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Ocular Features of West Nile Virus Infection in North America
Ocular Features of West Nile Virus Infection in North America A Study of 14 Eyes Clement K. Chan, MD, FACS,1,2 Scott A. Limstrom, MD,3 Dariusz G. Tarasewicz, MD, PhD,1 Steven G. Lin, MD1 Purpose: To present a case series of ocular findings of West Nile virus infection (WNVI) in North America. Design: Retrospective, noncomparative, observational case series. Participants: All patients were referred to the authors for WNVI with ocular involvement between the years 2002 and 2005. Methods: Chart review was performed on all participants. All participants underwent complete ophthalmic evaluation during each examination, including best-corrected Snellen visual acuity measurement, tonometry, slit-lamp biomicroscopy of the anterior and posterior segments, and dilated fundus examination with indirect ophthalmoscopy. Fundus photography and fluorescein angiography were also performed on all eyes. Relevant ocular findings associated with WNVI were recorded and tabulated. Main Outcome Measures: The authors studied the characteristics, frequency, and locations of ocular lesions found in participants’ eyes. Results: There were 14 eyes (7 patients) with ocular West Nile virus lesions from 2002 to 2005. Average patient age was 58.4 years (range, 32– 85 years). Ocular findings in descending order of frequency included multifocal chorioretinal target lesions in 12 eyes (85.7%), retinal hemorrhages in 7 eyes (50.0%), vitritis in 6 eyes (42.9%), chorioretinal linear streaks in 4 eyes (28.6%), perivascular sheathing and vasculitis in 4 eyes (28.6%), narrowed retinal vessels in 4 eyes (28.6%), disc edema in 4 eyes (28.6%), optic atrophy in 2 eyes (14.3%), vascular occlusion in 2 eyes (14.3%), and VIth nerve palsy in 1 eye (7.1%). Peripheral fundus lesions were found in all 14 eyes (100%), whereas posterior fundus lesions were found in 8 eyes (57.1%). Five patients (71.4%) were diabetic. Diabetic retinopathy was present in 7 eyes (70%). Conclusions: Multifocal choroiditis is the most common ocular manifestation associated with WNVI, with a typically benign clinical course. Less frequent ocular lesions, including optic neuritis and occlusive vasculitis, frequently induce persistent and likely permanent visual deficit. Diabetic patients and those older than 50 years of age are more vulnerable to the more severe features of WNVI, including more serious ocular lesions. Ophthalmology 2006;113:1539 –1546 © 2006 by the American Academy of Ophthalmology.
West Nile virus infection (WNVI) was first identified by Smithburn et al1 in Uganda in 1937. It is endemic in many parts of the world. The West Nile virus (WNV) is a singlestranded RNA arbovirus, because of its transmission by mosquitoes and possibly other arthropod vectors. It belongs to the Flaviviridae family of viruses, which includes Japanese Originally received: October 13, 2005. Accepted: April 17, 2006. Manuscript no. 2005-983. 1 Southern California Desert Retina Consultants, Palm Springs, California. 2 Department of Ophthalmology, Loma Linda University, Loma Linda, California. 3 Alaska Retinal Consultants, Anchorage, Alaska. Presented as a poster at: American Academy of Ophthalmology Annual Meeting, October 2005, Chicago, Illinois. The authors have no financial or proprietary interest in any commercial products mentioned in the study. Correspondence to Clement K. Chan, MD, FACS, P.O. Box 2467, Palm Springs, CA 92263. E-mail: [email protected]. © 2006 by the American Academy of Ophthalmology Published by Elsevier Inc.
encephalitis, St. Louis encephalitis, yellow fever, dengue, Murray Valley encephalitis, Kunjin encephalitis, and Western equine encephalitis viruses.2 Wild birds serve as the primary natural hosts.3 Birds of the crow family (Corvidae) are particularly sensitive to WNVI. However, migratory birds probably play an important role in the spread of the disease.4 Mosquitoes (primarily the Culex species) are responsible for transmitting this disease from the natural hosts to humans and other mammals.3,5 Until recent years, the virus was found only in the Eastern hemisphere, throughout Africa, parts of Asia, and the Middle East. Recent outbreaks have occurred in Romania, Israel, and New York.5 Nineteen ninety-nine (1999) was the first year that it entered the Western hemisphere via New York.6 Subsequent years saw rapid migration of this virus westward across the continent. Alaska, Hawaii, and Washington are the only states that have no reported human cases of WNVI.7 Since 1999, over 16 000 WNVI cases have been documented in the United States. Only 20% of infected individuals experience sysISSN 0161-6420/06/$–see front matter doi:10.1016/j.ophtha.2006.04.021
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Chan et al 䡠 Ocular West Nile Virus Infection temic symptoms, including fever, malaise, rash, lymph adenopathy, and anorexia.8 Only half of those infected seek medical care.8 Ocular symptoms such as photophobia, retrobulbar pain, and diplopia have been reported to be associated with WNVI.9 Approximately 1 in 150 (0.67%) infected individuals experience neuroinvasive diseases, which can include altered mental status, motor and sensory neurological deficits, as well as life-threatening meningoencephalitis.10 –14 Death occurs in 5% to 10% of this group of seriously infected patients.7 No known antiviral agents have yet been found to be effective against WNVI.5,9,10 For most WNV cases, however, supportive care is sufficient for recovery. The precise prevalence of ocular involvement associated with WNVI is unknown, primarily because of the transient nature of the active stage of the ocular infection. There are a number of recent case reports describing ocular findings in WNVI.15–22 We herein present 14 eyes of 7 patients with ocular WNVI in North America.
Patients and Methods This was a retrospective, nonrandomized, noncomparative, observational case series involving patients with ocular WNVI contracted in multiple states of North America (Iowa, Nebraska, Colorado, and California) between the years 2002 and 2005. The authors describe the characteristics, frequency, and locations of ocular lesions found in these patients’ eyes. Positive serologic results for the WNV were required for inclusion in this study. One or more of the following assays were used to demonstrate positive serologic results for patients with findings suggestive of ocular WNVI referred for tertiary vitreoretinal care: WNV-specific immunoglobulin M (IgM) antibody-capture enzyme-linked immunoabsorbent assay (ELISA), indirect fluorescent antibody assay for WNV, and plaque reduction neutralization test (PRNT) for WNV. The WNVI was confirmed with IgM antibody-capture ELISA in a serum sample for 3 patients, in a cerebrospinal fluid (CSF) sample for 1 patient, and in a serum sample and a CSF sample for 2 patients. In addition, elevated IgM titer with indirect fluorescent antibody assay for the WNV was found in the serum sample of 1 patient. The WNVI was confirmed with PRNT for 4 patients. All
study patients underwent complete ophthalmic examination, including best-corrected Snellen visual acuity, tonometry, biomicroscopy of the anterior and posterior segments, as well as indirect ophthalmoscopy. Dilated fundus examination was performed for all eyes. In addition, fundus photography and fluorescein angiography were performed on all eyes. Institutional review board approval was obtained for the retrospective chart review for this study. In addition, this study was compliant with the requirements of the Health Insurance Portability and Accountability Act (HIPAA). Informed consent was obtained from study participants.
