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.
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.
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.
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 andToxoplasma gondiion 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).
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.
- 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 the benefit of therapy started after 72 hours of is not established. Presence of vesicles correlates with viral replication and hence antiviral 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.
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.
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).
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).
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).
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).
CMV retinitis is the most common bewildering differential especially in patients with AIDS. It typically has granular, hemorrhagic retinal lesions with centrifugal spread with yellowish perivascular infiltration. There is retinal edema with or without vascular sheathing. Healed CMV shows RPE and retinal atrophy with fibrosis or affected retina. A rapidly progressing necrotizing retinitis in the periphery and/or involving the posterior pole without vitritis or hemorrhage may be more suggestive of PORN in an immunocompromised patient (44). Risk of endogenous endophthalmitis increases with a history of major surgery with indwelling catheter, bacterial sepsis, systemic antibiotics, hyperalimentation, immunosuppression, prolonged neutropenia and organ transplantation (44). Toxoplasma retinochoroiditis shows white focal lesions with overlying vitritis. Old healed pigmented and sharply demarcated chorioretinal atrophy scars may be present.
Behcet’s disease presents with a triad of oral and genital ulcers uveitis and arthritis. Associated cutaneous lesion, CNS involvement and necrotizing angitis may be seen. It has characteristic relapses and remissions. Sarcoidosis typically presents with phlebitis and not arteritis as in ARN. Also it does not cause retinal necrosis (44). Intraocular lymphoma has sub retinal lesions with retinal elevations and usually presents an intermediate uveitis and has a protracted course. It does not respond to antiviral therapy.
The major goals of treatment of ARN include stoppage of retinal necrosis so as to avoid retinal detachment and optic atrophy; to minimize collateral damage caused by severe inflammation and occlusive vasculitis; to protect the fellow eye (44).
- ANTI-VIRAL AGENTS - antivirals may be started even before a laboratory diagnosis of viral infection is sought (44). HSV and VZV are the most common causative viruses and hence intravenous acyclovir is recommended in a dose of 1500 mg/m2/day for 10 days followed by oral acyclovir 800 mg 5 times a day for 6-14 weeks for adults (50, 59, 60). It hastens the resolution of retinal lesions but does to appear to prevent the development of retinal detachment (60). For those patients who do not respond to acyclovir, oral famciclovir 500 mg 3 times a day is an alternative (61). Valciclovir can also be given in a dose of 1000 mg orally every 8 hours followed by 500-1000 mg orally every 8 hours (44).
The second line of management includes ganciclovir, valgiclovir and foscarnet (44). Intravitreal ganciclovir with or without foscarnet has also been given in immunocompetent patients who do not respond to acyclovir (62). CMV infections require ganciclovir or foscarnet.
NHR in AIDS patients require multiple agents. Multiple antiviral therapy or use of intravitreal injection or ganciclovir implant in combination with systemic agents may improve the otherwise dismal prognosis (55).
Duration of maintenance therapy in ARN is usually 3 months but may be longer in cases of immunosuppression or multiple recurrences. The treatment schedule of ARN can be summarized in the following table (44).
500 mg/m2 or 5-10mg/kg IV every 8 hours for 10-14 days
800 mg orally 5 times a day
500 mg orally every 8 hours
500 mg orally every 8 hours
1000 mg orally every 8 hours
500-1000 mg orally every 8 hours
Intravenous : 5-10 mg/kg/day for 14-21 days
Intravenous : 5 mg/kg/day daily or 1 g orally 3 times a day
900 mg orally every 12 hours for 3 weeks
900 mg orally daily
Intravenous : 90 mg/kg every 8 hours for 14 days
Intravenous : 90-120 mg/kg daily
Some cases do not respond to acyclovir therapy. Failure may be caused by drug resistance and CMV infection (44).
- ANTI-THROMBOTIC THERAPY - because ARN is an occlusive vasculitis, aspirin has been recommended in the dose of 125 mg to 650 mg once or twice a day however no clinical trials have proved its efficacy till now (50).
- CORTICOSTEROIDS -vitritis associated with ARN may reduce the visual acuity of the patient and make examination difficult. Peri-ocular or systemic steroids have been recommended within the first 24 hours of beginning acyclovir therapy (59). They suppress intraocular inflammation (49, 60) and aid in improvement of vision and evaluation of fundus.
