Ординатура / Офтальмология / Учебные материалы / Uveitis Text and Imaging Text and Imaging Text and Imaging 2009

infected become symptomatic with a self-limited febrile illness in most cases. Symptoms of affected patients include high-grade fever, headache, myalgia, arthralgia, malaise, nausea, vomiting, skin rash, weakness, and pharyngitis. The acute illness is selflimiting, typically lasting less than a week.

Severe neurologic disease (meningoencephalitis), frequently associated with advanced age and diabetes, was initially reported to occur in less than 1% of patients. However, over time, WNV infection has increased in severity.1-3

OPHTHALMIC MANIFESTATIONS

OF WNV INFECTION

Since the first descriptions of ocular involvement secondary to WNV infection in 2002 and 2003, several ophthalmologic findings have been recognised, including chorioretinitis, anterior uveitis, retinal vasculitis, optic neuritis, and congenital chorioretinal scarring.3-21

CHORIORETINITIS

A bilateral or rarely unilateral multifocal chorioretinitis, with typical clinical and fluorescein angiographic features, is the most common finding, occurring in almost 80% of patients with acute WNV infection associated with neurologic illness.8 Diabetes mellitus appears to be a potential risk factor for developing multifocal chorioretinitis, with more than 20% of patients having diabetic retinopathy in association with multifocal chorioretinitis. Most patients have no ocular symptoms or present with mildly reduced vision. An associated mild to moderate vitreous inflammation is frequently observed. The chorioretinal lesions commonly develop early in the course of the disease, appearing to be active (35%) or already inactive (65%) at presentation.8 Active chorioretinal lesions appear as circular, deep, creamy lesions on ophthalmoscopy, with early hypofluorescence and late staining on fluorescein angiography (Figures 1A-C). Inactive chorioretinal lesions typically are partially atrophic and partially pigmented with a “targetlike appearance”: central hypofluorescence by blockage from pigment and peripheral hyperfluorescence (Figures 2A and B). Some atrophic lesions are not pigmented. The lesions vary in number from less

than 20 to more than 50 per eye. Chorioretinal lesions involve the midzone and/or periphery in almost all eyes. The posterior pole is involved in nearly 2/3 of eyes. Lesion size range from 100 to 1500 μm, with most of the lesions measuring 200 to 500 μm. Linear clustering of chorioretinal lesions is a prominent feature, occurring in more than 80% of eyes with chorioretinitis (Figures 1A-C and 3A and B). The streaks vary in number, from one to more than 3 per eye, and in length approximately from 2 to 15 mm. They typically are oriented radially in the nasal and peripheral fundus or arranged in a curvilinear pattern in the temporal posterior fundus. The linear pattern of chorioretinitis appears to be related to the course of retinal nerve fibres, suggesting a contiguous spread of central nerve system disease22 (Figures 3A and B).

Indocyanine green angiography shows welldelineated hypofluorescent choroidal lesions, which are more numerous than those appreciated by fluorescein angiography or clinically (Figures 4A-C).20

Diabetes was found to be a risk factor for WNVassociated chorioretinitis. It was also associated with more severe chorioretinal involvement.24 A recent prospective, controlled case series study emphasized the value of the typical multifocal chorioretinitis as a specific marker of WNV infection, particularly in patients who present with meningoencephalitis.25

OTHER OPHTHALMIC MANIFESTATIONS

Although a typical multifocal chorioretinitis is the most common ocular manifestation of WNV infection, other findings can be observed. Anterior uveitis associated with vitritis in the absence of chorioretinitis has been reported.12 Numerous retinal vascular changes can occur, including retinal haemorrhages, focal or diffuse vascular sheathing, vascular leakage, and occlusive vasculitis.3,8,13,14 One patient with WNV infection had peripheral, segmental wedge-shaped zones of atrophy and mottling of the retinal pigment epithelium, which might be due to occlusion of ciliary artery.8 West Nile Virus-associated optic nerve involvement may occur, including optic neuritis, optic disc swelling, and optic disc staining on fluorescein angiography.8,15-18 Other reported neuro-ophthalmic manifestations include ocular nerve palsy and nystagmus.8 A case of congenital chorioretinal scarring secondary to intrauterine transmission of WNV infection has been reported.19

