- Email: [email protected]
Chorioretinal lesions in nonfatal cases of West Nile virus infection
Chorioretinal Lesions in Nonfatal Cases of West Nile Virus Infection Vrinda S. Hershberger, MD, PhD,1,2 James J. Augsburger, MD,1 Robert K. Hutchins, MD,1,2 Steven A. Miller, MD,3 Jeffrey A. Horwitz, MD,3 Mark Bergmann, MD4 Objective: West Nile virus (WNV) disease is a zoonotic infection with recent outbreaks in the United States. Recent reports have highlighted the intraocular findings associated with WNV disease. We describe the intraocular findings observed in two patients infected by the West Nile virus. Design: Observational case reports. Methods: During an outbreak of WNV disease in Southwest Ohio, two patients with an acute onset of a systemic febrile illness accompanied by myalgia, arthralgia, headache, and a maculopapular rash were referred for blurred vision. Complete ophthalmologic examination, fundus photographs, and fluorescein angiograms were obtained on both patients. Both patients underwent serologic testing for viruses and cultures for bacteria, viruses, and fungi. Results: Ophthalmologic examination in each patient revealed anterior segment and vitreous inflammatory cells and multiple partially atrophic and partially pigmented chorioretinal lesions clustered in the peripheral fundus. Fundus examination in case 2 also revealed mild disc edema in both eyes. Intracranial pressure as measured by lumbar puncture was borderline elevated. The chorioretinal lesions in both patients showed a striking similarity and appeared hypofluorescent centrally and hyperfluorescent around the edges on a fluorescein angiogram. Serologic testing for the WNV was positive in both patients, and tests for all other bacteria, fungi, and viruses were negative. Conclusions: WNV usually causes mild symptoms, but it occasionally causes neurologic illness with fatal outcome or severe morbidity. We present the cases of two patients with serology-proven WNV disease who developed chorioretinal lesions with a targetlike appearance and iridocyclitis. Ophthalmology 2003;110: 1732–1736 © 2003 by the American Academy of Ophthalmology.
West Nile virus (WNV) is a single-stranded RNA virus of the family Flaviviridae, first isolated in 1937 in the West Nile district of Uganda.1 It belongs to the Japanese encephalitis virus serocomplex, which also includes the Japanese encephalitis virus, St. Louis encephalitis virus (SLE), Murray Valley encephalitis virus, and Kunjin virus (an Australian subtype of WNV). WNV is the most widespread of the flaviviruses, having geographic distribution in Africa, West Asia, the Middle East, and Europe.2 Since 1937, notable outbreaks in Israel (1957), South Africa (1974), Romania (1996), Russia (1999), and Israel (2000) involved hundreds of persons and were associated with severe neurologic disease and death.1 Between August 1999 (when an outbreak Originally received: February 24, 2003. Accepted: April 25, 2003. Manuscript no. 230105. 1 Department of Ophthalmology, University of Cincinnati College of Medicine, Cincinnati, Ohio. 2 Cincinnati Eye Institute, Cincinnati, Ohio. 3 Dayton Vitreo-Retinal Associates, Dayton, Ohio. 4 EyeCare Associates, Cincinnati, Ohio. Supported in part by a Departmental Challenge Grant from Research to Prevent Blindness, Inc., New York, New York, to the Department of Ophthalmology, University of Cincinnati College of Medicine. The authors have no financial interest in any product, drug, instrument, or piece of equipment discussed in the manuscript. Reprint requests to Vrinda S. Hershberger, MD, 234 Goodman Street, ML 777, Cincinnati, OH 45219. E-mail: [email protected].
1732
© 2003 by the American Academy of Ophthalmology Published by Elsevier Inc.
of WNV encephalitis occurred in New York) and December 2001, 149 cases of WNV illness were documented in the United States.3 WNV is maintained in an enzootic cycle involving mainly the Culex genus of mosquitoes and birds. Birds are the natural hosts for the virus, and the virus can be transmitted from them to humans and other vertebrates by the bite of an infected mosquito.4 Peak onset occurs in late summer, although onset has occurred from July to December. The incubation period of the WNV ranges from 3 to 14 days. Only approximately 20% of human infections are clinically apparent, and only 1 in 150 infections result in meningitis or encephalitis.1 The clinical presentation is characterized by a febrile illness of sudden onset accompanied by myalgia, arthralgia, headache, conjunctivitis, lymphadenopathy, and a maculopapular or roseolar rash. Recent reports have described a WNV-associated multifocal chorioretinitis with strikingly similar ocular findings.5–7 We report two patients with chorioretinal lesions and intraocular inflammation associated with serology-proven WNV disease.