- PROPHYLACTIC LASER PHOTOCOAGULATION -prophylactic application of laser photocoagulation to the area of retinitis has been recommended. The incidence was found to reduce from 67% in untreated group to 17% in treated group (63). It should be performed once the inflammation has subsided (37). However, laser does not stop the progression of retinitis and may be repeated if required (50).
- VITRECTOMY -early vitrectomy combined with endolaser photocoagulation has been proposed to eliminate the role of vitreous traction on the necrotic retina (37)
- RETINAL DETACHMENT SURGERY - internal repair through vitrectomy and the use of silicone oil may be more successful in reattaching the detached retina than standard scleral buckling procedures because of extensive vitreous scarring and multiple posterior retinal tears (37).
Recurrences are uncommon in ARN. Two third eyes end up with visual acuity of 20/200 or worse due to retinal detachment, optic atrophy or retinal pathology (44). Visual prognosis depends on the anatomic area involved and on the severity of inflammation (17). Even if untreated, ARN usually heals by 6 to 12 weeks (10).
Visual loss due to progressive infection, optic nerve sheath effusion or retinal detachment occurs in 70-85% patients with AIDS (55). Blindness is bilateral in 59% in these patients (55). Encephalitis, myelitis, radiculitis or meningitis may complicate the course of NHR and may be fatal in up to 18% AIDS patients (55).
PROGRESSIVE OUTER RETINAL NECROSIS
Progressive outer necrotizing retinopathy (PORN) is a destructive rapidly progressing necrotizing herpetic retinopathy especially seen in patients with AIDS.
Similar to ARN, PORN is also a reactivation of a latent VZV or HSV infection. In immunosuppressed patients, PORN is the second most common form of infectious retinitis after CMV infection (44). Forster et al (64) first described it as a separate disease entity in AIDS patients. Margolois et al (65) further described similar features in patients and represented it to be a form of VZV retinopathy.
One recent study reported the mean age at presentation to be 44.7 years with median CD4 count of 12 cells/mm3. 57% of cases had a history of HZO and bilateral involvement (66).
Deep retinal infiltration with a multifocal distribution and involvement of the macula are frequently present initially. Inflammatory spots spread very rapidly to confluence, leaving large areas of necrosis in their wake. The outer layers are principally involved, with little involvement of the retinal vessels. This gives the characteristic ‘cracked mud’ appearance of the fundus. On the other hand, there is a conspicuous discrepancy from the rest of the accompanying inflammation. When low CD4 counts are present, the retinal necrosis is accompanied only by a slight vitritis, minimal vasculitis and neuritis (15-20%) and minimal inflammation of anterior chamber (10).
PORN is a disease of the immunosuppressed especially AIDS. Other diseases described are lymphoma, immunosuppressive therapy for optic neuropathy, nephritic syndrome, rheumatoid arthritis and graft versus host disease after bone marrow transplant (44). In AIDS, the disease occurs in the later stages of immunosuppression. One study revealed that mean CD4 count at the time of presentation was 21 cells/mm3 (range 0-130 cells/mm3) (44).
Patients usually complain of blurring of vision with contraction of visual field. Because the anterior segment is not involved, there is no photophobia and pain unlike ARN. Inflammation begins as patchy retinitis with outer retinal whitening. The posterior pole is affected early. There is no vitritis and minimal involvement of retinal vasculature. 71% patients have bilateral disease. Eventually, there are retinal detachment and optic atrophy occurring in more than 70% of cases (44).
Vichitvejpaisal P et al described a case of a young woman initially diagnosed with HIV infection, who presented with bilaterally decreased visual acuity after initiating HAART two months earlier. Multiple yellowish spots appeared in the deep retina without evidence of intraocular inflammation or retinal vasculitis. Her CD4+ T-cell count was 127 cells/µL and she was diagnosed as having PORN based on clinical features and positive VZV in the aqueous humor and vitreous by PCR. Despite treatment with intravenous acyclovir and intravitreous ganciclovir, her visual acuity worsened. They suggested that PORN may be a manifestation of the immune reconstitution syndrome and should be included in the differential diagnosis of reduced visual acuity in AIDS patients initiating HAART with higher CD4+ T-cell counts (67).
Park et al (68) reported a case of 34-year-old male with AIDS who developed retrobulbar optic neuritis and meningoencephalitis following bilateral PORN caused by CMV. They suggested a presumed association of PORN with retrobulbar optic neuritis and CMV meningoencephalitis in an AIDS.