DIAGNOSIS

Diagnosis of WNV infection requires a high index of suspicion and specific laboratory testing. The most common efficient diagnostic method is detection of WNV-specific IgM antibody in serum or cerebrospinal fluid using the antibody-capture enzyme-linked immunoabsorbent assay. Since IgM antibody does not cross the blood-brain barrier, its presence in the cerebrospinal fluid strongly suggests infection of the central nervous system. The plaque-reduction neutralisation test can help distinguish false-positive results of MAC-ELISA or other assays as well as to help to distinguish serologic cross-reactions among the flaviviruses.1

The unique pattern of multifocal chorioretinitis can help establish an early diagnosis of the disease while serologic testing is pending.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of WNV systemic disease include other arthropod-borne viral encephalitides, enteroviral aseptic meningitis, herpesvirus encephalitis, encephalopathy from systemic illnesses (Legionnaires’ disease, rickettsiosis, Epstein-Barr virus infectious mononucleosis, and systemic lupus erythematosus), epidural abscess, hypertensive encephalopathy, and drug-induced meningitis. Many infectious and inflammatory conditions may present with chorioretinitis. The differential diagnosis includes syphilis, tuberculosis, histoplasmosis, sarcoidosis, and idiopathic multifocal chorioretinitis.3 West Nile virusassociated chorioretinitis can be distinguished from these entities on the basis of history, systemic signs and symptoms, and particularly the unique pattern of chorioretinitis.

TREATMENT, EVOLUTION AND PROGNOSIS

There is, at present, no proven treatment for WNV infection. In cases of severe systemic disease, intensive supportive therapy is indicated, often involving hospitalisation, intravenous fluids, respiratory support, prevention of secondary infections, and good nursing care.

Antiviral agents such as ribavirin and interferon were found to be active only in vitro.26,27

Several clinical studies, including an open-label trial of interferon α-2b and a placebo-controlled trial using high-titre intravenous immunoglobulin, are ongoing.28 Prevention is the mainstay of WNV infection control: measures to reduce the number of mosquitoes (draining standing water, larvicides), personal protection (repellents, window screen, protective clothing). Vaccination, a long term solution, is still in the research

phase.3,28

Specific ophthalmic treatment may be required: topical steroids for anterior uveitis, peripheral retinal photocoagulation for neovascularisation due to occlusive vasculitis, pars plana vitrectomy for nonclearing vitreous haemorrhage or tractional retinal detachment, and intervention with laser, photodynamic therapy, or intravitreal injection of anti-VEGF for choroidal neovascularisation.13

Prognosis of WNV systemic disease is good in most patients. However, severe cases may result in neurologic sequelae or death, especially in patients who are elderly or debilitated.1,2

Ocular involvement usually have a self-limited course. Active chorioretinal lesions at presentation evolved to the typical inactive stage. Some inactive lesions become more prominent on both ophthalmoscopy and fluorescein angiography. Visual acuity returns to baseline in most patients. However, persistent visual impairment may occur due to a foveal chorioretinal scar, choroidal neovascularisation, complications of occlusive retinal vasculitis, such as vitreous haemorrhage secondary to retinal neovascularisation, severe ischaemic maculopathy (Figures 5A-C), optic atrophy, or retrogeniculate damage.3,12,13,15,16,20

KEY POINTS

•Chorioretinal involvement, frequently asymptomatic and self-limited, is present in almost 80% of patients with WNV infection associated with neurologic illness.

•A bilateral multifocal chorioretinitis, with typical clinical and fluorescein angiographic features, is the most common finding, but numerous other ocular manifestations can occur.

•Diabetes mellitus appears to be a potential risk factor for developing severe neurologic disease and also severe chorioretinitis.