Selected Case Reports Patient 2. A 71-year-old white woman sought treatment at the emergency department with a 10-day history of fatigue, joint pain, diarrhea, malaise, confusion, and fever of 104° F. Head computed tomography results showed pansinusitis but were otherwise normal. Complete blood count results were significant for slight leukocytosis with minimally elevated neutrophils. Liver enzymes were moderately elevated. Cerebrospinal fluid analysis revealed 10 white blood cells with 40% lymphocytes, 35% neutrophils, and 25% monocytes. Both serum and CSF ELISA test results were positive for WNV. This was confirmed by PRNT with a dilution of 1:320. The patient’s past ocular history was significant for mild nuclear sclerotic cataracts. One year before presentation, her visual acuity measured 20/20 for both eyes. One month after presentation with symptoms of WNVI, she reported blurred vision and floaters, more in the right eye than the left eye. She did not report ocular pain or photophobia. Her best-corrected visual acuity was 20/40 in the right eye and 20/30 in the left eye. Anterior segment examination showed mild cells in the anterior chambers. Examination of the posterior segment revealed moderate vitreous cells and debris in the right eye and minimal vitreous cells in the left eye. The optic nerves and macula were normal in both eyes. Small pigmented lesions surrounded with a creamy halo were present just outside the vascular arcades on the midperipheral fundus in both eyes (Fig 1A). The corresponding fluorescein angiogram showed hypofluorescence and a surrounding ring of hyperfluorescence on the chorioretinal lesions (Fig 1B). Treatment with topical prednisolone acetate was initiated. Several weeks later, the patient experienced further vision loss in the left eye. At that time, her visual acuity was 20/30 in the right
4™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™ Figure 1. Patient 2. A, Fundus examination revealed multiple cream-colored chorioretinal lesions (arrowheads), focal retinal hemorrhage, and ischemia superior to the disc in the left eye that highlight the partially active multifocal chorioretinal lesions in this 71-year-old woman with West Nile virus infection (subacute stage). B, Corresponding fluorescein angiogram showed hypofluorescence and a surrounding ring of hyperfluorescence (arrowheads) on the chorioretinal lesions superior to the disc of the left eye (subacute stage). C, Arterial narrowing, perivascular sheathing, and vascular occlusion (arrowheads) were found on the posterior and midperipheral fundus, both superior and inferior to the disc, of the right eye. Figure 2. A, Anterior segment examination results of patient 3 show perivascular sheathing with occlusive vasculitis, optic pallor, and numerous dot and blot hemorrhages on the superior and posterior fundus of the right eye of this 58-year-old diabetic woman with West Nile virus infection. B, Anterior segment examination of the left eye of patient 4, a 32-year-old man with West Nile virus infection, shows multiple intraretinal hemorrhages and adjacent perivascular sheathing involving multiple venous tributaries. Figure 3. A, Anterior segment examination results of patient 5, a 55-year-old Hispanic man with type 2 diabetes mellitus and West Nile virus infection, showing multiple active (arrow) and partially active (arrowhead) discrete cream-colored chorioretinal spots (100 –300 m) on the posterior and peripheral fundus of the left eye (acute and subacute stages). B, The corresponding fluorescein angiogram examination showed early hypofluorescence (arrow) on the active chorioretinal spots (acute stage) and focal hypofluorescence with a surrounding hyperfluorescent ring (arrowhead) on the partially active lesions (subacute stage). Subsequent images in the late phase of the same angiogram showed staining of the active lesions. Figure 4. Patient 6. A, Dilated fundus examination of the right eye of this 68-year-old diabetic woman with West Nile virus infection showed multifocal inactive chorioretinal atrophic lesions with a distinct margin (arrowheads; convalescent stage). B, Dilated fundus examination of the left eye showed similar chorioretinal atrophic lesions (arrowhead) and whitish-yellow chorioretinal linear streaks (arrow) on inferior midperipheral fundus. C, D, Fluorescein angiogram examination showed persistent focal hyperfluorescence of the same lesions throughout the study.
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Ophthalmology Volume 113, Number 9, September 2006 eye and 20/200 in the left eye. Anterior segment examination was normal with the exception of the resolving cells in the anterior chambers. Fundus examination showed arterial narrowing, perivascular sheathing, and vascular occlusion consistent with retinal vasculitis in the left eye (Fig 1C). Oral prednisone administration was begun in addition to increasing the dosing frequency of her topical prednisolone acetate. At the most recent examination, she displayed less vitreous and perivascular inflammation. Her visual acuity had improved to 20/25 in the right eye and 20/70 in the left eye. The persistent visual deficit of left eye was likely the result of ischemia associated with retinal vasculitis and vascular occlusion. Patient 3. A 58-year-old non–insulin-dependent diabetic white woman sought treatment for intractable nausea and vomiting, vertigo, severe weakness, and fever of 102° F. Head computed tomography with and without contrast revealed unremarkable results. White blood cell count was elevated to 18 000. Serologic examination (ELISA) was positive for IgM (titer of 4.46) associated with the WNV. Immunoglobulin G (IgG) test results were negative. Cerebrospinal fluid analysis was significant for a few white blood cells and elevated IgM (ELISA) titer of 5.33, but a normal IgG titer of less than 0.9 for the WNV. The patient’s past ocular history was significant for background diabetic retinopathy, clinically significant diabetic macular edema of the left eye treated with focal laser 4 months before presentation, and glaucoma controlled with latanoprost. Three months before presentation, her best-corrected visual acuity measured 20/40 in the right eye and 20/50 in the left eye. Seven days after her initial presentation with symptoms of WNVI, the patient experienced sudden vision loss in both eyes. She reported seeing multiple dots and decreased peripheral vision. On ocular examination, her best-corrected visual acuity was 20/400 in the right eye and 20/70 in the left eye. Confrontation visual fields were constricted nasally and temporally for both eyes. Pupillary reaction was sluggish. No afferent pupillary defect was noted. Anterior segment examination was significant for moderate cortical, nuclear, and posterior subcapsular cataracts in both eyes. There were rare cells in the anterior vitreous cavity in both eyes. Disc margins were sharp. There was mild disc pallor and a 0.6 cup-to-disc ratio in each eye. The right fundus displayed perivascular sheathing, cotton-wool spots, and numerous dot and blot hemorrhages in the periphery (Fig 2A). The left macula had residual hard exudates relating to previously treated diabetic macular edema. The retinal arteries were mildly narrowed in the left eye. Intravenous fluorescein angiography was significant for normal arteriovenous filling with late perivascular leakage, consistent with vasculitis. The patient’s systemic symptoms gradually resolved with supportive treatment. She returned for repeat ophthalmic examination 1 month later. At that time, her best-corrected visual acuity was 20/400 in the right eye and 20/200 in the left eye. The anterior segment examination showed unchanged results. There was arterial narrowing and perivascular sheathing in both eyes. There was diffuse optic nerve pallor and atrophy in both eyes. There were numerous round pigmented lesions with a surrounding creamy halo on the peripheral fundus of both eyes. At the most recent examination 5 months after her initial presentation, there was persistent obliterative vasculitis with no improvement in visual acuity. Patient 4. A 32-year-old previously healthy white man with no prior ocular problems was hospitalized with a 1-week history of severe headache, fever, nuchal rigidity, myalgia, malaise, and photophobia. Magnetic resonance imaging revealed subtle enhancement of the prepontine focal space and spinal cord, suggestive of myelitis. Prominent enhancement of the subarachnoidal space also was seen. Transesophageal echocardiogram results were negative for an embolic source. Complete blood count was within normal limits. Cerebrospinal fluid analysis was significant for 231
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white blood cells with 48% lymphocytes, 30% neutrophils, and 22% monocytes. Cerebrospinal fluid ELISA revealed elevated IgM titer (1:2) associated with the WNV. Cerebrospinal fluid IgG titer for WNV was negative (1:1). On the third day after admission, the patient reported blurred vision of his right eye. On ocular examination, his uncorrected visual acuity was 20/30 in the right eye and 20/20 in the left eye. Confrontation visual fields and ocular motility were normal. There was a subtle right afferent pupillary defect. Anterior segment examination results were normal. The superior margin of the right optic nerve was slightly blurred. The left optic nerve appeared normal. Prominent perivenous sheathing and intraretinal hemorrhages were present in the posterior fundus of the right eye (Fig 2B). The posterior fundus, including its retinal vasculature, in his left eye was normal. Several whitish chorioretinal streaks were present on the peripheral fundus in both eyes. The patient was treated empirically with ceftriaxone (Rocephin, Roche Pharmaceuticals, Hoffman-La Roche Inc., Nutley, NJ), acyclovir sodium (Zovirax, GlaxoSmithKline, Uxbridge, United Kingdom), and methylprednisolone sodium succinate (SoluMedrol, Pharmacia & Upjohn Inc., Kalamazoo, MI). His systemic symptoms gradually improved. His ocular symptoms remained unchanged. He was lost to follow-up after discharge. Patient 5. A 55-year-old Hispanic man with poorly controlled type 2 diabetes and systemic hypertension sought treatment at a local hospital emergency department on July 4, 2004, with progressive worsening headache, fever, chills, severe nausea and vomiting, as well as blurred vision, left eye more than right eye, since June 30, 2004. During his hospitalization, an extensive systemic workup revealed negative results for bacterial meningitis, altered mental status, and sensory or motor deficit. An infectious disease workup showed negative results for bacterial and fungal agents in the blood and CSF. He was treated for aseptic meningitis on an empirical basis. He recovered and was discharged home 5 days later. His ocular examination on August 4, 2004, showed a visual acuity of 20/40 in the right eye and 20/30 in the left eye. The anterior segment examination results were unremarkable with the exception of mild cataracts. There was absence of vitreous cells and infiltrates in both eyes. The discs were clear. There were mild perimacular scattered hard exudates, hemorrhages, and microaneurysms consistent with diabetic maculopathy in his right eye. There were also multiple discrete cream-colored chorioretinal spots, scattered throughout the posterior and peripheral fundus, left eye more than right eye (Fig 3A). These lesions measured from 100 to 300 m in diameter. The corresponding fluorescein angiogram showed either early hypofluorescence and late staining or focal hypofluorescence with a surrounding ring of hyperfluorescence, associated with active or partially active multifocal chorioretinal lesions, respectively (Fig 3B). There was absence of vasculitis and vascular occlusion. Three weeks later, the creamy halos associated with the chorioretinal lesions started to change into well-demarcated borders. A uveitis workup to rule out multiple entities, including tuberculosis, lues, sarcoidosis, collagen vascular diseases, herpes viruses, Epstein-Barr virus, Lyme disease, and so forth, was unremarkable. However, the patient’s serum sent to the Riverside County Health Department in mid-August, 2004, showed elevated IgM (5.44) and IgG (25.8) titers associated with the WNV on ELISA, as well as highly positive PRNT for WNV (titer of 1:840). During his last visit in February, 2005, his visual acuity remained 20/40 in the right eye and 20/30 in the left eye. There were no changes in the multiple pigmented fundus lesions in both eyes. Patient 6. A 68-year-old diabetic white woman was bitten by mosquitoes at a ranch in Colorado in August, 2003. Two weeks later, she sought treatment at an emergency department in Arizona