Franco-Paredes et al (69) reported a case of an HIV-infected individual who presented with VZV meningitis and retrobulbar optic neuritis that preceded the onset of PORN.
Literature describes cases presenting as an optic neuropathy and erroneously treated with methylprednisolone, after which fundus examination became consistent with PORN. They highlight the importance of careful examination of the retinal periphery before management of any presumed optic neuropathy with steroids (70).
A rare case of ARN and PORN in fellow eyes of an AIDS patient with HSV keratitis in one eye was described by Garino et al (71). Retinal detachment and vision loss ensued in both eyes despite antiviral therapy. They represent variant manifestations of the same underlying infection.
Diagnosis is based on the characteristic fundus picture. As in ARN; GWC, PCR analysis of intraocular fluid and retinochoroidal biopsy can be undertaken when indicated for diagnosis when the disease does not respond to treatment. Recently, optical coherence tomography (OCT) has been used to demonstrate full thickness tissue loss in PORN (72).
Walton et al (73) describe the use of fluorescein angiography during the various stages of the disease. They consist of zonal microvascular alterations, retinal pigment epithelium (RPE) destruction and choroidal leakage. Retinal damage correlates closely with regions of choroidal leakage and is clinically evident as outer retinal whitening. Disease reactivation occurs as a prominent brush-fire border of intense leakage involving the retina, RPE, and choroid. They suggest that PORN is a retinochoroiditis that involves the full thickness of retina as well as the RPE and choroid.
The differential diagnosis of PORN is similar to ARN. However, in the presence of immune suppression many diseases present in atypical forms (44). Toxoplasmosis may present with minimal vitritis in absence of chorioretinal scars. CMV retinitis typically has granular borders, hemorrhagic retinal involvement and progresses at a slower rate than PORN.
The antivirals used are same as those described for ARN. The duration of maintenance therapy is usually until the reconstitution of immune status and may be indefinite. This is so to prevent recurrences in the affected eye and protect the other eye. The disease may not respond to intravenous acyclovir alone. Hence, intravitreal ganciclovir or foscarnet may be required. Combination systemic therapy with ganciclovir and foscarnet is often used for maintenance of PORN. When response is observed and the patient has been started on HAART, treatment may be switched to oral acyclovir, valciclovir, famciclovir or valganciclovir. If a patient is not a candidate for HAART then intravitreal ganciclovir implant may be tried. (44).
Kim et al report successful long-term treatment of VZV-associated PORN with disease remission and preservation of 20/20 visual acuity out to 1 year, with aggressive treatment with ganciclovir implant, intravenous acyclovir (10 mg/kg every 8 h), intravitreal foscarnet (2.4 mg) and HAART (74).
The use of corticosteroids is not necessary in view of low grade inflammation. If significant vitritis occurs after immune reconstitution, systemic steroids may be given. PORN spares the retinal vasculature and hence anti platelet drugs are not required. Retinal laser and surgery may be performed for indications similar to ARN. Because there is low grade vitritis, retinal evaluation is easier and placement of laser can be attempted earlier in the disease course (44).
Without treatment, necrosis rapidly progresses to the entire retina. Even with antiviral therapy, the prognosis of PORN is guarded. Two third patients attain final visual acuity of no perception of light (44).
Distinguishing and diagnostic criteria have been summarized as follows:
Multifocal lesions characterized by deep retinal opacification without granular borders; there may be areas of confluent opacification
One or more foci of full-thickness retinal necrosis with discrete borders
Lesions located in the peripheral retina with or without macular involvement
Lesions located in the peripheral retina
Extremely rapid progression of lesions
Rapid progression of the disease
No consistent direction of disease spread
Circumferential spread of disease around the peripheral retina
Absence of vascular inflammation
Evidence of occlusive vasculopathy, with arteriolar involvement
Minimal or absent intraocular inflammation
Prominent inflammatory reaction in the vitreous and anterior chamber
Characteristics that support, but are not required, for diagnosis:
Characteristics that support, but are not required, for diagnosis:
Neuroretinitis is a distinct clinical syndrome occurring primarily in young adults. It is an inflammatory disorder of the optic disc which typically presents with acute, painless, unilateral visual loss in a young person (75). The term neuroretinitis evolved to encompass optic disc edema and macular star.
Several different names have been used in the past to denote neuroretinitis including Leber’s idiopathic stellate retinopathy (76), Leber’s idopiathic stellate neuroretinitis (77, 78), Leber’s idiopathic stellate maculopathy (79).
