UVEÍTIS VIRAL

VIRAL UVEITIS

LABETOUELLE MARC, MD; FRAU ERIC, MD

RESUMEN

La uveítis puede ser producida por varios tipos de virus, incluyendo los virus ARN y ADN. Los métodos diagnósticos tradicionales de cultivo utilizados en las infecciones virales o en la determinación de los títulos de anticuerpos contra los antígenos específicos, requieren un conocimiento de las condiciones imprescindibles para el crecimiento de algunos determinantes antigénicos específicos. Estas condiciones, sin embargo, han limitado nuestra posibilidad para identificar los virus que producen uveítis. Las nuevas técnicas de biología molecular, como la técnica de PCR, han mejorado nuestras posibilidades diagnósticas en esta enfermedad. En el presente trabajo, realizamos una revisión de los virus ADN y ARN relacionados con la uveítis en humanos, siendo los más frecuentes los virus del herpes. Varios tipos de virus del herpes pueden producir una inflamación uveal, con afectación de los segmentos anterior y posterior; otros virus ARN están implicados con menos frecuencia. El diagnóstico precoz y tratamiento inmediato de ciertas formas de uveítis de etiología viral, pueden prevenir las lesiones uveales y permitir una rápida recuperación de la visión.

SUMMARY

Uveitis may be caused by several types of viruses including RNA and DNA viruses. The traditional diagnostic approach for the cultivation of viral infections or demonstrating an increase in the antibody titer to specific antigen requires understanding of growth conditions for specific antigenic determinants. These requirements, however, have limited our ability to recognize and identify viruses that cause uveitis. Recent molecular biology techniques such as PCR have improved our ability in the diagnosis of viral uveitis. In this review, DNA viruses and RNA viruses causing uveitis in man are discussed. The most frequently encountered viruses that cause uveitis belong to the Herpes virus group. Several types of Herpes viruses may lead to inflammation of the uvea involving the anterior and posterior segment of the eye. Other types of RNA viruses are less frequently involved. Early diagnosis and prompt treatment of certain viral uveitis may prevent structural damage of the uvea and lead to rapid rehabilitation of vision.

INTRODUCTION

Intraocular inflammation syndromes may be related to infectious agents, particularly viruses. The latter can reach the uvea via the bloodstream and nerve pathways. Direct passage of viruses through the cornea may also occur. The close relationships of the eye with the central nervous system increases its sensitivity to viruses. Conversely, these relationships with blood and the meninges mean that evidence of ocular viral infection can be sought in several biological fluids (aqueous humor, vitreous, blood and cerebrospinal fluid). Most epidemiological studies on uveitis have been based on clinical and biological data. Until the beginning of the l990s, serological methods were the only reproducible tools (1,2). The polymerase chain reaction (PCR) has yielded new information on the role of viruses in ocular inflammation (3,4) and will further help ophthalmologists to understand such diseases. The frequency of viral etiologies among unselected cases of uveitis in immunocompetent patients is about 10%, but may be much higher in university referral patients (5). It is possible that the evolution of diagnostic methods explains the apparent increase over time in virus-related uveitis, from 2% in 1975 (6), to 4% in 1981 (7), 14% in 1994 (8) and even 17% in the elderly in 1998 (9). To test this hypothesis, a new epidemiological study using the same biological method (Witmer coefficient assessed by an ELISA technique) as a previous study done 10 years previously in the same unit was conducted in 1998. It was found that 13% of 226 unselected patients with uveitis had serological evidence of viral infection (10). These results were similar to those observed in 1987 (12% of 139 unselected patients) (11). Moreover, most studies have shown that viral uveitis in immunocompetent patients are almost exclusively related to herpes simplex virus (HSV) and varicella-zoster virus (VZV). Nevertheless, only a few antiviral antibodies were tested in these studies (usually against HSV, VZV, cytomegalovirus, measles and mumps viruses). It is therefore possible that some first events of non recurrent uveitis are related to infection with other viruses. Many types of viruses have been linked to intraocular inflammation, even if case series are generally small.

