift valley fever virus and Newcastle virus. Here we have discussed all the different types of viral uveitis except opportunistic viral infections in HIV.

ANTERIOR UVEITIS
Viral anterior uveitis is caused mainly by herpes simplex virus (HSV) type 1 and 2, varicella zoster virus (VZV), cytomegalovirus virus (CMV), Epstein-Barr virus (EBV) and human herpes virus (HHV) type 6, 7 and 8 (1-3). Herpes literally means ‘to crawl’ from the Greek word ‘herpein’. Herpes viruses are widely distributed in environment. HSV 1, HSV 2, VZV and HHV 8 form the subfamily alpha herpes viruses. CMV, HHV 6 and 7 form subfamily beta herpes viruses. EBV forms subfamily gamma herpes virus.
The virus mot commonly associated with anterior uveitis is HSV 1 which may be suspected in 1% to 9% of all cases of anterior uveitis (4-6). A recent study reported that the greatest relative risk of herpetic anterior and posterior uveitis was associated with HLA B44 and B51 antigens (7). Rarely there may be reactivation from a viral strain used for vaccination. Lin et al (8) report a case of a 16 year old child who presented more than 8 years after varicella vaccination, with keratouveitis, severe inflammatory glaucoma and Hutchinson's sign. It was unclear whether the source of herpes zoster which reactivated in this patient represented wild type virus or his previous vaccine strain.
The member viruses share common characteristics. The core contains a linear double-stranded DNA which is surrounded by a capsid and an envelope. The envelope is a derivative of the core membrane of the infected cells and consists of lipids with inserted viral glycoprotein. There are specific receptors of the glycoproteins of the envelope that recognize complementary receptors on the host cell membrane and bind to them (adsorption). The envelope and the cell membrane fuse and the viral nucleocapsid enters the cell. The viral proteins are then produced in a cascade. The synthesis of DNA and assembly of capsid take place in the nucleus. The production of infected particles in the cytoplasm leads to destruction of the host cell (3, 9). All known herpes viruses establish clinical or latent infection in the host.
Latency is restricted to a small number of susceptible cells. During latency, virus genomes form closed circular molecules, and only a small number of viral proteins are expressed, with no mature virus production (10).
HSV primarily affects the mucosa. The virus replicates intracellularly and infects other cells. It then travels in a retrograde fashion to reach the sensory ganglia and establishes latency which may keep on flaring up after exposure to a wide range of factors viz. ultraviolet light, fever or stress. Neither the mechanisms which maintain the status of latency nor the factors which cause reactivation are completely understood.

PATHOGENESIS
The iris stroma is infiltrated with lymphocytes. HSV infection causes swelling and obstruction of the trabecular meshwork by inflammatory cells. Eventually trabecular scarring develops. Sundmacher and Neumann-Haefelin report the presence of HSV from aqueous aspirated from eyes with endothelitis and trabeculitis (11).
Diseases like Posner-Schlossman (PS) syndrome and iridocorneal endothelial (ICE) syndrome which clinically have iris atrophy have shown the presence of virus in aqueous sample. Yamamoto et al (12) confirmed the presence of HSV in 3 eyes with PS syndrome after aspirating aqueous samples during acute attack. Alvarado et al (13) have also demonstrated the presence of HSV in eyes with ICE syndrome. They reported that HSV DNA was seen in a substantial percentage of ICE syndrome corneal specimens and was absent in normal corneas indicating towards its etiological role.
VZV shows polyneuritis and perivasculitis with chronic inflammatory cell infiltrate. Wenkel et al (14) believed that VZV uveitis represents an immune response against persistent inactivated viral antigens in the eye or continuing low grade viral replication. Naumann et al (15) reported that occlusive vasculitis may play an important role. Focal or sectoral iris atrophy was a result of iris ischemia. There may be accompanying necrosis of ciliary body causing hypotony.
Kezuka et al (16) reported that absence or loss of delayed type hypersensitivity to the VZV antigens as determined by skin testing seemed to be a concomitant feature of VZV uveitis of high intensity, implying that virus-specific delayed hypersensitivity may interfere with emergence of VZV induced anterior uveitis as it does for acute retinal necrosis. They also suggested that anterior chamber associated immune deviation (ACAID) may play an important role in patients with idiopathic reactivation of VZV in trigeminal ganglion. Spread of VZV particles to the anterior chamber may lead to suppression of virus specific T cells that mediate delayed hypersensitivity and hence removing the protection afforded by these cells. Aborting the ACAID might help to reduce the intraocular complications of VZV.