The viruses causing neuroretinitis are herpes virus (80), mumps virus (81), chikungunya virus (82), hepatitis B virus (HBV), herpes viruses associated with the acute retinal necrosis syndrome (83), and HIV (84).
There is a lack of identifiable pathophysiologic process which leads to neuroretinitis (85). Dreyer et al (77) and Gass (85) suggested that vascular damage results in leakage of proteinaceous fluid, which spreads from the optic disc into the outer plexiform layer of the retina. Gass et al (85) also suggested that optic nerve head is the principal target of acute neuroretinitis. A swollen disc has abnormal permeable capillaries deep within the disc (86). Newsom et al (87) and Fish et al (88) also suggest that damage occurring to the local vasculature is an important target.
This accumulation of fluid overwhelms the ability of retina-retinal pigment epithelium complex to drain it. Although this is most commonly seen in patients with infectious causes of disc swelling and leakage, it is not unique to any one process (85).
By two weeks, the absorption of disc and retinal edema begins. Faster resorption of aqueous phase leaves lipid deposits that track along the outer plexiform layer (75). As the transudate is resorbed, lipids precipitate to form the characteristic stellate pattern within Henle’s layer of the macula. Often macular star may be seen without optic disc edema, presumable because the disc edema resolves early in the disease course, unlike macular exudates which take months to resolve (86).
It has been presumed that the target tissue in neuroretinitis is disc vasculature rather than neural tissue (75). Cunnigham et al (85) and Gharbiya et al (85) believe that damaged capillaries rather than a persistent immune response are responsible for the prolonged leakage, even after removing the causative agent.
Patients usually have an acute loss of vision, with initial visual acuity ranging from 20/30 to counting fingers. The initial picture consists of florid disc edema with surrounding serous retinal detachment extending to the macula. In some cases disc edema is segmental rather than diffuse. Variable feature include a recent viral prodrome, retrobulbar pain, afferent papillary defect and vitreous cells (89). In children and young adults, neuroretinitis is preceded or accompanied by a viral illness or systemic infection or inflammation about 50% of the time (90). Although most cases of neuroretinitis are unilateral, bilateral symmetric cases are not uncommon (90).
Visual loss may be due to a combination of mechanisms including optic nerve inflammation, optic nerve edema or macular edema (89). Some authors however believe that the visual loss is largely due to macular edema rather than optic nerve dysfunction.
Foster et al (91) reported a case of a 15 year old boy with progressive visual loss in one eye. He had an ipsilateral relative afferent papillary defect, with no anterior segment inflammation. He had marked disc edema and hyperemia with a macular star. Centraocecal scotoma was seen on visual field testing. Imaging revealed an enlarged contralateral parotid gland. CSF analysis revealed lymphocytic pleocytosis, hypoglycorrhachia and raised protein levels. ELISA revealed raised IgG levels against mumps virus. He improved on treatment with intravenous steroids. Cause of infection was suspected to be vaccine failure.
Margolis et al (92) reported a peculiar case of ARN presenting with papillitis and what they called ‘arcuate neuroretinitis’. Patient was a middle aged female who presented with severe headache and decreased central vision in affected eye. she had relative afferent papillary defect, swollen disc and an arcuate band of whit nerve fibers that passed superior to the macula up to the horizontal raphe. Inferior to the arcuate, retina appeared edematous with folds radiating out from the fovea. Fluorescein angiography showed early blocked fluorescence by the arcuate band and late hyper fluorescence of both arcuate band and optic disc. Subsequently she developed anterior chamber reaction with a area of 360 degree retinal whitening in the far periphery with vasculitis in mid periphery and posterior pole. There was a corresponding inferior arcuate scotoma on visual field analysis. A presumed diagnosis of ARN was made and she was treated with oral anti virals and steroids. Following which retinitis resolved leaving an atrophic retina.