Case Reports Case 1 A 61-year-old woman reported a 2-day history of severe headaches associated with chills, fever to 103° Fahrenheit, anorexia, profound generalized weakness, and difficulty with fine motor coordination. One week after the onset of symptoms, she developed a ISSN 0161-6420/03/$–see front matter doi:10.1016/S0161-6420(03)00720-6
Hershberger et al 䡠 Chorioretinal Lesions in Cases of West Nile Virus Infection
Figure 1. Posterior fundus of the right eye with vitreous cells and multiple deep chorioretinal lesions in the macular region.
maculopapular rash involving the skin of both lower extremities. She also complained of blurred vision in both eyes without flashes, floaters, pain, or redness in either eye. Ophthalmologic examination 11 days after the onset of systemic symptoms revealed cells and flare in the aqueous and anterior vitreous in the right eye and multiple creamy to partially atrophic nummular chorioretinal lesions in both eyes. The differential diagnosis after that examination included multifocal choroiditis, birdshot choroiditis, and atypical primary vitreoretinal lymphoma. Complete blood count, serum electrolytes, Westergren sedimentation rate, and liver function tests were essentially normal, except for a white blood count of 12.6 ⫻ 103/l with 82% neutrophils. The patient was placed on topical prednisone and referred to ocular oncology for further evaluation. At initial ocular oncology evaluation 3 weeks after the onset of initial symptoms, the patient was still experiencing chronic headaches, profound generalized weakness, and anorexia. However, the rash, fever, and chills had resolved. She still complained of bilateral visual blurring, worse in the right eye. She denied flashes, floaters, or scotomata. She admitted to recent outdoor activities with a history of mosquito bites before onset of her systemic and ocular symptoms. Visual acuity was correctable to 20/30 in the right eye and 20/25 in the left eye. Intraocular pressure was 12 mmHg in both eyes by applanation. Slit-lamp biomicroscopy in the right eye revealed trace cells without flare in the aqueous, curvilinear deposits of brown pigment on the anterior lens capsule concentric with the pupillary margin, and 1⫹ pale cells in the anterior vitreous. The anterior segment in the left eye appeared normal. Fundus biomicroscopy of the right eye revealed 1⫹ fine, pale, midvitreous and posterior vitreous cells and multiple partially atrophic and partially pigmented nummular chorioretinal foci (Fig 1). Fundus biomicroscopy of the left eye revealed similar but less numerous chorioretinal lesions but no vitreous cells. There were no retinal hemorrhages, and there was no retinal vascular sheathing or optic disc edema in either eye. Most of the lesions ranged from 0.25 to 0.5 mm in diameter. A fluorescein angiogram (FA) confirmed the presence of multiple chorioretinal lesions that appeared hypofluorescent centrally and hyperfluorescent around the edges. The FA also showed many more chorioretinal lesions than were observed clinically (Fig 2). Some of the lesions in the midzone and periphery of each eye were arranged in a linear distribution corresponding to choroidal vessels (Fig 3).
Figure 2. Arteriovenous phase of the fluorescein angiogram (posterior fundus of the right eye) showing chorioretinal lesions with central hypofluorescence and peripheral hyperfluorescence. Many more chorioretinal lesions are seen than were observed clinically.
On our recommendation, the patient underwent serologic testing for infectious and inflammatory conditions including WNV. HLA-A29, HLA-B27, Rocky Mountain spotted fever IgG and IgM, toxoplasma IgG and IgM, Bartonella IgG and IgM, Ehrlichia IgG and IgM, antinuclear antibody, rapid plasma reagin, lysozyme, cytomegalovirus, and herpes simplex virus serology and chest x-ray were all negative. Magnetic resonance imaging of the head showed no abnormalities. However, serology for WNV was strikingly positive with the serum IgG titer at 1:512 and the serum IgM titer at 1:1054. On the basis of the serologic testing and a discussion with officials at the Centers for Disease Control and Prevention in Atlanta, the patient was regarded as having confirmed WNV disease. The patient’s systemic and ocular complaints resolved completely over the next 2 to 3 weeks. Repeat ophthalmologic exam-
Figure 3. Venous phase of fluorescein angiogram (superonasal fundus of the left eye) showing radially oriented linear clustering of chorioretinal lesions.
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Ophthalmology Volume 110, Number 9, September 2003 ination and FA 4 months after initial presentation showed mildly increased pigmentation in the chorioretinal lesions, although the anterior segment inflammation and vitreous cells had resolved.