Figures 5A-C: A 60-year-old diabetic patient with a history of WNV infection complained of severe visual loss in the right eye. Visual acuity was 20/400 OD and 20/40 OS. (A) Fundus photograph of the right eye shows deep retinal haemorrhages, focal retinal opacification, and retinal arterial sheathing in the macular area. Note the presence of proliferative diabetic retinopathy. (B) and (C) Fluorescein angiography shows severe macular capillary nonperfusion in the right eye (B) and chorioretinal lesions hypofluorescent centrally and hyperfluorescent peripherally, more prominent in the left eye (C). The macula of the left eye appears to be well-perfused

•The unique pattern of multifocal chorioretinitis can help establish an early diagnosis of the disease while serologic testing is pending. This might be of utmost importance in the near future for early initiation of promising drugs currently under investigation.

•Therefore, an ocular examination, including dilated fundus examination and fluorescein angiography in selected cases, should be part of the routine evaluation of patients with clinically suspected WNV infection.

•WNV infection should be considered in the differential diagnosis of multifocal chorioretinitis in patients living in or returning from specific endemic regions.

REFERENCES

1.Petersen LR, Marfin AA. West Nile virus: a primer for the clinician. Ann Intern Med 2002;137:173-9.

2.Nash D, Mostashari F, Fine A, et al. The outbreak of West Nile virus infection in the New York City area in 1999. N Engl J Med 2001;344:1807-14.

3.Garg S, Jampol LM. Systemic and intraocular manifestations of West Nile virus infection. Surv Ophthalmol 2005;50:3-13.

4.Bains HS, Jampol LM, Caughron MC, Parnell JR. Vitritis and chorioretinitis in a patient with West Nile virus infection. Arch Ophthalmol 2003;121:205-7.

5.Vandenbelt S, Shaikh S, Capone A Jr, Williams GA. Multifocal choroiditis associated with West Nile virus encephalitis. Retina 2003;23:97-9.

6.Adelman RA, Membreno JH, Afshari NA, Stoessel KM. West Nile virus chorioretinitis. Retina 2003;23:100-1.

7.Hershberger VS, Augsburger JJ, Hutchins RK, et al. Chorioretinal lesions in nonfatal cases of West Nile virus infection. Ophthalmology 2003;110:1732-6.

8.Khairallah M, Ben Yahia S, Ladjimi A, et al. Chorioretinal involvement in patients with West Nile virus infection. Ophthalmology 2004;111:2065-70.

9.Shaikh S, Trese MT. West Nile virus chorioretinitis. Br J Ophthalmol 2004;88:1599-1600.

10.Eidsness RB, Stockl F, Colleaux KM. West Nile chorioretinitis. Can J Ophthalmol 2005;40:721-4.

11.Myers JP, Leveque TK, Johnson MW. Extensive chorioretinitis and severe vision loss associated with West Nile virus meningoencephalitis. Arch Ophthalmol 2005;123: 1754-6.

12.Chan CK, Limstrom SA, Tarasewicz DG, Lin SG. Ocular features of West Nile virus infection in North America: a study of 14 eyes. Ophthalmology 2006;113:1539-46.

13.Seth RK, Stoessel KM, Adelman RA. Choroidal neovascularization associated with West Nile virus chorioretinitis. Semin Ophthalmol 2007;22:81-4.

14.Kuchtey RW, Kosmorsky GS, Martin D, Lee MS. Uveitis associated with West Nile virus infection. Arch Ophthalmol 2003;121:1648-9.

15.Kaiser PK, Lee MS, Martin DA. Occlusive vasculitis in a patient with concomitant West Nile virus infection. Am J Ophthalmol 2003;136:928-30.

16.Khairallah M, Ben Yahia S, Attia S, et al. Severe ischemic maculopathy in a patient with West Nile virus infection. Ophthalmic Surg Lasers Imaging 2006;37:240-2.

17.Vaispapir V, Blum A, Soboh S, Ashkenazi H. West Nile virus meningoencephalitis with optic neuritis. Arch Intern Med 2002;162:606-7.