G Mahesh et al (93) recently reported a case of bilateral neuroretinitis serologically proven to be caused by chikungunya virus. The patient was a middle aged female with diminution of vision in both eyes of one-week duration with a previous history of viral prodrome two weeks prior to the onset of blurring of vision. Visual acuity was 20/80 N18 in the right eye and 20/60 N6 in the left eye. There was absence of anterior chamber inflammation and relative afferent pupillary defect in both eyes. Color vision testing was normal. Fundus revealed few vitreous cells, optic disc edema, intra-retinal hemorrhages, peripapillary cotton wool spots and areas of retinitis with macular star in both eyes. Visual field analysis showed bilateral centrocaecal scotoma. Fluorescein angiography was characterized by leakage from disc margins and from peripapillary vessels and blocked fluorescence due to retinal hemorrhage. The area of retinitis showed staining in the late phase. She was treated with a course of systemic steroids tapered over six weeks. Subsequently her vision improved to 20/30, N6 in right eye and 20/20, N6 in the left eye. Fundus examination revealed bilateral resolution of disc edema with decrease in the retinal hemorrhages and cotton wool spots. Repeat visual field analysis showed improvement of scotomas. Other authors also report cases of bilateral neuroretinitis caused by chikungunya virus (94).
Lalitha et al (95) studied 37 patients with serologically confirmed chikungunya virus infection and found the incidence of neuroretinitis at a tertiary hospital to be 2.70%. Therapy included topical and systemic steroids.
Bilateral neuroretinitis is described in viral infections caused by measles, influenza, Epstein-Barr virus, dengue virus and Rift valley fever virus. This typically occurs subsequent to an acute viral systemic illness. A case of bilateral neuroretinitis with peipapillary serous retinal detachment in a patient with serologically proven HIV with concomitant active HBV infection was described by Forooghian et al (84). Further investigation revealed previous exposure (IgG) without evidence of recent exposure (IgM) with respect to EBV, HSV, VZV andToxoplasma gondi.A similar case with bilateral neuroretinitis in a homosexual patient with acute HBV infection who tested for HIV infection 1 year later after initial examination was reported during the advent of HIV epidemic by Farthing et al. They proposed that the patient was HIV positive at the first visit but serum testing at the time for testing was not sensitive enough to detect the virus (84).
Marshall et al (96) observed a child with blindness due to diffuse neuroretinitis temporally associated with measles, mumps, and rubella vaccination and the development of a post vaccination measles syndrome. Interestingly Saxena et al (97) reported a case of bilateral neuroretinitis after chick embryo cell anti rabies vaccination.
There are many infectious and non-infectious causes reported including syphilis, salmonella, leptospirosis, Toxocara canis, Toxoplasma gondi and cat scratch disease. Nematode species have been implicated in diffuse unilateral subacute neuroretinitis (89). Non-infectious causes include marked hypertension, diabetes mellitus, increased intracranial pressure and ischemic optic neuropathy (86).
The diagnosis is suspicious at initial presentation when absence of pain, large disc edema and retinal edema and small relative afferent papillary defect are present. The diagnosis can be confirmed when macular star appears (75).
This appearance of macular star aids in narrowing the differential diagnosis. Few disorders are associated with lipid deposits presenting with this pattern. Disc edema secondary to raised intracranial pressure is occasionally associated with a macular star but involves both optic discs and does not cause marked optic nerve dysfunction.
Hypertensive retinopathy is bilateral and is usually associated with widespread retinal exudates, hemorrhages and cotton wool spots (75). Leavitt et al (98) reported several features which help differentiating the two: visual loss is acute in neuroretinitis but not in hypertensive neuroretinitis; unilaterality is seen in neuroretinitis in contrast to hypertension; and presence of arterial attenuation, hemorrhages, arteriovenous nicking, and venous engorgement are seen in hypertension and not in neuroretinitis.
Optic disc edema with macular star formation may be a presenting feature of anterior ischemic optic neuropathy, retinal vein occlusion, papilledema (75) or optic neuritis.
Fluorescein angiography shows optic disc swelling and leakage of dye from the vessels on the surface of the disc. The macular vessels do not leak (90). Visual field analysis reveals large central or centrocaecal scotoma. The visual loss is caused in large part by retinal edema rather than optic nerve dysfunction. Evidenced by a relative afferent papillary defect that is small in comparison to the extent of visual loss (75).
Unlike direct infections of the retina or choroids, infectious organisms are rarely isolated from vitreous or ocular tissues in neuroretinitis (85). Rothova et al (99) however have recently described the use of Goldmann-Witmer coefficient (GMC) for the diagnosis of infectious posterior uveitis. They isolated a case of varicella zoster virus associated neuroretinitis who was positive for the virus on aqueous humour analysis with GMC.