Case 2 A 56-year-old man reported a 5-day history of fever to 104° Fahrenheit, cough, myalgia, confusion, tremor, and gait disturbance with difficulty walking. Complete blood count, Westergren sedimentation rate, serum electrolytes, chest x-ray, and liver function tests were essentially normal. The patient denied any infectious exposure, insect bites, or travel outside the United States. The patient was admitted for presumed meningoencephalitis of possibly viral etiology. The general physical examination was remarkable for a blanching macular rash over the lower extremities without involvement of the palms or soles. There were no petechiae. Neurologic findings included action and postural tremor, a wide-based gait with mild ataxia, confusion, and garbled speech. Repeat CBC showed a white blood count of 4.2 ⫻ 103/l with 80% neutrophils. Computed tomography of the head showed no abnormalities, but a magnetic resonance imaging scan with gadolinium showed mild cortical atrophy and lacunar infarcts involving the left basal ganglia and left periventricular white matter. Lumbar puncture revealed an opening pressure of 20.5 cm (borderline elevated). Cerebrospinal fluid analysis was significant for an elevated white blood count of 188/ml with 100% neutrophils. The patient underwent serologic testing for WNV, herpes simplex virus, cytomegalovirus, California encephalitis virus, Western equine encephalitis virus, and SLE virus, as well as routine blood and urine cultures for bacteria and fungi. The serum IgM and IgG titers for WNV were positive at ⬎1:10 each. The SLE IgM was negative, but the SLE IgG was positive. Serologic tests for the other viruses, blood, urine, and cerebrospinal fluid cultures for bacteria, viruses, and fungi, rapid plasma reagin, and Venereal Disease Research Laboratory test for syphilis were negative. The plaque reduction neutralization test, the most specific test for the WNV, was positive. On the basis of serologic testing, the patient was considered to have WNV meningoencephalitis. Over the next few days, the patient complained of floaters in both eyes. At initial ophthalmologic examination 18 days after the onset of acute illness, visual acuity was correctable to 20/25 in both eyes. Intraocular pressure was 13 mmHg in both eyes by applanation. Slit-lamp biomicroscopy of the anterior segment revealed no pertinent abnormalities in both eyes. A few blot retinal hemorrhages were seen in the right eye, but no retinal hemorrhages were present in the left eye. At examination by a vitreoretinal specialist 4 days later, the patient’s best-corrected visual acuity had declined to 20/50 in the right eye but remained 20/25 in the left eye. Slit-lamp biomicroscopy revealed trace to 1⫹ cells and flare in the aqueous in the right eye but normal anterior segment features in the left eye. Vitreous cells were present in both eyes, in the right eye greater than in the left eye. Fundus biomicroscopy revealed small clumps of cells overlying the superonasal and inferonasal disc margins in the right eye, mild disc edema in both eyes, bilateral retinal hemorrhages with central areas of clearing in both eyes, and numerous small white deep chorioretinal lesions in the right eye scattered mostly in the temporal midzone but also involving the nasal and superonasal fundus. One lesion in the inferotemporal area in the right eye seemed active. All chorioretinal lesions measured approximately 0.2 to 0.5 mm in diameter. An FA confirmed the presence of multiple chorioretinal lesions and a few scattered peripheral retinal hemorrhages in both eyes (Fig 4). The chorioretinal lesions appeared hypofluorescent centrally and hyperfluorescent around the edges, similar to case 1 (Fig 5). A radially oriented linear hyperfluorescence was seen along a choroidal blood vessel similar to the fundus findings in case 1. No
1734
Figure 4. Venous phase of fluorescein angiogram (superonasal midzone of the right eye) showing characteristic chorioretinal lesions with few scattered hemorrhages.
retinal vascular abnormalities were present in either eye. Visual fields by dynamic perimetry were normal in both eyes. On the basis of the history, serologic testing, and fundus findings, we regard this patient as having WNV meningoencephalitis with chorioretinal inflammation. The patient’s systemic complaints resolved over the next 4 weeks, except for the profound myalgias and weakness, which persisted for approximately 3 months. Repeat ophthalmologic examination and FA 4 months after onset of illness showed mildly increased pigmentation in the chorioretinal lesions, with complete resolution of the anterior segment inflammation and vitreitis, similar to case 1. The optic disc edema had resolved in both eyes.
Figure 5. Venous phase of fluorescein angiogram (temporal midzone of the right eye) showing multiple discrete chorioretinal folds, all of which exhibit a dark center and bright surrounding rim.