DNA viruses and uveitis Herpesviridae

The most frequent intraocular inflammation syndromes related to Herpesviridae are HSV and VZV iridocyclitis (with or without trabeculitis or retinitis) in immunocompetent patients, and cytomegalovirus (CMV) retinitis in immunocompromised patients. All these diseases have been extensively reviewed (12-20). We shall thus focus on other clinical and biological findings. For example, CMV is not only able to infect the retina. Some rare cases of uveitis in young patients with Rasmussen's encephalitis have been described (21) and the virus has been cultured from lens material of a young child with severe iridocyclitis and cataract but no other signs of congenital disease (22). The viral genome was found in the corneal endothelial deposits of macrophages in human immunodeficiency syndrome virus (HIV)-infected patients with CMV retinitis. However, there was no evidence of direct viral infection of corneal endothelial cells (23). Conversely, another post-mortem study found infection of endothelial cells of the cornea and the aqueous drainage system (24). The infection was also found in the smooth muscle cells of the iris and ciliary body. A recent pathological and immunochemical study confirmed that CMV can cause iritis in HIV-infected patients (25).

A link between intraocular inflammation and Epstein-Barr virus (EBV) infection has been described during the acute disease, infectious mononucleosis. Retinal vasculitis and optic neuritis are the most common features, but chorioretinitis and secondary glaucoma have also been described (18,26-30). Ocular inflammation has also been reported during chronic EBV infection, ranging from steroid-sensitive anterior uveitis to severe posterior uveitis with optic disk swelling and macular edema (31,32). So-called EBV-associated uveitis may be diagnosed when ocular inflammation appears after cold-like symptoms in patients with high levels of anti-viral-capsid antigen (VCA) antibodies in the aqueous humor. This EBV-associated uveitis is described as usually bilateral, sometimes granulomatous in the anterior chamber but without severe vitritis. The syndrome is steroid-sensitive but commonly recurrent. The visual prognosis is usually good (33,34). Anti-VCA antibody levels were higher in the serum of patients with anterior uveitis than in control groups and in patients with pan-uveitis (35). On the other hand, EBV-DNA was found more frequently in the aqueous humor of HIV-seronegative immunocompromised patients with uveitis than in other patients with uveitis (36). The test did not seem to be reliable in the management of unselected uveitis, as the direct role of EBV in the pathogenesis of ocular inflammation is not clear. Presumed EBV-related uveitis rarely responds clearly to antiviral therapy (e.g. aciclovir), and direct proof of viral infection by culture is rarely obtained. For these reasons, the reality of EBV as a direct causative agent of infectious uveitis remains unproven (37).

Human herpesvirus type 6 (HHV6) is able to infect the retina of HIV-infected patients, sometimes simultaneously with CMV (38-40). Routine testing for local production of specific antibodies in ocular fluid of HIV-infected patients with uveitis yielded no significant results (41). Concomitant HHV6 infection in children and recurrence of iridocyclitis associated with juvenile rheumatoid arthritis have been reported (42). In addition, some studies have tentatively suggested that HHV6 is involved in the pathogenesis of multiple sclerosis (43), a neurological syndrome frequently associated with retinal vasculitis and/or posterior, intermediate or anterior uveitis. It must however be stressed that the pathogenic role of HHV6 in multiple sclerosis is controversial (44).

Herpes B, a simian alphaherpesvirus, has been clearly linked to pan-uveitis and optic neuritis in two monkey handlers (45,46). The clinical features of the severe chorioretinitis with vitreous hemorrhage were very close to those of the acute retinal necrosis syndrome (47-49). Moreover, Herpes B necrotizing retinitis may be associated with severe encephalitis, as is the case in some patients with HSV retinitis.

DNA viruses other than Herpesviridae

Intraocular inflammation can occur in humans during severe adenovirus keratoconjunctivitis. Increased intraocular pressure (50) or retrobulbar optic neuropathy may also occur in this context (51). In rabbits, intrastromal inoculation of human adenovirus type 5 leads to severe keratoconjunctivitis with iritis (52,53) and in dogs, canine adenovirus type 1 causes diffuse clouding of the cornea and anterior uveitis (54). Nevertheless, adenovirus-related uveitis without keraconjunctivitis is very rare. Witmer reported two cases of iridocyclitis with a high level of anti-adenovirus serotype 8 antibodies in the aqueous humor (55), but systematic testing for local production of specific antibodies in the anterior chamber of patients with intermediate uveitis did not give significant results (56).

