Neuroinvasive West Nile Virus Presenting as Subacute Progressive Quadriparesis and Intractable Pain: A Case Report

To the Editor: West Nile virus (WNV) is a single-stranded RNA virus in the family Flaviviridae that is transmitted to humans by mosquitoes. Approximately 80% of WNV infections in humans are asymptomatic, whereas ≈20% of infected persons experience fever, often accompanied by a rash. Less than 1% of infections are manifested as neuroinvasive disease, such as meningoencephalitis, polyradiculoneuritis, and polio-like flaccid paralysis (1). WNV is endemic in Africa, southern Asia, and northern Australia, and only sporadic cases or small epidemics are seen in Europe (2). In 1999, WNV emerged in North America. By 2010, ≈1.8 million persons had become infected, with 12,852 reported cases of meningoencephalitis and 1,308 deaths (2). In Europe, the last notable outbreak of WNV infection occurred in Greece in 2010; 197 persons were infected, and 33 died (3). The Czech Republic, Denmark, France, and the Netherlands reported laboratory-confirmed WNV infections in travelers returning from North America (1). We report a case of WNV meningoencephalitis in a 28-year-old German woman, who sought treatment the emergency department of a hospital in Potsdam, Germany, on September 7, 2011. She had a 3-day history of fever of up to 40°C and mental confusion. Six days before admission, she had returned from a 2-week holiday trip to Ottawa, Ontario, Canada. She had spent most of her time in the city of Ottawa. The patient’s medical history was unremarkable. She was in a reduced general condition because of a severe encephalitic syndrome characterized by somnolence, meningism, fever, and mental confusion. Laboratory investigations revealed leukocytosis with 15.000 leukocytes/µL (reference range 4,400–11,300 leukocytes/µL) and elevated C-reactive protein of 14.8 mg/L (reference <3 mg/L). Cerebrospinal fluid (CSF) analysis on the day of admission showed pleocytosis, 430 cells/µL (72% granulocytes, 27% lymphocytes. and 1% monocytes); elevated levels for total protein, 1,023 mg/L (reference range 150–450 mg/L); an albumin level of 637 mg/L (normal range 0–350 mg/L); and a moderately elevated level of the albumin quotient of 20 (reference range <6.5). The CSF/serum diagrams demonstrated a moderate disturbance of the blood–CSF barrier and a substantial intrathecal IgM synthesis of 27.6% (6.15 mg/L) but no intrathecal IgA or IgG synthesis. Results of magnetic resonance imaging of the brain were unremarkable. No parenchymal lesions were found. Antimicrobial drug therapy was initiated with ceftriaxone and ampicillin. Acyclovir was administered empirically for herpes simplex encephalitis until this diagnosis was excluded. Molecular and serologic testing of serum and CSF samples revealed no acute infection with herpesviruses, enteroviruses, alphaviruses, orthobunyaviruses, and arenaviruses or with mycobacteria, Borrelia spp., Toxoplasma gondii, Chlamydia spp., Leptospira spp., and Mycoplasma pneumoniae. CSF and blood cultures were negative for fungi and bacteria, including mycobacteria. An encephalitic syndrome caused by N-methyl-D-aspartate antibodies was also excluded. On the basis of the patient’s travel history, the clinical symptoms, and the initial laboratory findings, WNV infection was suspected. Indirect immunofluorescence assays and virus neutralization tests (VNT) for WNV and other flaviviruses were performed as described (4). IgM and IgG against WNV were detected in serum and in CSF by indirect immunofluorescence assay with an 8-fold (IgM) and 32-fold (IgG) increase in serum titer from day 4 to day 26 (Table). WNV IgG and WNV IgM titers were higher than the titers of antibodies against the other flaviviruses tested (Table), indicating that the antibodies resulted from a WNV infection. The serologic diagnosis was further substantiated by detection of WNV neutralizing antibodies at day 11 (VNT titer 640). The VNT titer further increased to 2,560 on day 26 after onset of disease. Results of reverse transcription PCR were negative for WNV and members of genus Flavivirus in serum and CSF samples taken 4 days after disease onset. Attempts to isolate WNV from serum and CSF samples in cell culture failed as well. The patient recovered slowly and was discharged from the hospital in Potsdam on September 15, 2011. She was then referred to a neurologic rehabilitation center in Berlin and was discharged from there after 2 months with a characterization of restitutio ad integrum (i.e., full recovery, restoration to original condition). Table Results of indirect immunofluorescence assays performed on serum and CSF samples from patient with suspected WNV infection, Germany, 2011* We report a case of WNV infection imported into Germany that was unambiguously confirmed by laboratory testing. WNV meningoencephalitis was diagnosed on the basis of strict serologic criteria established by the Centers for Disease Control and Prevention (Atlanta, GA, USA) (5). In 2011, 69 clinical cases of WNV infection were reported from the province of Ontario, although no cases in the city of Ottawa were reported (Public Health Agency of Canada; www.eidgis.com/wnvmonitorca). This imported case adds to these cases and suggests that travelers are at risk, even if they visit only Ottawa. Physicians in Germany should be aware of the risk for WNV infection among travelers returning from Canada, especially during late summer.