Hershberger et al 䡠 Chorioretinal Lesions in Cases of West Nile Virus Infection
Discussion Recent reports have highlighted a multifocal chorioretinitis seen in patients with WNV disease.5–7 These reports show a striking similarity in both the funduscopic and angiographic appearance of the chorioretinal lesions. In addition, our review of literature has revealed a single patient with WNV meningoencephalitis who developed optic disc edema, extraocular muscle paresis, and nystagmus.8 Cerebrospinal fluid opening pressure was not reported, hence it is unclear whether the optic disc edema was secondary to optic neuritis or papilledema. The unique features in both of our case reports are (1) unilateral iridocyclitis, and (2) strikingly similar multifocal bilateral chorioretinal lesions with a “targetlike” appearance similar to those reported in recent literature.5–7 The iridocyclitis in both patients was nongranulomatous, relatively mild, and responded favorably to topical corticosteroids in patient 1. Both patients developed ocular symptoms approximately 7 to 14 days after onset of systemic illness. The chorioretinal lesions in both of our patients were small round spots that tended to be clustered in several areas of the fundus, most prominently in the temporal and nasal regions in the midzone and periphery. These lesions bear a remarkable similarity in both patients and do not correspond to any other known pattern of chorioretinitis in their clinical appearance. Because we did not examine either patient during the first 2 weeks after the onset of symptoms of the WNV disease, we cannot be sure when the chorioretinal lesions appeared in the course of the disease or how they appeared during the initial manifestation. In addition, because the chorioretinal lesions in the first patient resembled foci of well-circumscribed chorioretinal atrophy (similar to chorioretinal spots seen 1 to 2 weeks after laser therapy), we speculate that these lesions had evolved through a previous active stage. We propose that the active-appearing chorioretinal lesions and vitreous cells seen in the second patient might represent this prior active stage. The FAs in both patients bear a striking similarity and show uniform-appearing lesions with central hypofluorescent areas with peripheral hyperfluorescence that increases in the late frames (not shown). Although bilateral optic disc edema was observed in the second patient, the cause of this finding is not entirely clear. However, given the normal visual field and the borderline high opening pressure recorded at lumbar puncture, we believe that the bilateral disc edema in our patient is consistent with resolving papilledema related to the meningoencephalitis rather than with optic neuritis as previously reported.8 The diagnosis of systemic WNV disease rests on a high index of clinical suspicion and results of specific laboratory tests. When confronted with a patient with headache, myalgias, fever, rash, chorioretinitis, and focal neurologic findings, a variety of disorders must be included in the differential diagnosis. Neuroimaging studies, serology for viruses such SLE, California encephalitis virus, herpes simplex virus, and cytomegalovirus, tests for syphilis, Bartonella, Lyme, and negative cultures help narrow the differential diagnosis. WNV disease and other arboviral diseases, such as SLE, should be included in the differential diagnosis of
persons experiencing an acute febrile illness associated with symptoms suggestive of encephalitis or meningitis, especially if the patient is an older or debilitated adult and the disease occurs in late summer or early fall in an area of WNV disease outbreak. Because of close antigenic relationships among the flaviviruses, persons recently vaccinated with yellow fever or Japanese encephalitis vaccines or persons recently infected with a related flavivirus (e.g., SLE) might have positive results on antibody tests for WNV. The plaque reduction neutralization assay, the most specific test for the arthropod-borne flaviviruses, can be used to help distinguish false-positive results on IgM antibody-capture enzyme-linked immunosorbent assay or other assays (for example, indirect immunofluorescence and hemagglutination inhibition).1 The most commonly used laboratory method for diagnosis of WNV is detection of IgM antibody to the virus in serum. This test has a sensitivity approaching 100% at titers greater than 1:30. Our patient in case 1 had an IgM titer of 1:1012. Because of this high titer and negativity for all other tests, the Centers for Disease Control and Prevention deemed it unnecessary to test the plaque reduction neutralization assay in this patient. The patient in case 2 tested positive by the plaque reduction neutralization assay, and thus also has confirmed WNV infection. The positivity for SLE IgG in this patient is believed to be due to cross-reactivity with WNV. In addition, no case of SLE or any other flaviviruses was reported in Ohio in 2002, the same year 14 cases of serology-proven WNV disease were reported in the Greater Cincinnati area. Although all laboratory tests for simulating ocular lesions were negative, we recognize that in the absence of a direct demonstration of WNV in the eye or indirect evidence from ocular antibody levels, the association between the ocular findings and the systemic illness remains presumptive. However, considering the striking similarity of the chorioretinal lesions in both patients, the confirmed diagnosis of WNV disease in both patients, the development of ocular symptoms shortly after the onset of systemic symptoms, and in the absence of any other known etiology that would account for the intraocular findings, we consider it very likely that the ocular findings were directly related to the WNV. In conclusion, we present two patients with unusual ocular signs and symptoms associated with a systemic febrile illness secondary to WNV disease. The WNV chorioretinitis in both patients had a self-limited course without the need for significant intervention other than topical steroids for the anterior chamber involvement.