Chan et al 䡠 Ocular West Nile Virus Infection Table 1. Demographics of Patients with Ocular West Nile Virus Infection Gender
n (%)
Age (yrs)
Diabetic
Symptom Duration before Examination
Male 4 (57.1%) ⬍50, 2 (28.6%) 5 (71.4%) Within 7 d, 3 (42.9%) Female 3 (42.9%) ⬎50, 5 (71.4%) 8–30 d, 1 (14.3%) Mean, 58.4 31–90 d, 3 (42.9%) Range, 32–85
with a 3-day history of headache, fever, malaise, vomiting, and visual disturbance. On presentation, she showed aphasia, ataxia, and a VIth cranial nerve palsy. Lumbar puncture analysis revealed elevated white blood cells. Magnetic resonance imaging showed no abnormalities. Blood and cerebrospinal fluid cultures had negative results. She was admitted to the intensive care unit to rule out bacterial versus viral meningoencephalitis. Subsequent serologic examination revealed positive results for elevated IgM titers with the indirect fluorescent antibody assay (1:160) and the PRNT (1:20) for WNV. She responded well to supportive care. During her hospital stay, she noted a central scotoma in her right eye. Ophthalmic examination revealed background diabetic retinopathy and a central retinal artery occlusion in her right eye. No treatment was recommended. The patient was discharged 4 days later and was instructed to follow up with her physicians at home. The patient first sought treatment at our clinic in California in November, 2003. On examination, her visual acuity was 20/30 in both eyes. There was no afferent pupillary defect. Extraocular movements were full. Confrontational visual fields showed a superior deficit in the right eye and a normal field in the left eye. Intraocular pressure was normal. Anterior segment examination showed quiet anterior chambers with no cells and keratic precipitates in both eyes. Dilated fundus examination showed no vitreous cells, but did show the presence of peripapillary dot hemorrhages and subtle nerve fiber layer edema around the margins of the optic nerves in the right eye more than the left eye. There was absence of optic nerve pallor. There were multiple small round chorioretinal punched-out atrophic lesions with well-demarcated borders involving both the posterior and peripheral fundi (Fig 4A). There was a predominant perivascular distribution associated with these chorioretinal lesions. None seemed to be active. There was no cherry-red spot. There were also whitish-yellow chorioretinal streaks on the midperipheral fundi (Fig 4B). Fluorescein angiography examination showed normal vascular filling in both eyes and no signs of obstruction. There was staining of the multifocal small punched-out atrophic lesions (Fig 4C, D). There was absence of hyperfluorescent leakage on the discs. Humphrey 24-2 visual field analysis showed a superior field cut in the right eye and mild superior field loss in the left eye. Farnsworth-Munsell 15 color plate testing showed no significant deficit. Four months after presentation, her right eye experienced diffuse clinically significant diabetic macular edema requiring focal grid laser treatment. The severe diabetic macular edema caused a persistent visual deficit (visual acuity of 5/200) in her right eye despite laser therapy. Her left eye maintained a visual acuity of 20/30 1 year later. In addition, the visual field loss for both eyes persisted.
Results Tables 1, 2, and 3 outline the results of this study. This retrospective case series included 14 eyes in 7 patients. There were 4 men
(57.1%) and 3 women (42.9%). The mean age was 58.4 years, and the age range was from 32 to 85 years. Follow-up time ranged from 1 to 18 months, with a mean of 8.3 months. Five patients (71.4%) were diabetics. Three patients (42.9%) presented within 7 days, 1 patient (14.3%) presented between 8 and 30 days, and 3 patients (42.9%) presented between 31 and 90 days from the onset of symptoms for ocular examination. Systemic symptoms included fever in 6 patients (85.7%), headache in 4 patients (57.1%), nausea and vomiting in 4 patients (57.1%), malaise in 4 patients (57.1%), myalgia in 2 patients (28.6%), nuchal rigidity in 1 patient (14.3%), vertigo in 1 patient (14.3%), confusion in 1 patient (14.3%), diarrhea in 1 patient (14.3%), ataxia in 1 patient (14.3%), and aphasia in 1 patient (14.3%). Six patients (85.7%) reported blurred vision. Bilateral ocular findings were detected in all 7 patients. The most common ocular manifestation was multifocal chorioretinitis found in 12 eyes (85.7%). Other ocular lesions in descending order of frequency included retinal hemorrhages in 7 eyes (50.0%), vitritis in 6 eyes (42.9%), chorioretinal linear streaks in 4 eyes (28.6%), perivascular sheathing and vasculitis in 4 eyes (28.6%), narrowed retinal vessels in 4 eyes (28.6%), disc edema in 4 eyes (28.6%), optic atrophy in 2 eyes (14.3%), vascular occlusion in 2 eyes (14.3%), and VIth cranial nerve palsy in 1 eye (7.1%). Midperipheral and far peripheral retinal lesions were found in all 14 eyes (100%), whereas posterior lesions were found in 8 eyes (57.1%). Of the 10 eyes in 5 patients with diabetes mellitus, diabetic retinopathy was present in 7 eyes (70%). It should be noted that for this article, the term disc edema indicates blurring of the disc margin associated with nerve fiber edema independent of any retinal vasculitis or retinal vascular occlusion. The term optic atrophy signifies either primary optic nerve degeneration or secondary optic atrophy after retinal vascular occlusion. In addition, the term optic neuropathy may denote either disc edema or optic atrophy. The precise mechanisms of the above relating to the WNVI are unknown.
Discussion Most previous publications on ocular WNVI consisted of single case reports (Table 4).15–20 Besides the report by Hershberger et al21 of 2 patients, the report by Khairallah et al22 was the exception (Table 5). They presented a prospective study of 23 of 29 patients with WNVI showing ocular lesions during an outbreak of WNVI in Tunisia in 2003. The transient nature of the anterior uveitis that responds well to topical medical therapy during the incipient stage of ocular WNVI easily may be missed (e.g., Table 2. Ocular and Systemic Symptoms and Signs Associated with Ocular West Nile Virus Infection Symptom
No. of Patients
%
Fever Blurred vision Headache Nausea, vomiting Malaise Myalgia Nuchal rigidity Vertigo Confusion Diarrhea Ataxia Aphasia
6 6 4 4 4 2 1 1 1 1 1 1
85.7 85.7 57.1 57.1 57.1 28.6 14.3 14.3 14.3 14.3 14.3 14.3
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Ophthalmology Volume 113, Number 9, September 2006 Table 3. Ocular Findings of 14 Eyes with Ocular West Nile Virus Infection Ocular Finding
No. of Eyes
%
Multifocal chorioretinal round lesions Creamy lesions (acute stage), and pigmented lesions surrounded with creamy halos (subacute stage) or target lesions Atrophic lesions with well-demarcated margins (convalescent stage) Retinal hemorrhages Diabetics Nondiabetics Vitreous cells Chorioretinal linear streaks Perivascular sheathing and vasculitis Narrowed retinal vessels Disc edema Optic atrophy Vascular occlusion Sixth nerve palsy Diabetes with diabetic retinopathy Diabetes without diabetic retinopathy Posterior fundus lesions Midperipheral and far peripheral fundus lesions
12 8
85.7 66.7
4 7 6 1 6 4 4 4 4 2 2 1 7 3 8 14
33.3 50.0 86 14 42.9 28.6 28.6 28.6 28.6 14.3 14.3 7.1 70 30 57.1 100
patient 2). Only 4 patients (13.8%) had documented anterior nongranulomatous reaction in the series by Khairallah et al.22 Supportive care in the form of antiinflammatory topical medical therapy for the self-limited acute uveitis is usually sufficient and is reserved only for the acute stage of the ocular WNVI. The bilateral ocular manifestation for all of our patients also was consistent with predominantly bilateral ocular involvement of WNVI found in previous published case reports.15–22 Similar to previous reports on ocular involvement of WNVI,15–22 multifocal choroiditis was the most common and characteristic ocular manifestation in our patients (Table 3). These multiple small round chorioretinal lesions were scattered throughout the posterior as well as the peripheral fundus for most of our patients. Active multifocal chorioretinal lesions are typically deep, round, and creamcolored lesions (acute stage). In contrast, partially active lesions are partially pigmented and atrophic with surrounding creamy halos (subacute stage). The former show early hypofluorescence and late staining, whereas the latter tend to show central hypofluorescence with peripheral hyperfluorescence on the fluorescein angiogram (patient 1; Fig 1A, B, patient 2; patient 3; and Fig 3, patient 5). Thus, such lesions
also are sometimes referred to as target lesions.21 Old multifocal chorioretinal round lesions (convalescent stage) consist of pigmentary atrophic lesions with surrounding well-demarcated borders. They show more uniform focal fluorescein transmission and staining throughout the angiographic sequence in comparison with the acute and subacute lesions (Fig 4, patient 6, and patient 7). The multifocal chorioretinal lesions have an average measurement of 250 m in diameter (range, 100 –1500 m).15–22 Whitish-yellow chorioretinal linear streaks (patient 4; Fig 4B, patient 6) were not as common as the round chorioretinal spots. They were present in 28.7% of eyes in our series (Table 3). In contrast, linear streaks were present in up to 81.8% of eyes in Khairallah et al’s series. As pointed out by Khairallah et al, equatorial chorioretinal linear streaks also can be found in fundi associated with presumed ocular histoplasmosis syndrome, idiopathic multifocal choroiditis, and Vogt-Koyanagi-Harada syndrome.22–25 The pathogenesis of chorioretinal lesions associated with WNVI is unknown. However, it has been speculated that hematogenous dissemination of WNV to the choroidal circulation may result in multifocal granulomatous chorioretinitis similar to presumed ocular histoplasmosis syndrome
Table 4. Summary of Ocular Findings in Case Reports of Single Patients with West Nile Virus Infection Patient
Authors 19
Age (yrs)
Gender
Diabetes
Tests
Eye Findings
Eye(s)
Uveitis Uveitis, chorioretinitis Uveitis, chorioretinitis Uveitis, chorioretinitis, retinal hemorrhage Occlusive vasculitis Uveitis, chorioretinitis, optic neuropathy
Both Both Right Both
1 2 3 4
Kuchtey et al Adelman et al18 Vandenbelt et al17 Bains et al16
56 81 61 60
F M M F
Yes Yes No No
IgM, IgG, PRNT NA IgM IgM
5 6
Kaiser et al20 Anninger et al15
46 55
F F
Yes No
IgM IgM
Left Both
F ⫽ female; IgG ⫽ immunoglobulin G; IgM ⫽ immunoglobulin M; M ⫽ male; NA ⫽ not available; optic neuropathy ⫽ disc edema or optic atrophy; PRNT ⫽ plaque reduction neutralization test.