The visual prognosis is excellent even when neuroretinitis is not treated. Previous reports of neuroretinitis have emphasized the self limiting nature of this condition. Most patients experience no further recurrence of attacks. Spontaneous recovery is typical in idiopathic neuroretinitis with visual acuity returning to 20/40 or better in 97% of patients (89).
MISCELLANEOUS VIRAL UVEITIS
Measles is an acute contagious disease. It is caused by SSRNA virus belonging toMorbillivirusgenus of the Paramyxoviridae family. Because of low incidence of measles infection in adults, congenital infection is rare as compared to acquired one. However, maternal measles can result in fetal death or congenital anomalies (100).
Newborns with congenital infection have cardiopathy, pyloric stenosis, genu valgum, deafness, mongolism, vertebral anomalies, cleft lip, cleft palate or rudimentary ear. Congenital ocular measles infections include dacryostenosis, cataract and pigmentary retinopathy. Retinopathy may be associated with macular star and arteriolar attenuation (100).
There is a catarrhal reaction of mucosae. Few days prior to development of rash, Koplik’s spots appear. Conjunctivitis, cough and coryza form the classic triad of measles. It is usually papillary and non purulent with pseudomembranes. Epithelial keratitis is the most common manifestation of acquired measles infection. Koplik’s spots which occur on the conjunctiva and on the caruncle are called Hirschberg’s spots. A sharp transverse linear injection present on lower lid margin is called Stimon’s line (100)
Patients typically present within few days of blurring of vision of both eyes. Fundus reveals blurred disc margins, diffuse retinal edema, attenuated arterioles, scattered retinal hemorrhages and macular edema. Rubeola retinopathy may occur in the presence or absence of encephalitis. After resolution fundus reveals disc pallor, parapapillary vascular sheathing and secondary pigmentary retinopathy with a characteristic salt-pepper pattern (100)
Subacute sclerosing panencephalitis (SSPE) is a chronic degeneration of the CNS, a complication of measles infection. It typically has three stages. Ocular symptoms may precede neurological finding by weeks to years. Pigment epithelial changes can focal retinitis is the most common finding. There is minimal if any vitreous inflammation. Other findings include disc edema, optic nerve edema, preretinal membrane, vasculitis, chorioretinitis, papillitis, macular hole, cortical blindness and ptosis (100).
Diagnosis is based on the course of clinical symptoms. Fundus fluorescein angiography reveals a generalized decrease in transmission of choroidal fluorescence. This is due to widespread pigment disturbance. Visual field analysis reveals constriction. ERG may be normal or reduced (100)
Systemic complications include encephalitis, glomerulonephritis, disseminated intravascular coagulation, otitis media, pneumonia, appendicitis, myocarditis. Ocular complication include cornel vascularization, optic atrophy, optic neuritis, papilloedema, CRVO, neuroretinitis, chorioretinitis, extraocular muscle palsies and cortical blindness (100)
There is no definitive treatment for SSPE. Intracameral IFN-α may induce remission (100). In the developing world, 1% children develop permanent ocular damage. Associated vitamin A deficiency, HSV infection worsens the prognosis further.
Rubella is an acute, exanthematous disease. It is caused by rubella virus fromRubivirusgenus of Togaviridae family. It is an RNA virus.
Congenital rubella typically has a triad of hearing, ocular and cardiac defects. Cataract and microphthalmia are the most important causes of poor vision. Pigmentary retinopathy is present on fundus evaluation. KPs have been reported after cataract surgeries (101). Acquired rubella has an incubation period of 2 to 3 weeks. Skin rash is the first sign of ocular manifestations include conjunctivitis, epithelial keratitis and retinitis. Mild AC reaction may be present. Retina reveals dark grey atrophic lesions of RPE, flat detachment of neuroretina at the posterior pole and bullous and diffuse detachment of the retina (101).
A recent study by Ruokonen et al shows association between FHC and intraocular antibody synthesis against rubella virus (102). Similar results were shown by another study carried out by de Visser (103).
Diagnosis of rubella infection is difficult because of lack of pathognomonic findings. However, rubella occurs in pandemics. FFA in acquired infection shows hyperfluorscent areas with no leakage from retinal vessels.
Treatment is symptomatic. Response is well to systemic steroids. Prognosis is excellent in acquired cases.
OTHER VIRAL UVEITIS
Other causes of uveitis associated with vial infection include West Nile virus, mumps virus, hepatitis B virus, enterovirus, vaccinia virus and rift valley fever.
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