References 1. Petersen LR, Marfin AA. West Nile virus: a primer for the clinician. Ann Intern Med 2002;137(3):173–9. 2. Huba´ lek Z, Halouzka J. West Nile fever—a reemerging mosquitoborne viral disease in Europe. Emerg Infect Dis 1999;5:643–50. 3. West. Nile virus activity—United States, 2001. MMWR Morb Mortal Wkly Rep 2002;51:497–501. 4. Turell MJ, Sardelis MR, Dohm DJ, O’Guinn ML. Potential North American vectors of West Nile virus. Ann N Y Acad Sci 2001;951:317–24. 5. Bains HS, Jampol LM, Caughron MC, Parnell JR. Vitritis and
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Ophthalmology Volume 110, Number 9, September 2003 chorioretinitis in a patient with West Nile virus infection. Arch Ophthalmol 2003;121:205–7. 6. Vandenbelt S, Shaikh S, Capone A Jr, Williams GA. Multifocal choroiditis associated with West Nile virus encephalitis. Retina 2003;23:97–9.
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7. Adelman RA, Membreno JH, Afshari NA, Stoessel KM. West Nile virus chorioretinitis. Retina 2003;23:100 –1. 8. Vaispapir V, Blum A, Soboh S, Ashkenazi H. West Nile virus meningoencephalitis with optic neuritis. Arch Intern Med 2002; 162:606 –7.
West Nile virus (WNV) is a single-stranded RNA virus of the family Flaviviridae, first isolated in 1937 in the West Nile district of Uganda.1 It belongs to the Japanese encephalitis virus serocomplex, which also includes the Japanese encephalitis virus, St. Louis encephalitis virus (SLE), Murray Valley encephalitis virus, and Kunjin virus (an Australian subtype of WNV). WNV is the most widespread of the flaviviruses, having geographic distribution in Africa, West Asia, the Middle East, and Europe.2 Since 1937, notable outbreaks in Israel (1957), South Africa (1974), Romania (1996), Russia (1999), and Israel (2000) involved hundreds of persons and were associated with severe neurologic disease and death.1 Between August 1999 (when an outbreak Originally received: February 24, 2003. Accepted: April 25, 2003. Manuscript no. 230105. 1 Department of Ophthalmology, University of Cincinnati College of Medicine, Cincinnati, Ohio. 2 Cincinnati Eye Institute, Cincinnati, Ohio. 3 Dayton Vitreo-Retinal Associates, Dayton, Ohio. 4 EyeCare Associates, Cincinnati, Ohio. Supported in part by a Departmental Challenge Grant from Research to Prevent Blindness, Inc., New York, New York, to the Department of Ophthalmology, University of Cincinnati College of Medicine. The authors have no financial interest in any product, drug, instrument, or piece of equipment discussed in the manuscript. Reprint requests to Vrinda S. Hershberger, MD, 234 Goodman Street, ML 777, Cincinnati, OH 45219. E-mail: [email protected].
1732
© 2003 by the American Academy of Ophthalmology Published by Elsevier Inc.
of WNV encephalitis occurred in New York) and December 2001, 149 cases of WNV illness were documented in the United States.3 WNV is maintained in an enzootic cycle involving mainly the Culex genus of mosquitoes and birds. Birds are the natural hosts for the virus, and the virus can be transmitted from them to humans and other vertebrates by the bite of an infected mosquito.4 Peak onset occurs in late summer, although onset has occurred from July to December. The incubation period of the WNV ranges from 3 to 14 days. Only approximately 20% of human infections are clinically apparent, and only 1 in 150 infections result in meningitis or encephalitis.1 The clinical presentation is characterized by a febrile illness of sudden onset accompanied by myalgia, arthralgia, headache, conjunctivitis, lymphadenopathy, and a maculopapular or roseolar rash. Recent reports have described a WNV-associated multifocal chorioretinitis with strikingly similar ocular findings.5–7 We report two patients with chorioretinal lesions and intraocular inflammation associated with serology-proven WNV disease.