Some rare cases of ocular inflammation or tonic pupil have been linked to parvovirus B19 infection (57). The role of parvoviridae in extraocular vasculitis has been suggested (58,59). However, systematic testing for local production of anti-parvovirus antibodies in the aqueous humor of patients with in intermediate uveitis did not give significant results (56).

Hepatitis B may be associated with uveitis, papillitis and retrobulbar optic neuritis (60-63). Cases of uveitis and optic neuritis have also been described after hepatitis B vaccination (64,65) suggesting that clinical manifestations are more probably immunologically mediated. Although the virus has been associated with forms of systemic vasculitis such as glomerulonephritis and polyarteritis nodosa, serologic testing for hepatitis B virus infection in unselected patients with uveitis did not suggest that the virus played a significant role in the general epidemiology of uveitis (66,67).

Since the eradication of variola (smallpox), poxviruses have been a very rare cause of intraocular inflammation. One case of keratouveitis following auto-inoculation from a vaccination site was reported in a patient who used contact lenses (68).

DNA viruses in other syndromes

Biological signs of viral infection have been found in some ocular diseases in which a viral aetiology is not considered the most probable. This is the case with the Posner-Schlossman syndrome (69). Bloch-Michel et al found high levels of anti-CMV antibodies in the aqueous humor of 7 among 11 patients with Posner-Schlossman syndrome but not in patients with other clinical diagnoses (70). More recently, Yamamoto found the HSV genome in the aqueous humor of all three patients tested during the acute phase of the disease, whereas aqueous humor from 10 patients undergoing cataract extraction was negative (71).

On the basis of serological data, EBV infection has been linked to multifocal choroiditis and panuveitis syndrome, but the results are controversial (72-74). Similarly, local synthesis of anti-VZV or anti-HSV antibodies was found in the aqueous humor of 3 among 7 patients (75). Multifocal choroiditis has been reported after herpes zoster ophthalmicus (76).

Given the 'flu-like illness that often precedes acute posterior multifocal placoid pigment epitheliopathy, a viral cause has been suggested. Azar et al reported high levels of serum anti-adenovirus serotype 5 antibodies in this disease (77). Even in diseases which are clearly related to immune disorders, like the Vogt-Koyanagi-Harada syndrome, some authors have found high levels of antiviral antibodies (CMV and mumps) or the EBV genome in aqueous humor (55,78,79). Recently, Human Herpesvirus type 8 has been linked to primary intraocular lymphomas, a cause of pseudo-uveitis (masquerade syndrome) (80).

RNA viruses and uveitis Ortho-and Paramyxoviridae

The association of 'flu, mumps and measles with ocular inflammation has been known for several decades (12,49,81). Acute influenza virus infection can lead to posterior segment disease with macular lesions and optic neuritis. There may be macular hemorrhage related to posterior vasculopathy. Some cases of neuroretinitis have been described (82-86). Similarly, mumps can be associated with intraocular inflammation. Typically, mumps iritis coincides with the parotiditis or occurs during convalescence, and is often associated with orchitis. Intraocular pressure may be increased or reduced. The outcome is generally good with topical steroids and cycloplegics (87-89). Several cases of optic neuritis have been reported, sometimes with the clinical features of neuroretinitis (90,91). Ocular complications of acquired measles can involve the retina and/or the optic nerve. Clinical manifestations include retinal vasculitis, paravenous pigmentary dystrophy, neuroretinitis and papillitis (12,92-96). Congenital measles can also cause retinitis (97,98).

Persistent infection by defective measles virus can lead to subacute sclerosing panencephalitis. In this disease, macular changes are frequent and can be the first clinical sign (99-102). Ocular abnormalities are present in more than half the patients (103). They may consist of macular edema, retinal infiltrates and/or hemorrhage, optic disk edema or atrophy (81,102-108).

An increased titer of anti-measles antibodies has been found in ocular fluids of patients with both multiple sclerosis and uveitis, but not in control patients (109). Antiviral antibodies are frequently increased in the cerebrospinal fluid of multiple sclerosis patients, but these results are not reproducible and do not correlate with disease activity (110,111). For these reasons, the apparent increase in anti-measles antibodies in the aqueous humor remains to be elucidated. The possibility of a cross-reaction with other antiviral antibodies was recently raised (112).