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Chan et al 䡠 Ocular West Nile Virus Infection Table 5. Summary of Ocular Findings in Case Reports of Multiple Patients with West Nile Virus Infection Authors
No. Eyes (No. Patients)
Age (yrs)
Hershberger et al21
2 (1)
56
M⫽1
No
2 (1)
61
F⫽1
No
Gender
Diabetes
Tests IgM IgG PRNT
Khairallah et al22
44 (23)
22–74, mean ⫽ 53
M ⫽ 17 (73.9%) F ⫽ 6 (2.1%)
IgM IgG Yes, n ⫽ 15 IgM (65.2%)
Chan et al (current study)
14 (7)
32–85,
M ⫽ 4 (57.1%)
Yes, n ⫽ 5
mean ⫽ 58.4
F ⫽ 3 (42.9%)
(71.4%)
IgM ⫽ 3 PRNT ⫽ 4
Eye Findings Uveitis Chorioretinitis Retinal hemorrhage Optic neuropathy Uveitis Chorioretinitis Uveitis Chorioretinitis Retinal hemorrhage Disc edema Nystagmus Subconjunetival hemorrhage VIth nerve palsy Uveitis
Bilateral (No. Patients) 1
1 21
7
Chorioretinitis Retinal hemorrhage Optic neuropathy Vasculitis Vascular occlusion Narrow vessels
F ⫽ female; IgG ⫽ immunoglobulin G; IgM ⫽ immunoglobulin M; M ⫽ male; optic neuropathy ⫽ disc edema or optic atrophy; PRNT ⫽ plaque reduction neutralization test.
and idiopathic multifocal choroiditis.17,22 Besides WNVI, the findings of vitritis (patients 1, 2, and 3), multifocal choroiditis (patient 1; Fig 1A, B, patient 2; patient 3; Fig 3, patient 5; Fig 4, patient 6; patient 7), and vasculitis (Fig 1C, patient 2; Fig 2A, patient 3; Fig 2B, patient 4) also may be manifested in other viral entities, for example, Rift Valley fever (another arbovirus in the family of Bunyaviridae),26 rubella, and subacute sclerosing panencephalitis.27 Consistent with previous reports,15–22 our study showed a relatively benign clinical course for the multifocal chorioretinal lesions associated with WNVI. However, their long-term sequelae are unknown. For instance, it is not known whether perimacular chorioretinal lesions associated with WNVI would predispose one to the development of submacular choroidal neovascularization years later, as in the case of presumed ocular histoplasmosis syndrome. It is clear that those patients with more serious ocular lesions (i.e., optic atrophy and retinal vasculitis and occlusion) do result in substantial visual loss, including visual field deficit over the long term. In fact, multiple patients in our series (patients 1, 2, 3, 6, and 7) developed ocular lesions early in the course of the disease, resulting in prolonged visual deficit. They included retinal vasculitis in 4 eyes (28.6%), retinal vascular occlusion in 2 eyes (14.3%), and optic atrophy in 2 eyes (Table 3). A previous report showed mononuclear perivascular inflammation in pathologic specimens of neuroinvasive cases with WNVI.28 A similar mechanism is likely at play for patients with retinal occlusive vasculitis. The precise mechanisms for optic neuropathy associated with WNVI are unknown. However, optic nerve degeneration related to primary occlusion of posterior ciliary vessels and secondary optic nerve atrophy after retinal vascular occlusion are probable mechanisms. The high rate of diabetic patients with ocular WNVI in
our series (71.4%) is consistent with a similarly high rate of diabetic patients (65.2%) in Khairallah et al’s report. Both reports also showed that most infected patients with ocular lesions were older than 50 years (mean age, 58.4 in our report and 53.0 in Khairallah et al’s report). Other reports also showed high rates of diabetes mellitus and ages older than 50 years among patients with ocular WNVI.15–21 Perhaps these patients vulnerable to more serious systemic and ocular manifestations of WNVI were more likely to be referred for subspecialty care. Finally, the differences in the rates of ocular lesions between Khairallah et al’s and our reports (e.g., higher rates of multifocal chorioretinitis and lower rates of chorioretinal linear streaks and retinal hemorrhage in our study) can be explained by different characteristics in diverse patient populations infected with WNV in North America in comparison with North Africa, as well as discrepancies between a retrospective study and a prospective study. Our data also showed that 28.6% to 85.7% of our patients with ocular WNVI exhibited systemic symptoms associated with WNVI (e.g., fever, headache, malaise, nausea, myalgia, etc.), in contrast to the epidemiologic data of only 20% of the general population infected with the WNV with the same systemic symptoms reported in the literature (Table 2).8 The higher rates in our series are likely related to the retrospective nature of this study involving a select group of patients with more serious systemic and ocular manifestations of the WNVI referred for subspecialty care. In conclusion, we present a retrospective case series of 14 eyes in 7 patients with WNVI from the continental United States. Multifocal chorioretinitis involving both eyes with a self-limited clinical course is the most common ocular manifestation. However, less common ocular lesions (i.e., optic atrophy and occlusive vasculitis) may result in
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Ophthalmology Volume 113, Number 9, September 2006 more serious persistent visual deficit. Diabetic patients and those older than 50 years of age are likely to experience more serious systemic and ocular manifestations of WNVI.
References 1. Smithburn KC, Hughes TP, Burke AW, Paul JH. A neurotropic virus isolated from the blood of a native of Uganda. Am J Trop Med 1940;20:471–92. 2. Mukhopadhyay S, Kuhn RJ, Rossmann MG. A structural perspective of the Flavivirus life cycle. Nat Rev Microbiol 2005;3:13–22. 3. Craven RB, Roehrig JT. West Nile virus. JAMA 2001;286: 651–3. 4. Rappole JH, Derrickson SR, Hubálek Z. Migratory birds and spread of West Nile virus in the Western Hemisphere. Emerg Infect Dis 2000;46:319 –28. 5. Petersen LR, Marfin AA. West Nile virus: a primer for the clinician. Ann Intern Med 2002;137:173–9. 6. Nash D, Mostashari F, Fine A, et al, 1999 West Nile Outbreak Response Working Group. The outbreak of West Nile virus infection in the New York city area in 1999. N Engl J Med 2001;344:1807–14. 7. MMWR weekly report. Update: West Nile virus activity— United States, 2005. 2005;54(38):964 –5. Available at http:// www.cdc.gov/mmwr. Accessed September 30, 2005. 8. Mostashari F, Bunning ML, Kitsutani PT, et al. Epidemic West Nile virus encephalitis, New York, 1999: results of a household-based seroepidemiological survey. Lancet 2001; 358:261– 4. 9. Weiss D, Carr D, Kellachan J, et al. Clinical findings of West Nile virus infection in hospitalized patients, New York and New Jersey, 2000. Emerg Infect Dis 2001;7:654 – 8. 10. Hardinger KL, Miller B, Storch GA, et al. West Nile virusassociated meningoencephalitis in two chronically immunosuppressed renal transplant recipients. Am J Transplant 2003; 3:1312–5. 11. Sejvar JJ, Haddad MB, Tierney BC, et al. Neurologic manifestations and outcome of West Nile virus infection. JAMA 2003;290:511–5. 12. Klein C, Kimiagar L, Pollak L, et al. Neurological features of West Nile virus infection during the 2000 outbreak in a regional hospital in Israel. J Neurol Sci 2002;200:63– 6.