18.Gilad R, Lamp Y, Sadeh M, et al. Optic neuritis complicating West Nile virus meningitis in a young adult. Infection 2003; 31:55-6.

19.Anninger WV, Lomeo MD, Dingle J, et al. West Nile virus associated optic neuritis and chorioretinitis. Am J Ophthalmol 2003;136:1183-5.

20.Anninger W, Lubow M. Visual loss with West Nile virus infection: a wider spectrum of a “new” disease. Clin Infect Dis 2004;38:e55-6.

21.Alpert SG, Fergerson J, Noel LP. Intrauterine West Nile virus: ocular and systemic findings. Am J Ophthalmol 2003;136:733-5.

22.Khairallah M, Ben Yahia S, Attia S, Zaouali S, Ladjimi A, Messaoud R. Linear pattern of West Nile virus-associated chorioretinitis is related to retinal nerve fibres organization. Eye 2007;21:952-5.

23.Khairallah M, Ben Yahia S, Attia S, Zaouali S, Jelliti B, Jenzri S, Ladjimi A, Messaoud R. Indocyanine green

angiographic features in multifocal chorioretinitis associated with West Nile virus infection. Retina 2006;26:358-9.

24.Khairallah M, Ben Yahia S, Letaief M, Attia S, Kahloun R, Jelliti B, Zaouali S, Messaoud R. A prospective evaluation of factors associated with chorioretinitis in patients with West Nile virus infection. Ocular Immunology and Inflammation (In press)

25.Abroug F, Ouanes-Besbes L, Letaief M, et al. A cluster study of predictors of severe West Nile virus infection. Mayo Clin Proc 2006;81(1):12-6.

26.Jordan I, Briese N, Fischer N, et al. Ribavirin inhibits West Nile virus replication and cytopathic effect in neutral cells. J Infect Dis 2000;182:1214-7.

27.Samuel MA, Diamond MS. Alpha/beta interferon protects against lethal West Nile virus infection by restricting cellular tropism and enhancing neuronal survival. J Virol 2005;79:13350-61.

28.Gea-Banacloche J, Johnson RT, Bagic A, et al. West Nile virus: pathogenesis and therapeutic options. Ann Intern Med 2004;140:545-53.

INTRODUCTION

Dengue fever is the most common mosquito-borne viral disease in humans. It is caused by the dengue virus, a flavivirus, of which there are 4 serotypes, and is transmitted by the Aedes aegypti mosquito. It is considered to be one of the most important arthropod borne disease in the tropical and subtropical regions, being endemic in more than 100 countries. It afflicts 100 million people annually thereby putting 2.5 billion people at risk worldwide.1

Dengue fever is endemic in Singapore but the number of cases has risen dramatically in the last few years.2 In addition to fever, dengue fever also causes headache, myalgia and thrombocytopenia, resulting in bleeding manifestations such as a purpuric rash. Hypotension may also occur in the Dengue Shock syndrome which carries a high mortality rate.1

More recently, dengue fever has also been found to affect the eyes, with resultant loss of vision.3-8

EPIDEMIOLOGY OF DENGUE OCULAR INVOLVEMENT

Ocular involvement in dengue fever has recently been reported from Singapore, Thailand, Taiwan, India, Mexico, and Brazil.3-13 In a cross-sectional observational study conducted in Singapore in 2005 during a dengue epidemic,14 we found that the prevalence of dengue maculopathy among patients hospitalised for dengue fever was 10 percent.

DEMOGRAPHICS

These patients tend to be young, with an average age of 29 years, ranging from 11 to 61 years.9 There is no sex or racial predilection.9,14

OCULAR MANIFESTATIONS OF DENGUE FEVER

OCULAR SYMPTOMS

The ocular symptoms my range from mild blurring of vision to catastrophic and severe blindness and

they usually occur within a monthe of the dengueinfection.