Picornaviridae

Enteroviruses are a frequent cause of lymphocytic meningitis, and several studies have shown that the acute infection may be associated with uveitis. Experimental enteroviral uveitis (e.g. with echo-, coxsackie- and poliomyelitis virus) has been obtained in monkeys (113). Many of the clinical reports were published in the ex-USSR during echovirus epidemics (especially echovirus types 11 and 19) in children under 3 years (114-116). A link between enterovirus 70 conjunctivitis and uveitis has been found in Africa (117). The role of coxsackievirus B3 and B4 in panuveitis and/or chorioretinitis has been suggested in American and Japanese reports (118-120). Similarly, optic neuritis has been reported after infection with poliovirus and coxsackievirus (121-123).

Retroviridae

The third family of RNA viruses involved in uveitis is the retroviruses. HIV is presumed to directly trigger uveitis in some patients. Some HIV-infected patients without other known infections had uveitis that resolved completely with the beginning of antiretroviral treatment, whereas steroids alone were ineffective. In some of them, only HIV was cultured from aqueous humor or vitreous (124-126). In situ hybridization studies have shown HIV-1 RNA in retinal vascular wells (127). Nevertheless, the exact pathogenesis of HIV-related uveitis is unclear.

The association of HTLV-1 virus with uveitis has been well described by Japanese authors. This etiology should be searched for in uveitis patients coming from regions where HTLV-1 is most frequent. Outside Japan, HTLV-1 carriers are essentially found among equatorial Africans, African-Americans, Amerindians and some people from the Philippines and Oceania (128). The frequency of HTLV-1 carriers among patients with idiopathic uveitis is highly variable with age and location. Transmission is most frequently vertical (mother to child) or horizontal (sexual contact), but may also be secondary to blood transfusion. The clinical manifestations include iritis, vitreous opacities, retinal vasculitis and optic neuritis. The intraocular inflammation may occur with or without associated myelopathy (129-134).

Miscellaneous

Rubivirus (responsible for rubella, a member of the Togaviridae family) is a well-known cause of congenital ocular diseases, including retinitis (12). Chronic anterior uveitis has been observed post-natally, leading to permanent damage of the irido-corneal angle (81). Cases of acquired disease with optic neuritis, with and without retinal vasculitis or retinal pigment epitheliitis, have been reported (135-138).

Lymphocytic choriomeningitis virus (LCMV), a member of the Arenaviridae, is also known to be responsible for congenital chorioretinitis (139-141) but ocular signs of acquired infection in adults are at the most very rare. Experimental LCMV infection in animals has shown that the disease can be transmitted from female rats to their pups (142) and that acquired disease in newborns is essentially immune-mediated (143). Lassa virus, another member of the Anenaviridae, is able to induce experimental uveitis and encephalitis in monkeys (144).

The 1977 epidemics of Rift Valley fever in the Nile delta stressed the occurrence of retinitis and/or optic neuritis during the acute phase of the disease (145-147). Because the Rift Valley fever virus, a member of the Bunyaviridae, is found in a 7000-kilometre north-south range (146), this etiology should be sought in uveitis patients who have recently travelled in Africa.

Among the Flaviviridae, hepatitis C virus is associated with immune ocular diseases like Mooren's ulcer and Sjogren's syndrome. This virus has also been linked to a case of retinal pigment epitheliitis (148). Concerning other Flaviviridae, serosurveys of yellow fever and antigenically related viruses in patients with uveitis of unknown etiology did not give significant results (149).

Case reports or small series of uveitis related to other RNA viruses have been published. Although uveitis is not the main clinical finding in patients with rabies, Haltia found ciliary and choroidal inflammation with retinal endothelial damage and antigens in retinal ganglion cells from a patient who died of rabies (150). In Marburg fever, the uveitis may appear several weeks after the acute phase. The virus has been cultured from aqueous humor of one patient (151,152). Among survivors of the 1995 Ebola outbreak in the Democratic Republic of Congo, about 20% developed intraocular inflammation that resolved with topical steroids and cycloplegics (153). The African horsesickness virus (Reoviridae family) may also be responsible for acute retinal necrosis with optic neuritis among laboratory workers (154).

This review of the viruses involved in intraocular inflammation highlights the very broad range of virus-related ocular diseases. The development of new diagnostic methods will no doubt provide new epidemiological information on viral etiologies of uveitis.

REFERENCES