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13. Petersen LR, Roehrig JT, Hughes JM. West Nile virus encephalitis. N Engl J Med 2002;347:1225– 6. 14. Vaispapir V, Blum A, Soboh S, Ashkenazi H. West Nile virus meningoencephalitis with optic neuritis. Arch Intern Med 2002;162:606 –7. 15. Anninger WV, Lomeo MD, Dingle J, et al. West Nile virusassociated optic neuritis and chorioretinitis. Am J Ophthalmol 2003;136:1183–5. 16. 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. 17. Vandenbelt S, Shaikh S, Capone A Jr, Williams GA. Multifocal choroiditis associated with West Nile virus encephalitis. Retina 2003;23:97–9. 18. Adelman RA, Membreno JH, Afshari NA, Stoessel KM. West Nile virus chorioretinitis. Retina 2003;23:100 –1. 19. Kuchtey RW, Kosmorsky GS, Martin D, Lee MS. Uveitis associated with West Nile virus infection. Arch Ophthalmol 2003;121:1648 –9. 20. Kaiser PK, Lee MS, Martin DA. Occlusive vasculitis in a patient with concomitant West Nile virus infection. Am J Ophthalmol 2003;136:928 –30. 21. Hershberger VS, Augsburger JJ, Hutchins RK, et al. Chorioretinal lesions in nonfatal cases of West Nile virus infection. Ophthalmology 2003;110:1732– 6. 22. Khairallah M, Ben Yahia S, Ladjima L, et al. Chorioretinal involvement in patients with West Nile virus infection. Ophthalmology 2004;111:2065–70. 23. Fountain JA, Schlaegel TF Jr. Linear streaks of the equator in the presumed ocular histoplasmosis syndrome. Arch Ophthalmol 1981;99:246 – 8. 24. Spaide RF, Yannuzzi LA, Freund KB. Linear streaks in multifocal choroiditis and panuveitis. Retina 1991;11:229 –31. 25. Chung YM, Yeh TS. Linear streak lesions of the fundus equator associated with Vogt-Koyanagi-Harada syndrome. Am J Ophthalmol 1990;109:745– 6. 26. Siam AL, Meegan JM, Gharbawi KF. Rift Valley fever ocular manifestations: observations during the 1977 epidemic in Egypt. Br J Ophthalmol 1980;64:366 –74. 27. Caruso JM, Robbins-Tien D, Brown WD, et al. Atypical chorioretinitis as an early presentation of subacute sclerosing panencephalitis. J Pediatr Ophthalmol Strabismus 2000;37: 119 –22. 28. Sampson BA, Armbrustmacher V. West Nile encephalitis: the neuropathology of four fatalities. Ann N Y Acad Sci 2001; 951:172– 8.
West Nile virus infection (WNVI) was first identified by Smithburn et al1 in Uganda in 1937. It is endemic in many parts of the world. The West Nile virus (WNV) is a singlestranded RNA arbovirus, because of its transmission by mosquitoes and possibly other arthropod vectors. It belongs to the Flaviviridae family of viruses, which includes Japanese Originally received: October 13, 2005. Accepted: April 17, 2006. Manuscript no. 2005-983. 1 Southern California Desert Retina Consultants, Palm Springs, California. 2 Department of Ophthalmology, Loma Linda University, Loma Linda, California. 3 Alaska Retinal Consultants, Anchorage, Alaska. Presented as a poster at: American Academy of Ophthalmology Annual Meeting, October 2005, Chicago, Illinois. The authors have no financial or proprietary interest in any commercial products mentioned in the study. Correspondence to Clement K. Chan, MD, FACS, P.O. Box 2467, Palm Springs, CA 92263. E-mail: [email protected]. © 2006 by the American Academy of Ophthalmology Published by Elsevier Inc.
encephalitis, St. Louis encephalitis, yellow fever, dengue, Murray Valley encephalitis, Kunjin encephalitis, and Western equine encephalitis viruses.2 Wild birds serve as the primary natural hosts.3 Birds of the crow family (Corvidae) are particularly sensitive to WNVI. However, migratory birds probably play an important role in the spread of the disease.4 Mosquitoes (primarily the Culex species) are responsible for transmitting this disease from the natural hosts to humans and other mammals.3,5 Until recent years, the virus was found only in the Eastern hemisphere, throughout Africa, parts of Asia, and the Middle East. Recent outbreaks have occurred in Romania, Israel, and New York.5 Nineteen ninety-nine (1999) was the first year that it entered the Western hemisphere via New York.6 Subsequent years saw rapid migration of this virus westward across the continent. Alaska, Hawaii, and Washington are the only states that have no reported human cases of WNVI.7 Since 1999, over 16 000 WNVI cases have been documented in the United States. Only 20% of infected individuals experience sysISSN 0161-6420/06/$–see front matter doi:10.1016/j.ophtha.2006.04.021
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Chan et al 䡠 Ocular West Nile Virus Infection temic symptoms, including fever, malaise, rash, lymph adenopathy, and anorexia.8 Only half of those infected seek medical care.8 Ocular symptoms such as photophobia, retrobulbar pain, and diplopia have been reported to be associated with WNVI.9 Approximately 1 in 150 (0.67%) infected individuals experience neuroinvasive diseases, which can include altered mental status, motor and sensory neurological deficits, as well as life-threatening meningoencephalitis.10 –14 Death occurs in 5% to 10% of this group of seriously infected patients.7 No known antiviral agents have yet been found to be effective against WNVI.5,9,10 For most WNV cases, however, supportive care is sufficient for recovery. The precise prevalence of ocular involvement associated with WNVI is unknown, primarily because of the transient nature of the active stage of the ocular infection. There are a number of recent case reports describing ocular findings in WNVI.15–22 We herein present 14 eyes of 7 patients with ocular WNVI in North America.
Patients and Methods This was a retrospective, nonrandomized, noncomparative, observational case series involving patients with ocular WNVI contracted in multiple states of North America (Iowa, Nebraska, Colorado, and California) between the years 2002 and 2005. The authors describe the characteristics, frequency, and locations of ocular lesions found in these patients’ eyes. Positive serologic results for the WNV were required for inclusion in this study. One or more of the following assays were used to demonstrate positive serologic results for patients with findings suggestive of ocular WNVI referred for tertiary vitreoretinal care: WNV-specific immunoglobulin M (IgM) antibody-capture enzyme-linked immunoabsorbent assay (ELISA), indirect fluorescent antibody assay for WNV, and plaque reduction neutralization test (PRNT) for WNV. The WNVI was confirmed with IgM antibody-capture ELISA in a serum sample for 3 patients, in a cerebrospinal fluid (CSF) sample for 1 patient, and in a serum sample and a CSF sample for 2 patients. In addition, elevated IgM titer with indirect fluorescent antibody assay for the WNV was found in the serum sample of 1 patient. The WNVI was confirmed with PRNT for 4 patients. All
study patients underwent complete ophthalmic examination, including best-corrected Snellen visual acuity, tonometry, biomicroscopy of the anterior and posterior segments, as well as indirect ophthalmoscopy. Dilated fundus examination was performed for all eyes. In addition, fundus photography and fluorescein angiography were performed on all eyes. Institutional review board approval was obtained for the retrospective chart review for this study. In addition, this study was compliant with the requirements of the Health Insurance Portability and Accountability Act (HIPAA). Informed consent was obtained from study participants.