Importation of West Nile Virus Infection from Nicaragua to Spain

In 1999 West Nile virus (WNV) surfaced in the United States in the city of New York and spread over successive summers to most of the continental United States, Canada, and Mexico. Because WNV immunoglobulin M (IgM) antibodies have been shown to persist for up to 1 year, residents in areas of endemicity can have persistent WNV IgM antibodies that are unrelated to a current illness with which they present. We present data on the use of IgG avidity testing for the resolution of conflicting data arising from the testing of serum or plasma for antibodies to WNV. Thirteen seroconversion panels, each consisting of a minimum of four samples, were used. All samples were tested for the presence of WNV IgM and IgG antibodies, and the avidity index for the WNV IgG-positive samples was calculated. Panels that exhibited a rise in the WNV IgM level followed by a sequential rise in the WNV IgG level were designated "primary." Panels that exhibited a marked rise in the WNV IgG level followed by a sequential weak WNV IgM response and that had serological evidence of a prior flavivirus infection were designated "secondary." All samples from the "primary" panels exhibited low avidity indices (less than 40%) for the first 20 to 30 days after the recovery of the index sample (the sample found to be virus positive). All of the "secondary" samples had elevated WNV IgG levels with avidity indices of > or =55%, regardless of the number of days since the recovery of the index sample. These data demonstrate that it is possible to differentiate between recent and past exposure to WNV or another flavivirus through the measurement of WNV IgG avidity indices.

To the Editor: West Nile virus (WNV) is a mosquito-borne flavivirus that primarily causes an asymptomatic or mild disease in humans; however, in <1% of infected persons, it causes neurologic disease. The virus has received increased attention since 2002 when it was established that WNV is transmissible by blood transfusion and organ transplantation (1). A major WNV outbreak occurred in 2010 in Greece; most cases occurred in the northern part of the country (2). Of the 197 WNV neuroinvasive cases reported, 33 were fatal (3). Many nonneuroinvasive cases were observed (4). A lineage 2 WNV (Nea Santa-Greece-2010 strain) was detected in Culex pipiens mosquitoes collected at 2 locations where WNV cases had been reported (5). Although this strain shows high genetic identity to a Hungarian WNV strain isolated from birds in 2004, it has the amino acid substitution H249P in nonstructural protein 3 (NS3) (6). This mutation has been associated with increased virulence in WNV lineage 1 strains (7). Clinical WNV disease in humans had not been previously documented in Greece, and surveillance of blood donors in 2006 and 2007 did not show any WNV-positive result (8). On August 11, 2010, shortly after confirmation of the outbreak of WNV infections in humans in Greece, an action plan for the protection of blood safety was initiated. All donors were asked to report any fever-like illness up to 15 days after donation. Individual donation nucleic acid testing (NAT) of all blood donors living in the WNV-affected areas was implemented on August 22, 2010. The first WNV-positive by NAT result was obtained from a sample donated on August 22. Testing was performed by using the automated Procleix TIGRIS System (Chiron Corporation, Emeryville, CA, USA). The WNV-positive blood donor was a 40-year-old immunocompetent woman, a resident of a village in northern Greece. The village is located between 2 lakes, and the area is one of Europe’s major wetlands. The 2 locations where the WNV-positive mosquitoes were collected are near each other (Figure A1). The woman was working in an open-air fish market and reported numerous mosquito bites. At the time of blood donation, she was asymptomatic; 2 days later she had myalgia, arthralgia, and severe retro-orbital pain, lasting 2–3 days each. A second blood sample taken on August 26 was also NAT positive. Serologic testing for WNV IgM and IgG was performed by ELISA (WNV IgM Capture DxSelect and WNV IgG DxSelect; Focus Diagnostics Inc., Cypress, CA, USA). An index ≥1.5 for IgM and ≥1.1 for IgG was considered positive. No antibodies were detected in the initial and second serum samples; however, a third sample taken on September 20 was positive for WNV IgM and IgG (indices 4.7 and 3.8, respectively). Nested reverse transcription PCRs with the initial blood sample gave positive results (9,10). WNV lineage 2 sequences were obtained and were identical to those of the Nea Santa-Greece-2010 strain (6). One milliliter of each 1:10 and 1:100 dilution of whole blood in minimum essential medium containing antimicrobial drugs and 2% fetal bovine serum was placed on Vero E6 cell monolayers in 25-cm2 cell culture flasks. The procedure was performed in a biosafety level 3 laboratory, in which WNV lineage 2 had never been handled. After the sample was incubated 1 hour at 37°C in a 5% CO2 incubator, 9 mL of fresh medium containing 4% fetal bovine serum was added. Cytopathic effects were observed in the flask inoculated with the 1:100 dilution on day 3 after infection. An aliquot of supernatant was used to infect fresh cell monolayers. WNV growth in the cell culture was demonstrated by reverse transcription PCR and immunofluorescence assay. Sequences of the cell culture isolate were identical to those of the directly detected virus. To check whether the isolate possessed the H249P substitution, a set of nested primers spanning the region 5140–5660 from the WNV genome was designed: NS3a-5′-GCTGGCTTCGAACCTGA-3′ and NS3b-5′-CAATCATCGTTCTTGC-3′ for the first round PCR and NS3c-5′-GCTGCTGAGATGTCTGA-3′ and NS3d-5′-TCATATCCAGTGTTCCA-3′ for the nested PCR. The H249P substitution was present. Sequences were submitted to GenBank (accession nos. {type:entrez-nucleotide,attrs:{text:JF917091,term_id:349806861}}JF917091, {type:entrez-nucleotide,attrs:{text:JF917092,term_id:349806863}}JF917092). Virus isolation from WNV patients is usually unsuccessful because viremia levels are low and last only a short time. WNV strains are usually isolated from immunocompromised patients, blood donors, IgM-negative immunocompetent patients who seroconverted, or autopsy brain samples. For the donor reported here, WNV was isolated 2 days before illness onset, when no antibodies were present. The WNV-positive blood donor was detected 1 day after the introduction of blood screening. The early diagnosis of the initial human WNV cases in Greece, which resulted in prompt implementation of NAT testing, had a substantial positive impact on the safety of the blood supply in the affected areas. The risk for virus transmission was reduced for blood recipients, in particular those who receive multiple transfusions and immunocompromised patients in need of transfusion.