CLINICAL FEATURES
The primary infection with HSV 1 is usually asymptomatic but may present as gingivostomatitis or conjunctivitis or keratitis. In most cases, HSV 2 infection is of acquired nature after infection with HSV 1 and hence can be regarded as ‘reinfection’. The infection with HSV 2 usually remains asymptomatic because of partial immune response already present. However, primary infection with HSV 2 without any preexisting HSV 1 infection may be symptomatic. Primary infection with VZV causes chicken pox. Zoster occurs after reactivation of latent virus in sensory ganglia (10). Alpha viruses typically cause endothelitis, trabeculitis, iridocyclitis, ARN and other variants of herpetic necrotizing retinopathy (10). The clinical features produced by intraocular inflammation caused by alpha viruses share common characteristics and hence it may not be possible to differentiate HSV from VZV.
Patients usually present with redness, photophobia, watering and blurred vision. Anterior segment typically reveals ciliary flush, varying anterior chamber reaction or even fine to mutton fat keratic precipitates (KP). Corneal involvement may be in the form of old healed herpetic scars or active keratitis (10). Iridocyclitis accompanying HSV is seen more commonly with stromal and disciform keratitis. In these patients, KPs tend to cluster on the endothelium in the region of corneal disciform edema (17).
Iritis is usually seen with stromal keratitis and endothelitis. Herpetic iritis may be focal or diffuse. In focal iritis, iris hyperemia and posterior synechia are circumscribed. The diffuse form is characterized by diffuse iris edema, severe anterior chamber reaction, hypopyon, posterior synechia and secondary glaucoma (10). Keratouveitis is usually immune mediated but sectoral iritis especially focal endothelitis is thought to be a marker of live virus released into the aqueous from the sympathetic nerves (18).
The inflammation of the trabecular meshwork endothelium is called trabeculitis. It presents with increased intraocular pressure (IOP) and decompensation of corneal endothelium (11, 19). Usually the rise in IOP is temporary but may sometimes leads to glaucomatous damage to optic nerve.
VZV commonly presents with iridocyclitis and presents within the first week of acute disease. Herpes zoster ophthalmicus (HZO) has been observed in 66% of patients with HZV infections that involve the ophthalmic division of trigeminal nerve. It is usually seen in older or immunosuppressed patients and may be the initial manifestation of an underlying HIV infection (20). The most common finding is a vesicular rash which respects the midline along the third division of trigeminal nerve. Patients who develop these skin lesions are at risk for both keratitis and chronic iridocyclitis. Diagnosis may be difficult in cases where there is no skin lesion (sine herpete). Clinical features are varying grade of anterior chamber reaction, ciliary flush, miosis, keratic precipitates and iris hyperemia. Healed cases reveal sector iris atrophy and sphincter damage. Hyphema, hypotony and phthisis bulbi have also been reported (20).
Thean et al (21) reported that most patients with VZV uveitis were immunocompetent with a short duration of disease course. They found high incidence of secondary glaucoma in up to 15% of all cases requiring surgical intervention.
Van der Leilij (22) reported the presence of either HSV or HZV infection in every patient seen initially with unilateral anterior uveitis with sector iris atrophy but without evidence of epithelial or stromal keratitis. They also reported that VZV iritis was commoner in patients more than 50 years of age accounting to up to 60% cases. They also found that recurrences tended to occur at an average once every year.
Miserocchi et al (23) studied clinical characteristics and outcomes in uveitis caused by HSV and VZV. They reported recurrence in 70% of eyes with HSV. Patients with HSV were more likely to have a recurrence and required more periocular steroids than VZV patients; whereas VZV had a more chronic course and presented with more posterior complications usually ARN.
A recent retrospective study by Soon-Phaik et al (24) reports cases of PCR proven CMV anterior uveitis in HIV negative immunocompetent patients. Aqueous samples of these patients were found to be positive for CMV and negative for HSV, VZV and Toxoplasma gondii on PCR. Clinically there was mild anterior chamber reaction with no flare. There was absence of posterior synechia and iris nodules. All the eyes had raised intraocular pressure with few having diffuse iris atrophy and only one had sector iris atrophy. None of them had iris heterochromia. The main patterns of clinical presentations were simulating either PS syndrome (75%) or Fuch’s heterochromic iridocyclitis (20.8%). Approximately one third of patients had systemic associations. Of the 12 patients who completed the treatment with ganciclovir, 9 had recurrences within 8 months of stopping the treatment and required further course of ganciclovir. Since it may be associated with retinitis, it is recommended that all patients with CMV anterior uveitis receive a baseline dilated retinal examination.
Recently HIV has also been reported to be a cause for anterior uveitis. Zaborowski et al (25) reported uveitis in children with HIV associated arthritis. 7 black children were studied who had no systemic involvement other than HIV. All were negative for antinuclear antibody. 4 had intermediate uveitis and 3 had non granulomatous anterior uveitis.
Ocular hypertension is a common feature in herpetic keratouveitis. Nakano et al (26) describe fluid accumulation and flap displacement in late postoperative period (28 months) of LASIK associated with ocular hypertension caused by herpetic keratouveitis. The presence of ocular hypertension may lead to corneal edema and fluid accumulation in the interface.
EBV has also been shown to be associated with severe bilateral iritis and iridocyclitis (27). HTLV 1 associated uveitis may be granulomatous or non granulomatous, may affect one or both eyes and is recurrent in 50% cases. About 15% patients may have associated posterior segment findings (17).

DIAGNOSIS
History may be positive for similar episodes in past. Corneal sensations may be depressed when compared to unaffected area. The diagnosis is based on typical clinical findings viz. KPs, mild anterior chamber reaction, focal or diffuse iris hyperemia, raised IOP and foci of iris atrophy. Endothelial decompensation, raised IOP and KPs are specific for trabeculitis. Pavan-Langston and Dunkel (28) report that iritis in an eye with a known history of herpetic keratitis must be considered herpetic until proven otherwise by clinical findings or laboratory testing.
HSV has been isolated from aqueous humour and virions have been demonstrated by electron microscopy (17).
In VZV uveitis, fluorescein angiography reveals occluded iris vessels at the site of atrophy. This is in contrast to HSV uveitis which shows an intact iris circulation (29). The use of polymerase chain reaction (PCR) in the detection of viral DNA in zoster ‘sine herpete’ has been described. It is newer technique by which minute quantities of DNA from the intraocular fluid sample can be amplified using DNA polymerase and primers and detected. It may also be applied to cases without typical corneal lesions.

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