SUBCONJUNCTIVAL HAEMORRHAGE

The commonest ocular involvement reported in an East Indian population was a petechial type of subconjunctival haemorrhage (37%), which was associated with a platelet count of less than 50,000/μl.10

ANTERIOR SEGMENT FINDINGS

Anterior segment involvement is ususally mild and may be easily missed. In 17 percent clls may be seen in the anterior chamber versus 16 percent in the vitreous.

POSTERIOR SEGMENT FINDINGS

The fundal manifestations typically occur one week after the onset of fever, just as the fever has settled and the platelet count is recovering.6,8 The patients may present with a sudden decrease in vision (87%), a central scotoma (63%) or floaters (1%).9,14 The involvement is bilateral in 73 percent but tends to be asymmetrical. Disc hyperhemia is present in 14 percent of cases and disc edema in 11 percent. Fundus findings9 include retinal Haemorrhages (45%) (Figure 1), venular sheathing (45%) (Figures 2 and 3),

yellow subretinal dots (28%) (Figure 4), retinal pigment epithelium mottling (17%) and round foveal swelling (foveolitis) in 16 percent (Figure 5). Arteriolar sheathing is seen in 4 percent.

PATHOPHYSIOLOGY OF DENGUE MACULOPATHY

The above signs occur as a result of involvement of the retinal and/or choroidal vessels and the macula is preferentially involved in Dengue.

The pathophysiologic mechanism of dengue maculopathy is still unclear. The average onset of ocular symptoms from the onset of illness is about 7 days.6,8,9,14 This delay as well as the lower the serum complement C3 levels in patients with maculopathy as compared to those without maculopathy supports an immune-mediated mechanism rather than direct viral infection of the eye.9,14

DIAGNOSIS

The diagnosis of dengue fever is based on the typical clinical presentation of and a positive dengue IgM serology. The diagnosis of dengue maculopathy is based on clinical features as well as the imaging studies described below.

Dengue maculopathy involves both the retinal as well as the choroidal circulation, hence fluorescein and

indocyanine green angiography are important modalities in the assessment of its severity, as some of the changes may not be evident clinically and may therefore be missed. 9

tends to be greater.9 Furthermore, eyes with occlusive vascular involvement tend to have residual scotomas, corresponding to depressed multifocal ERG recordings.15

FUNDAL FLUORESCEIN ANGIOGRAPHY (FFA)

The main findings9 include:

•Blocked fluorescence (33%) (Figure 4 Top left, Middle left)

•Venular occlusion (25%) (Figure 4, Top right, Middle right)

•Venular leakage (13%) (Figures 2 and 3)

•Knobby capillary hyperfluorescence (13%)

•Retinal pigment epithelium (RPE) hyperfluorescence (10%) (Figure 4 middle left)

•Venular leakage with occlusion (5%)

•Arteriolar leakage (3%)

•RPE window defect (3%)

•Arteriolar occlusion (2%)

•Capillary nonperfusion (2%)

Interestingly, in 3% of eyes, fundal fluorescein angiography (FFA) is unremarkable despite clinically observed venous sheathing on fundus examination.9 When the maculopathy involves larger retinal vessels, regardless of whether they are inflammatory or occlusive in nature, the visual acuity and field loss

INDOCYANINE GREEN ANGIOGRAPHY (ICG)

Yellow subretinal dots appear as early RPE hyperfluorescence on FFA, but these changes are seen in only 15% of the cases (Figure 4 Top left, middle left). In comparison, ICG showed hypofluorescent spots during the mid to late phase, corresponding to these yellow dots as well as additional spots in areas without clinically evident dots in 29% of cases. The angiogram findings suggest that the yellow subretinal dots involve the choriocapillaries and/or RPE (Figure 4). These lesions resolve clinically without residual visual loss.9

Large choroidal vasculopathy with hyperfluoresence and leakage (Figure 6) is also seen on ICG (31%) and is associated with mild reversible visual disability.9

OPTICAL COHERENCE TOMOGRAM

Optical coherence tomogram (OCT) is indispensable in eyes with decreased visual acuity but no apparent lesions can be observed on angiography. Foveolitis, clinically seen as a well-circumscribed pale yellowish