Selected Case Reports Patient 2. A 71-year-old white woman sought treatment at the emergency department with a 10-day history of fatigue, joint pain, diarrhea, malaise, confusion, and fever of 104° F. Head computed tomography results showed pansinusitis but were otherwise normal. Complete blood count results were significant for slight leukocytosis with minimally elevated neutrophils. Liver enzymes were moderately elevated. Cerebrospinal fluid analysis revealed 10 white blood cells with 40% lymphocytes, 35% neutrophils, and 25% monocytes. Both serum and CSF ELISA test results were positive for WNV. This was confirmed by PRNT with a dilution of 1:320. The patient’s past ocular history was significant for mild nuclear sclerotic cataracts. One year before presentation, her visual acuity measured 20/20 for both eyes. One month after presentation with symptoms of WNVI, she reported blurred vision and floaters, more in the right eye than the left eye. She did not report ocular pain or photophobia. Her best-corrected visual acuity was 20/40 in the right eye and 20/30 in the left eye. Anterior segment examination showed mild cells in the anterior chambers. Examination of the posterior segment revealed moderate vitreous cells and debris in the right eye and minimal vitreous cells in the left eye. The optic nerves and macula were normal in both eyes. Small pigmented lesions surrounded with a creamy halo were present just outside the vascular arcades on the midperipheral fundus in both eyes (Fig 1A). The corresponding fluorescein angiogram showed hypofluorescence and a surrounding ring of hyperfluorescence on the chorioretinal lesions (Fig 1B). Treatment with topical prednisolone acetate was initiated. Several weeks later, the patient experienced further vision loss in the left eye. At that time, her visual acuity was 20/30 in the right
4™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™ Figure 1. Patient 2. A, Fundus examination revealed multiple cream-colored chorioretinal lesions (arrowheads), focal retinal hemorrhage, and ischemia superior to the disc in the left eye that highlight the partially active multifocal chorioretinal lesions in this 71-year-old woman with West Nile virus infection (subacute stage). B, Corresponding fluorescein angiogram showed hypofluorescence and a surrounding ring of hyperfluorescence (arrowheads) on the chorioretinal lesions superior to the disc of the left eye (subacute stage). C, Arterial narrowing, perivascular sheathing, and vascular occlusion (arrowheads) were found on the posterior and midperipheral fundus, both superior and inferior to the disc, of the right eye. Figure 2. A, Anterior segment examination results of patient 3 show perivascular sheathing with occlusive vasculitis, optic pallor, and numerous dot and blot hemorrhages on the superior and posterior fundus of the right eye of this 58-year-old diabetic woman with West Nile virus infection. B, Anterior segment examination of the left eye of patient 4, a 32-year-old man with West Nile virus infection, shows multiple intraretinal hemorrhages and adjacent perivascular sheathing involving multiple venous tributaries. Figure 3. A, Anterior segment examination results of patient 5, a 55-year-old Hispanic man with type 2 diabetes mellitus and West Nile virus infection, showing multiple active (arrow) and partially active (arrowhead) discrete cream-colored chorioretinal spots (100 –300 m) on the posterior and peripheral fundus of the left eye (acute and subacute stages). B, The corresponding fluorescein angiogram examination showed early hypofluorescence (arrow) on the active chorioretinal spots (acute stage) and focal hypofluorescence with a surrounding hyperfluorescent ring (arrowhead) on the partially active lesions (subacute stage). Subsequent images in the late phase of the same angiogram showed staining of the active lesions. Figure 4. Patient 6. A, Dilated fundus examination of the right eye of this 68-year-old diabetic woman with West Nile virus infection showed multifocal inactive chorioretinal atrophic lesions with a distinct margin (arrowheads; convalescent stage). B, Dilated fundus examination of the left eye showed similar chorioretinal atrophic lesions (arrowhead) and whitish-yellow chorioretinal linear streaks (arrow) on inferior midperipheral fundus. C, D, Fluorescein angiogram examination showed persistent focal hyperfluorescence of the same lesions throughout the study.
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Ophthalmology Volume 113, Number 9, September 2006 eye and 20/200 in the left eye. Anterior segment examination was normal with the exception of the resolving cells in the anterior chambers. Fundus examination showed arterial narrowing, perivascular sheathing, and vascular occlusion consistent with retinal vasculitis in the left eye (Fig 1C). Oral prednisone administration was begun in addition to increasing the dosing frequency of her topical prednisolone acetate. At the most recent examination, she displayed less vitreous and perivascular inflammation. Her visual acuity had improved to 20/25 in the right eye and 20/70 in the left eye. The persistent visual deficit of left eye was likely the result of ischemia associated with retinal vasculitis and vascular occlusion. Patient 3. A 58-year-old non–insulin-dependent diabetic white woman sought treatment for intractable nausea and vomiting, vertigo, severe weakness, and fever of 102° F. Head computed tomography with and without contrast revealed unremarkable results. White blood cell count was elevated to 18 000. Serologic examination (ELISA) was positive for IgM (titer of 4.46) associated with the WNV. Immunoglobulin G (IgG) test results were negative. Cerebrospinal fluid analysis was significant for a few white blood cells and elevated IgM (ELISA) titer of 5.33, but a normal IgG titer of less than 0.9 for the WNV. The patient’s past ocular history was significant for background diabetic retinopathy, clinically significant diabetic macular edema of the left eye treated with focal laser 4 months before presentation, and glaucoma controlled with latanoprost. Three months before presentation, her best-corrected visual acuity measured 20/40 in the right eye and 20/50 in the left eye. Seven days after her initial presentation with symptoms of WNVI, the patient experienced sudden vision loss in both eyes. She reported seeing multiple dots and decreased peripheral vision. On ocular examination, her best-corrected visual acuity was 20/400 in the right eye and 20/70 in the left eye. Confrontation visual fields were constricted nasally and temporally for both eyes. Pupillary reaction was sluggish. No afferent pupillary defect was noted. Anterior segment examination was significant for moderate cortical, nuclear, and posterior subcapsular cataracts in both eyes. There were rare cells in the anterior vitreous cavity in both eyes. Disc margins were sharp. There was mild disc pallor and a 0.6 cup-to-disc ratio in each eye. The right fundus displayed perivascular sheathing, cotton-wool spots, and numerous dot and blot hemorrhages in the periphery (Fig 2A). The left macula had residual hard exudates relating to previously treated diabetic macular edema. The retinal arteries were mildly narrowed in the left eye. Intravenous fluorescein angiography was significant for normal arteriovenous filling with late perivascular leakage, consistent with vasculitis. The patient’s systemic symptoms gradually resolved with supportive treatment. She returned for repeat ophthalmic examination 1 month later. At that time, her best-corrected visual acuity was 20/400 in the right eye and 20/200 in the left eye. The anterior segment examination showed unchanged results. There was arterial narrowing and perivascular sheathing in both eyes. There was diffuse optic nerve pallor and atrophy in both eyes. There were numerous round pigmented lesions with a surrounding creamy halo on the peripheral fundus of both eyes. At the most recent examination 5 months after her initial presentation, there was persistent obliterative vasculitis with no improvement in visual acuity. Patient 4. A 32-year-old previously healthy white man with no prior ocular problems was hospitalized with a 1-week history of severe headache, fever, nuchal rigidity, myalgia, malaise, and photophobia. Magnetic resonance imaging revealed subtle enhancement of the prepontine focal space and spinal cord, suggestive of myelitis. Prominent enhancement of the subarachnoidal space also was seen. Transesophageal echocardiogram results were negative for an embolic source. Complete blood count was within normal limits. Cerebrospinal fluid analysis was significant for 231