Case Reports Case 1 A 61-year-old woman reported a 2-day history of severe headaches associated with chills, fever to 103° Fahrenheit, anorexia, profound generalized weakness, and difficulty with fine motor coordination. One week after the onset of symptoms, she developed a ISSN 0161-6420/03/$–see front matter doi:10.1016/S0161-6420(03)00720-6
Hershberger et al 䡠 Chorioretinal Lesions in Cases of West Nile Virus Infection
Figure 1. Posterior fundus of the right eye with vitreous cells and multiple deep chorioretinal lesions in the macular region.
maculopapular rash involving the skin of both lower extremities. She also complained of blurred vision in both eyes without flashes, floaters, pain, or redness in either eye. Ophthalmologic examination 11 days after the onset of systemic symptoms revealed cells and flare in the aqueous and anterior vitreous in the right eye and multiple creamy to partially atrophic nummular chorioretinal lesions in both eyes. The differential diagnosis after that examination included multifocal choroiditis, birdshot choroiditis, and atypical primary vitreoretinal lymphoma. Complete blood count, serum electrolytes, Westergren sedimentation rate, and liver function tests were essentially normal, except for a white blood count of 12.6 ⫻ 103/l with 82% neutrophils. The patient was placed on topical prednisone and referred to ocular oncology for further evaluation. At initial ocular oncology evaluation 3 weeks after the onset of initial symptoms, the patient was still experiencing chronic headaches, profound generalized weakness, and anorexia. However, the rash, fever, and chills had resolved. She still complained of bilateral visual blurring, worse in the right eye. She denied flashes, floaters, or scotomata. She admitted to recent outdoor activities with a history of mosquito bites before onset of her systemic and ocular symptoms. Visual acuity was correctable to 20/30 in the right eye and 20/25 in the left eye. Intraocular pressure was 12 mmHg in both eyes by applanation. Slit-lamp biomicroscopy in the right eye revealed trace cells without flare in the aqueous, curvilinear deposits of brown pigment on the anterior lens capsule concentric with the pupillary margin, and 1⫹ pale cells in the anterior vitreous. The anterior segment in the left eye appeared normal. Fundus biomicroscopy of the right eye revealed 1⫹ fine, pale, midvitreous and posterior vitreous cells and multiple partially atrophic and partially pigmented nummular chorioretinal foci (Fig 1). Fundus biomicroscopy of the left eye revealed similar but less numerous chorioretinal lesions but no vitreous cells. There were no retinal hemorrhages, and there was no retinal vascular sheathing or optic disc edema in either eye. Most of the lesions ranged from 0.25 to 0.5 mm in diameter. A fluorescein angiogram (FA) confirmed the presence of multiple chorioretinal lesions that appeared hypofluorescent centrally and hyperfluorescent around the edges. The FA also showed many more chorioretinal lesions than were observed clinically (Fig 2). Some of the lesions in the midzone and periphery of each eye were arranged in a linear distribution corresponding to choroidal vessels (Fig 3).
Figure 2. Arteriovenous phase of the fluorescein angiogram (posterior fundus of the right eye) showing chorioretinal lesions with central hypofluorescence and peripheral hyperfluorescence. Many more chorioretinal lesions are seen than were observed clinically.
On our recommendation, the patient underwent serologic testing for infectious and inflammatory conditions including WNV. HLA-A29, HLA-B27, Rocky Mountain spotted fever IgG and IgM, toxoplasma IgG and IgM, Bartonella IgG and IgM, Ehrlichia IgG and IgM, antinuclear antibody, rapid plasma reagin, lysozyme, cytomegalovirus, and herpes simplex virus serology and chest x-ray were all negative. Magnetic resonance imaging of the head showed no abnormalities. However, serology for WNV was strikingly positive with the serum IgG titer at 1:512 and the serum IgM titer at 1:1054. On the basis of the serologic testing and a discussion with officials at the Centers for Disease Control and Prevention in Atlanta, the patient was regarded as having confirmed WNV disease. The patient’s systemic and ocular complaints resolved completely over the next 2 to 3 weeks. Repeat ophthalmologic exam-
Figure 3. Venous phase of fluorescein angiogram (superonasal fundus of the left eye) showing radially oriented linear clustering of chorioretinal lesions.
1733
Ophthalmology Volume 110, Number 9, September 2003 ination and FA 4 months after initial presentation showed mildly increased pigmentation in the chorioretinal lesions, although the anterior segment inflammation and vitreous cells had resolved.