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white blood cells with 48% lymphocytes, 30% neutrophils, and 22% monocytes. Cerebrospinal fluid ELISA revealed elevated IgM titer (1:2) associated with the WNV. Cerebrospinal fluid IgG titer for WNV was negative (1:1). On the third day after admission, the patient reported blurred vision of his right eye. On ocular examination, his uncorrected visual acuity was 20/30 in the right eye and 20/20 in the left eye. Confrontation visual fields and ocular motility were normal. There was a subtle right afferent pupillary defect. Anterior segment examination results were normal. The superior margin of the right optic nerve was slightly blurred. The left optic nerve appeared normal. Prominent perivenous sheathing and intraretinal hemorrhages were present in the posterior fundus of the right eye (Fig 2B). The posterior fundus, including its retinal vasculature, in his left eye was normal. Several whitish chorioretinal streaks were present on the peripheral fundus in both eyes. The patient was treated empirically with ceftriaxone (Rocephin, Roche Pharmaceuticals, Hoffman-La Roche Inc., Nutley, NJ), acyclovir sodium (Zovirax, GlaxoSmithKline, Uxbridge, United Kingdom), and methylprednisolone sodium succinate (SoluMedrol, Pharmacia & Upjohn Inc., Kalamazoo, MI). His systemic symptoms gradually improved. His ocular symptoms remained unchanged. He was lost to follow-up after discharge. Patient 5. A 55-year-old Hispanic man with poorly controlled type 2 diabetes and systemic hypertension sought treatment at a local hospital emergency department on July 4, 2004, with progressive worsening headache, fever, chills, severe nausea and vomiting, as well as blurred vision, left eye more than right eye, since June 30, 2004. During his hospitalization, an extensive systemic workup revealed negative results for bacterial meningitis, altered mental status, and sensory or motor deficit. An infectious disease workup showed negative results for bacterial and fungal agents in the blood and CSF. He was treated for aseptic meningitis on an empirical basis. He recovered and was discharged home 5 days later. His ocular examination on August 4, 2004, showed a visual acuity of 20/40 in the right eye and 20/30 in the left eye. The anterior segment examination results were unremarkable with the exception of mild cataracts. There was absence of vitreous cells and infiltrates in both eyes. The discs were clear. There were mild perimacular scattered hard exudates, hemorrhages, and microaneurysms consistent with diabetic maculopathy in his right eye. There were also multiple discrete cream-colored chorioretinal spots, scattered throughout the posterior and peripheral fundus, left eye more than right eye (Fig 3A). These lesions measured from 100 to 300 m in diameter. The corresponding fluorescein angiogram showed either early hypofluorescence and late staining or focal hypofluorescence with a surrounding ring of hyperfluorescence, associated with active or partially active multifocal chorioretinal lesions, respectively (Fig 3B). There was absence of vasculitis and vascular occlusion. Three weeks later, the creamy halos associated with the chorioretinal lesions started to change into well-demarcated borders. A uveitis workup to rule out multiple entities, including tuberculosis, lues, sarcoidosis, collagen vascular diseases, herpes viruses, Epstein-Barr virus, Lyme disease, and so forth, was unremarkable. However, the patient’s serum sent to the Riverside County Health Department in mid-August, 2004, showed elevated IgM (5.44) and IgG (25.8) titers associated with the WNV on ELISA, as well as highly positive PRNT for WNV (titer of 1:840). During his last visit in February, 2005, his visual acuity remained 20/40 in the right eye and 20/30 in the left eye. There were no changes in the multiple pigmented fundus lesions in both eyes. Patient 6. A 68-year-old diabetic white woman was bitten by mosquitoes at a ranch in Colorado in August, 2003. Two weeks later, she sought treatment at an emergency department in Arizona
Chan et al 䡠 Ocular West Nile Virus Infection Table 1. Demographics of Patients with Ocular West Nile Virus Infection Gender
n (%)
Age (yrs)
Diabetic
Symptom Duration before Examination
Male 4 (57.1%) ⬍50, 2 (28.6%) 5 (71.4%) Within 7 d, 3 (42.9%) Female 3 (42.9%) ⬎50, 5 (71.4%) 8–30 d, 1 (14.3%) Mean, 58.4 31–90 d, 3 (42.9%) Range, 32–85
with a 3-day history of headache, fever, malaise, vomiting, and visual disturbance. On presentation, she showed aphasia, ataxia, and a VIth cranial nerve palsy. Lumbar puncture analysis revealed elevated white blood cells. Magnetic resonance imaging showed no abnormalities. Blood and cerebrospinal fluid cultures had negative results. She was admitted to the intensive care unit to rule out bacterial versus viral meningoencephalitis. Subsequent serologic examination revealed positive results for elevated IgM titers with the indirect fluorescent antibody assay (1:160) and the PRNT (1:20) for WNV. She responded well to supportive care. During her hospital stay, she noted a central scotoma in her right eye. Ophthalmic examination revealed background diabetic retinopathy and a central retinal artery occlusion in her right eye. No treatment was recommended. The patient was discharged 4 days later and was instructed to follow up with her physicians at home. The patient first sought treatment at our clinic in California in November, 2003. On examination, her visual acuity was 20/30 in both eyes. There was no afferent pupillary defect. Extraocular movements were full. Confrontational visual fields showed a superior deficit in the right eye and a normal field in the left eye. Intraocular pressure was normal. Anterior segment examination showed quiet anterior chambers with no cells and keratic precipitates in both eyes. Dilated fundus examination showed no vitreous cells, but did show the presence of peripapillary dot hemorrhages and subtle nerve fiber layer edema around the margins of the optic nerves in the right eye more than the left eye. There was absence of optic nerve pallor. There were multiple small round chorioretinal punched-out atrophic lesions with well-demarcated borders involving both the posterior and peripheral fundi (Fig 4A). There was a predominant perivascular distribution associated with these chorioretinal lesions. None seemed to be active. There was no cherry-red spot. There were also whitish-yellow chorioretinal streaks on the midperipheral fundi (Fig 4B). Fluorescein angiography examination showed normal vascular filling in both eyes and no signs of obstruction. There was staining of the multifocal small punched-out atrophic lesions (Fig 4C, D). There was absence of hyperfluorescent leakage on the discs. Humphrey 24-2 visual field analysis showed a superior field cut in the right eye and mild superior field loss in the left eye. Farnsworth-Munsell 15 color plate testing showed no significant deficit. Four months after presentation, her right eye experienced diffuse clinically significant diabetic macular edema requiring focal grid laser treatment. The severe diabetic macular edema caused a persistent visual deficit (visual acuity of 5/200) in her right eye despite laser therapy. Her left eye maintained a visual acuity of 20/30 1 year later. In addition, the visual field loss for both eyes persisted.
Results Tables 1, 2, and 3 outline the results of this study. This retrospective case series included 14 eyes in 7 patients. There were 4 men
(57.1%) and 3 women (42.9%). The mean age was 58.4 years, and the age range was from 32 to 85 years. Follow-up time ranged from 1 to 18 months, with a mean of 8.3 months. Five patients (71.4%) were diabetics. Three patients (42.9%) presented within 7 days, 1 patient (14.3%) presented between 8 and 30 days, and 3 patients (42.9%) presented between 31 and 90 days from the onset of symptoms for ocular examination. Systemic symptoms included fever in 6 patients (85.7%), headache in 4 patients (57.1%), nausea and vomiting in 4 patients (57.1%), malaise in 4 patients (57.1%), myalgia in 2 patients (28.6%), nuchal rigidity in 1 patient (14.3%), vertigo in 1 patient (14.3%), confusion in 1 patient (14.3%), diarrhea in 1 patient (14.3%), ataxia in 1 patient (14.3%), and aphasia in 1 patient (14.3%). Six patients (85.7%) reported blurred vision. Bilateral ocular findings were detected in all 7 patients. The most common ocular manifestation was multifocal chorioretinitis found in 12 eyes (85.7%). Other ocular lesions in descending order of frequency included retinal hemorrhages in 7 eyes (50.0%), vitritis in 6 eyes (42.9%), chorioretinal linear streaks in 4 eyes (28.6%), perivascular sheathing and vasculitis in 4 eyes (28.6%), narrowed retinal vessels in 4 eyes (28.6%), disc edema in 4 eyes (28.6%), optic atrophy in 2 eyes (14.3%), vascular occlusion in 2 eyes (14.3%), and VIth cranial nerve palsy in 1 eye (7.1%). Midperipheral and far peripheral retinal lesions were found in all 14 eyes (100%), whereas posterior lesions were found in 8 eyes (57.1%). Of the 10 eyes in 5 patients with diabetes mellitus, diabetic retinopathy was present in 7 eyes (70%). It should be noted that for this article, the term disc edema indicates blurring of the disc margin associated with nerve fiber edema independent of any retinal vasculitis or retinal vascular occlusion. The term optic atrophy signifies either primary optic nerve degeneration or secondary optic atrophy after retinal vascular occlusion. In addition, the term optic neuropathy may denote either disc edema or optic atrophy. The precise mechanisms of the above relating to the WNVI are unknown.