Case 2 A 56-year-old man reported a 5-day history of fever to 104° Fahrenheit, cough, myalgia, confusion, tremor, and gait disturbance with difficulty walking. Complete blood count, Westergren sedimentation rate, serum electrolytes, chest x-ray, and liver function tests were essentially normal. The patient denied any infectious exposure, insect bites, or travel outside the United States. The patient was admitted for presumed meningoencephalitis of possibly viral etiology. The general physical examination was remarkable for a blanching macular rash over the lower extremities without involvement of the palms or soles. There were no petechiae. Neurologic findings included action and postural tremor, a wide-based gait with mild ataxia, confusion, and garbled speech. Repeat CBC showed a white blood count of 4.2 ⫻ 103/l with 80% neutrophils. Computed tomography of the head showed no abnormalities, but a magnetic resonance imaging scan with gadolinium showed mild cortical atrophy and lacunar infarcts involving the left basal ganglia and left periventricular white matter. Lumbar puncture revealed an opening pressure of 20.5 cm (borderline elevated). Cerebrospinal fluid analysis was significant for an elevated white blood count of 188/ml with 100% neutrophils. The patient underwent serologic testing for WNV, herpes simplex virus, cytomegalovirus, California encephalitis virus, Western equine encephalitis virus, and SLE virus, as well as routine blood and urine cultures for bacteria and fungi. The serum IgM and IgG titers for WNV were positive at ⬎1:10 each. The SLE IgM was negative, but the SLE IgG was positive. Serologic tests for the other viruses, blood, urine, and cerebrospinal fluid cultures for bacteria, viruses, and fungi, rapid plasma reagin, and Venereal Disease Research Laboratory test for syphilis were negative. The plaque reduction neutralization test, the most specific test for the WNV, was positive. On the basis of serologic testing, the patient was considered to have WNV meningoencephalitis. Over the next few days, the patient complained of floaters in both eyes. At initial ophthalmologic examination 18 days after the onset of acute illness, visual acuity was correctable to 20/25 in both eyes. Intraocular pressure was 13 mmHg in both eyes by applanation. Slit-lamp biomicroscopy of the anterior segment revealed no pertinent abnormalities in both eyes. A few blot retinal hemorrhages were seen in the right eye, but no retinal hemorrhages were present in the left eye. At examination by a vitreoretinal specialist 4 days later, the patient’s best-corrected visual acuity had declined to 20/50 in the right eye but remained 20/25 in the left eye. Slit-lamp biomicroscopy revealed trace to 1⫹ cells and flare in the aqueous in the right eye but normal anterior segment features in the left eye. Vitreous cells were present in both eyes, in the right eye greater than in the left eye. Fundus biomicroscopy revealed small clumps of cells overlying the superonasal and inferonasal disc margins in the right eye, mild disc edema in both eyes, bilateral retinal hemorrhages with central areas of clearing in both eyes, and numerous small white deep chorioretinal lesions in the right eye scattered mostly in the temporal midzone but also involving the nasal and superonasal fundus. One lesion in the inferotemporal area in the right eye seemed active. All chorioretinal lesions measured approximately 0.2 to 0.5 mm in diameter. An FA confirmed the presence of multiple chorioretinal lesions and a few scattered peripheral retinal hemorrhages in both eyes (Fig 4). The chorioretinal lesions appeared hypofluorescent centrally and hyperfluorescent around the edges, similar to case 1 (Fig 5). A radially oriented linear hyperfluorescence was seen along a choroidal blood vessel similar to the fundus findings in case 1. No
1734
Figure 4. Venous phase of fluorescein angiogram (superonasal midzone of the right eye) showing characteristic chorioretinal lesions with few scattered hemorrhages.
retinal vascular abnormalities were present in either eye. Visual fields by dynamic perimetry were normal in both eyes. On the basis of the history, serologic testing, and fundus findings, we regard this patient as having WNV meningoencephalitis with chorioretinal inflammation. The patient’s systemic complaints resolved over the next 4 weeks, except for the profound myalgias and weakness, which persisted for approximately 3 months. Repeat ophthalmologic examination and FA 4 months after onset of illness showed mildly increased pigmentation in the chorioretinal lesions, with complete resolution of the anterior segment inflammation and vitreitis, similar to case 1. The optic disc edema had resolved in both eyes.
Figure 5. Venous phase of fluorescein angiogram (temporal midzone of the right eye) showing multiple discrete chorioretinal folds, all of which exhibit a dark center and bright surrounding rim.
Hershberger et al 䡠 Chorioretinal Lesions in Cases of West Nile Virus Infection
Discussion Recent reports have highlighted a multifocal chorioretinitis seen in patients with WNV disease.5–7 These reports show a striking similarity in both the funduscopic and angiographic appearance of the chorioretinal lesions. In addition, our review of literature has revealed a single patient with WNV meningoencephalitis who developed optic disc edema, extraocular muscle paresis, and nystagmus.8 Cerebrospinal fluid opening pressure was not reported, hence it is unclear whether the optic disc edema was secondary to optic neuritis or papilledema. The unique features in both of our case reports are (1) unilateral iridocyclitis, and (2) strikingly similar multifocal bilateral chorioretinal lesions with a “targetlike” appearance similar to those reported in recent literature.5–7 The iridocyclitis in both patients was nongranulomatous, relatively mild, and responded favorably to topical corticosteroids in patient 1. Both patients developed ocular symptoms approximately 7 to 14 days after onset of systemic illness. The chorioretinal lesions in both of our patients were small round spots that tended to be clustered in several areas of the fundus, most prominently in the temporal and nasal regions in the midzone and periphery. These lesions bear a remarkable similarity in both patients and do not correspond to any other known pattern of chorioretinitis in their clinical appearance. Because we did not examine either patient during the first 2 weeks after the onset of symptoms of the WNV disease, we cannot be sure when the chorioretinal lesions appeared in the course of the disease or how they appeared during the initial manifestation. In addition, because the chorioretinal lesions in the first patient resembled foci of well-circumscribed chorioretinal atrophy (similar to chorioretinal spots seen 1 to 2 weeks after laser therapy), we speculate that these lesions had evolved through a previous active stage. We propose that the active-appearing chorioretinal lesions and vitreous cells seen in the second patient might represent this prior active stage. The FAs in both patients bear a striking similarity and show uniform-appearing lesions with central hypofluorescent areas with peripheral hyperfluorescence that increases in the late frames (not shown). Although bilateral optic disc edema was observed in the second patient, the cause of this finding is not entirely clear. However, given the normal visual field and the borderline high opening pressure recorded at lumbar puncture, we believe that the bilateral disc edema in our patient is consistent with resolving papilledema related to the meningoencephalitis rather than with optic neuritis as previously reported.8 The diagnosis of systemic WNV disease rests on a high index of clinical suspicion and results of specific laboratory tests. When confronted with a patient with headache, myalgias, fever, rash, chorioretinitis, and focal neurologic findings, a variety of disorders must be included in the differential diagnosis. Neuroimaging studies, serology for viruses such SLE, California encephalitis virus, herpes simplex virus, and cytomegalovirus, tests for syphilis, Bartonella, Lyme, and negative cultures help narrow the differential diagnosis. WNV disease and other arboviral diseases, such as SLE, should be included in the differential diagnosis of
persons experiencing an acute febrile illness associated with symptoms suggestive of encephalitis or meningitis, especially if the patient is an older or debilitated adult and the disease occurs in late summer or early fall in an area of WNV disease outbreak. Because of close antigenic relationships among the flaviviruses, persons recently vaccinated with yellow fever or Japanese encephalitis vaccines or persons recently infected with a related flavivirus (e.g., SLE) might have positive results on antibody tests for WNV. The plaque reduction neutralization assay, the most specific test for the arthropod-borne flaviviruses, can be used to help distinguish false-positive results on IgM antibody-capture enzyme-linked immunosorbent assay or other assays (for example, indirect immunofluorescence and hemagglutination inhibition).1 The most commonly used laboratory method for diagnosis of WNV is detection of IgM antibody to the virus in serum. This test has a sensitivity approaching 100% at titers greater than 1:30. Our patient in case 1 had an IgM titer of 1:1012. Because of this high titer and negativity for all other tests, the Centers for Disease Control and Prevention deemed it unnecessary to test the plaque reduction neutralization assay in this patient. The patient in case 2 tested positive by the plaque reduction neutralization assay, and thus also has confirmed WNV infection. The positivity for SLE IgG in this patient is believed to be due to cross-reactivity with WNV. In addition, no case of SLE or any other flaviviruses was reported in Ohio in 2002, the same year 14 cases of serology-proven WNV disease were reported in the Greater Cincinnati area. Although all laboratory tests for simulating ocular lesions were negative, we recognize that in the absence of a direct demonstration of WNV in the eye or indirect evidence from ocular antibody levels, the association between the ocular findings and the systemic illness remains presumptive. However, considering the striking similarity of the chorioretinal lesions in both patients, the confirmed diagnosis of WNV disease in both patients, the development of ocular symptoms shortly after the onset of systemic symptoms, and in the absence of any other known etiology that would account for the intraocular findings, we consider it very likely that the ocular findings were directly related to the WNV. In conclusion, we present two patients with unusual ocular signs and symptoms associated with a systemic febrile illness secondary to WNV disease. The WNV chorioretinitis in both patients had a self-limited course without the need for significant intervention other than topical steroids for the anterior chamber involvement.
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Ophthalmology Volume 110, Number 9, September 2003 chorioretinitis in a patient with West Nile virus infection. Arch Ophthalmol 2003;121:205–7. 6. Vandenbelt S, Shaikh S, Capone A Jr, Williams GA. Multifocal choroiditis associated with West Nile virus encephalitis. Retina 2003;23:97–9.
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