Discussion Most previous publications on ocular WNVI consisted of single case reports (Table 4).15–20 Besides the report by Hershberger et al21 of 2 patients, the report by Khairallah et al22 was the exception (Table 5). They presented a prospective study of 23 of 29 patients with WNVI showing ocular lesions during an outbreak of WNVI in Tunisia in 2003. The transient nature of the anterior uveitis that responds well to topical medical therapy during the incipient stage of ocular WNVI easily may be missed (e.g., Table 2. Ocular and Systemic Symptoms and Signs Associated with Ocular West Nile Virus Infection Symptom
No. of Patients
%
Fever Blurred vision Headache Nausea, vomiting Malaise Myalgia Nuchal rigidity Vertigo Confusion Diarrhea Ataxia Aphasia
6 6 4 4 4 2 1 1 1 1 1 1
85.7 85.7 57.1 57.1 57.1 28.6 14.3 14.3 14.3 14.3 14.3 14.3
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Ophthalmology Volume 113, Number 9, September 2006 Table 3. Ocular Findings of 14 Eyes with Ocular West Nile Virus Infection Ocular Finding
No. of Eyes
%
Multifocal chorioretinal round lesions Creamy lesions (acute stage), and pigmented lesions surrounded with creamy halos (subacute stage) or target lesions Atrophic lesions with well-demarcated margins (convalescent stage) Retinal hemorrhages Diabetics Nondiabetics Vitreous cells Chorioretinal linear streaks Perivascular sheathing and vasculitis Narrowed retinal vessels Disc edema Optic atrophy Vascular occlusion Sixth nerve palsy Diabetes with diabetic retinopathy Diabetes without diabetic retinopathy Posterior fundus lesions Midperipheral and far peripheral fundus lesions
12 8
85.7 66.7
4 7 6 1 6 4 4 4 4 2 2 1 7 3 8 14
33.3 50.0 86 14 42.9 28.6 28.6 28.6 28.6 14.3 14.3 7.1 70 30 57.1 100
patient 2). Only 4 patients (13.8%) had documented anterior nongranulomatous reaction in the series by Khairallah et al.22 Supportive care in the form of antiinflammatory topical medical therapy for the self-limited acute uveitis is usually sufficient and is reserved only for the acute stage of the ocular WNVI. The bilateral ocular manifestation for all of our patients also was consistent with predominantly bilateral ocular involvement of WNVI found in previous published case reports.15–22 Similar to previous reports on ocular involvement of WNVI,15–22 multifocal choroiditis was the most common and characteristic ocular manifestation in our patients (Table 3). These multiple small round chorioretinal lesions were scattered throughout the posterior as well as the peripheral fundus for most of our patients. Active multifocal chorioretinal lesions are typically deep, round, and creamcolored lesions (acute stage). In contrast, partially active lesions are partially pigmented and atrophic with surrounding creamy halos (subacute stage). The former show early hypofluorescence and late staining, whereas the latter tend to show central hypofluorescence with peripheral hyperfluorescence on the fluorescein angiogram (patient 1; Fig 1A, B, patient 2; patient 3; and Fig 3, patient 5). Thus, such lesions
also are sometimes referred to as target lesions.21 Old multifocal chorioretinal round lesions (convalescent stage) consist of pigmentary atrophic lesions with surrounding well-demarcated borders. They show more uniform focal fluorescein transmission and staining throughout the angiographic sequence in comparison with the acute and subacute lesions (Fig 4, patient 6, and patient 7). The multifocal chorioretinal lesions have an average measurement of 250 m in diameter (range, 100 –1500 m).15–22 Whitish-yellow chorioretinal linear streaks (patient 4; Fig 4B, patient 6) were not as common as the round chorioretinal spots. They were present in 28.7% of eyes in our series (Table 3). In contrast, linear streaks were present in up to 81.8% of eyes in Khairallah et al’s series. As pointed out by Khairallah et al, equatorial chorioretinal linear streaks also can be found in fundi associated with presumed ocular histoplasmosis syndrome, idiopathic multifocal choroiditis, and Vogt-Koyanagi-Harada syndrome.22–25 The pathogenesis of chorioretinal lesions associated with WNVI is unknown. However, it has been speculated that hematogenous dissemination of WNV to the choroidal circulation may result in multifocal granulomatous chorioretinitis similar to presumed ocular histoplasmosis syndrome
Table 4. Summary of Ocular Findings in Case Reports of Single Patients with West Nile Virus Infection Patient
Authors 19
Age (yrs)
Gender
Diabetes
Tests
Eye Findings
Eye(s)
Uveitis Uveitis, chorioretinitis Uveitis, chorioretinitis Uveitis, chorioretinitis, retinal hemorrhage Occlusive vasculitis Uveitis, chorioretinitis, optic neuropathy
Both Both Right Both
1 2 3 4
Kuchtey et al Adelman et al18 Vandenbelt et al17 Bains et al16
56 81 61 60
F M M F
Yes Yes No No
IgM, IgG, PRNT NA IgM IgM
5 6
Kaiser et al20 Anninger et al15
46 55
F F
Yes No
IgM IgM
Left Both
F ⫽ female; IgG ⫽ immunoglobulin G; IgM ⫽ immunoglobulin M; M ⫽ male; NA ⫽ not available; optic neuropathy ⫽ disc edema or optic atrophy; PRNT ⫽ plaque reduction neutralization test.
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Chan et al 䡠 Ocular West Nile Virus Infection Table 5. Summary of Ocular Findings in Case Reports of Multiple Patients with West Nile Virus Infection Authors
No. Eyes (No. Patients)
Age (yrs)
Hershberger et al21
2 (1)
56
M⫽1
No
2 (1)
61
F⫽1
No
Gender
Diabetes
Tests IgM IgG PRNT
Khairallah et al22
44 (23)
22–74, mean ⫽ 53
M ⫽ 17 (73.9%) F ⫽ 6 (2.1%)
IgM IgG Yes, n ⫽ 15 IgM (65.2%)
Chan et al (current study)
14 (7)
32–85,
M ⫽ 4 (57.1%)
Yes, n ⫽ 5
mean ⫽ 58.4
F ⫽ 3 (42.9%)
(71.4%)
IgM ⫽ 3 PRNT ⫽ 4
Eye Findings Uveitis Chorioretinitis Retinal hemorrhage Optic neuropathy Uveitis Chorioretinitis Uveitis Chorioretinitis Retinal hemorrhage Disc edema Nystagmus Subconjunetival hemorrhage VIth nerve palsy Uveitis
Bilateral (No. Patients) 1
1 21
7
Chorioretinitis Retinal hemorrhage Optic neuropathy Vasculitis Vascular occlusion Narrow vessels
F ⫽ female; IgG ⫽ immunoglobulin G; IgM ⫽ immunoglobulin M; M ⫽ male; optic neuropathy ⫽ disc edema or optic atrophy; PRNT ⫽ plaque reduction neutralization test.
and idiopathic multifocal choroiditis.17,22 Besides WNVI, the findings of vitritis (patients 1, 2, and 3), multifocal choroiditis (patient 1; Fig 1A, B, patient 2; patient 3; Fig 3, patient 5; Fig 4, patient 6; patient 7), and vasculitis (Fig 1C, patient 2; Fig 2A, patient 3; Fig 2B, patient 4) also may be manifested in other viral entities, for example, Rift Valley fever (another arbovirus in the family of Bunyaviridae),26 rubella, and subacute sclerosing panencephalitis.27 Consistent with previous reports,15–22 our study showed a relatively benign clinical course for the multifocal chorioretinal lesions associated with WNVI. However, their long-term sequelae are unknown. For instance, it is not known whether perimacular chorioretinal lesions associated with WNVI would predispose one to the development of submacular choroidal neovascularization years later, as in the case of presumed ocular histoplasmosis syndrome. It is clear that those patients with more serious ocular lesions (i.e., optic atrophy and retinal vasculitis and occlusion) do result in substantial visual loss, including visual field deficit over the long term. In fact, multiple patients in our series (patients 1, 2, 3, 6, and 7) developed ocular lesions early in the course of the disease, resulting in prolonged visual deficit. They included retinal vasculitis in 4 eyes (28.6%), retinal vascular occlusion in 2 eyes (14.3%), and optic atrophy in 2 eyes (Table 3). A previous report showed mononuclear perivascular inflammation in pathologic specimens of neuroinvasive cases with WNVI.28 A similar mechanism is likely at play for patients with retinal occlusive vasculitis. The precise mechanisms for optic neuropathy associated with WNVI are unknown. However, optic nerve degeneration related to primary occlusion of posterior ciliary vessels and secondary optic nerve atrophy after retinal vascular occlusion are probable mechanisms. The high rate of diabetic patients with ocular WNVI in
our series (71.4%) is consistent with a similarly high rate of diabetic patients (65.2%) in Khairallah et al’s report. Both reports also showed that most infected patients with ocular lesions were older than 50 years (mean age, 58.4 in our report and 53.0 in Khairallah et al’s report). Other reports also showed high rates of diabetes mellitus and ages older than 50 years among patients with ocular WNVI.15–21 Perhaps these patients vulnerable to more serious systemic and ocular manifestations of WNVI were more likely to be referred for subspecialty care. Finally, the differences in the rates of ocular lesions between Khairallah et al’s and our reports (e.g., higher rates of multifocal chorioretinitis and lower rates of chorioretinal linear streaks and retinal hemorrhage in our study) can be explained by different characteristics in diverse patient populations infected with WNV in North America in comparison with North Africa, as well as discrepancies between a retrospective study and a prospective study. Our data also showed that 28.6% to 85.7% of our patients with ocular WNVI exhibited systemic symptoms associated with WNVI (e.g., fever, headache, malaise, nausea, myalgia, etc.), in contrast to the epidemiologic data of only 20% of the general population infected with the WNV with the same systemic symptoms reported in the literature (Table 2).8 The higher rates in our series are likely related to the retrospective nature of this study involving a select group of patients with more serious systemic and ocular manifestations of the WNVI referred for subspecialty care. In conclusion, we present a retrospective case series of 14 eyes in 7 patients with WNVI from the continental United States. Multifocal chorioretinitis involving both eyes with a self-limited clinical course is the most common ocular manifestation. However, less common ocular lesions (i.e., optic atrophy and occlusive vasculitis) may result in
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Ophthalmology Volume 113, Number 9, September 2006 more serious persistent visual deficit. Diabetic patients and those older than 50 years of age are likely to experience more serious systemic and ocular manifestations of WNVI.
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