<h3>Objective:</h3> We report a case of concomitant West Nile virus (WNV) encephalitis and acute ischemic strokes and review the literature documenting cases of WNV encephalitis with associated cerebrovascular disease. <h3>Background:</h3> Cases of WNV have risen since 2002, but neuroinvasive disease in uncommon, occurring in 1 in 150. The most common presentation of neuroinvasive WNV is a meningo-encephalitis. Cerebrovascular presentations are exceedingly rare. <h3>Design/Methods:</h3> We report a case of concomitant neuro-invasive WNV infection and acute stroke. We include magnetic resonance imaging (MRI), serologic and cerebrospinal fluid (CSF) laboratory data, and electroencephalogram (EEG) findings. We also present a review of PubMed, Embase, and Web of Science databases for cases of WNV encephalitis associated with cerebral infarctions. <h3>Results:</h3> A 70-year-old woman without significant cardiovascular history was admitted with depressed level of consciousness, hypophonia, and inability to participate in examination. MRI and computed tomography angiography demonstrated bilateral corona radiata strokes without obvious large vessel occlusion. Transthoracic echocardiogram demonstrated a patent foramen ovale; lower extremity ultrasound did not reveal any venous thrombosis. Low-density lipoprotein was elevated. Urine toxicology screen was positive for cocaine. Poor mental status could not be explained by the infarcts alone thus further testing was pursued. Testing for toxic and metabolic abnormalities was unrevealing. EEG demonstrated mild generalized delta slowing. CSF testing showed elevated WNV IgM and IgG. Upon discharged to a rehabilitation facility, her examination was unchanged from presentation. A review of the literature yielded 28 cases of WNV encephalitis complicated by cerebrovascular disease. Most cases were multi-territorial ischemic strokes but etiology of infarction appears varied. <h3>Conclusions:</h3> Pursuit of uncommon etiologies is imperative when presenting symptoms and imaging are not explained by routine testing. The association of neurotropic viruses and strokes may be underappreciated, and possible pathophysiologic connections remain unexplained. <b>Disclosure:</b> Dr. Hingorani has nothing to disclose. Dr. Feske has received publishing royalties from a publication relating to health care. Dr. Cervantes-Arslanian has nothing to disclose.

Persistent Neurobehavioral Signs and Symptoms Following West Nile Fever

West Nile virus neuroinvasive disease: Clinical characteristics and prognostic factors.

The role of IgG avidity determination in diagnosis of West Nile virus infection

Successful Reduced Intensity Stem Cell Transplant in a Patient with Myeloproliferative Neoplasm/Myelodysplastic (MPN/MDS) Overlap Syndrome Diagnosed with West Nile Virus Encephalitis.

A case of juvenile rheumatoid arthritis with sclerodactylia and calcinosis.

Myasthenia Gravis (MG) is an autoimmune disease which is characterised by disruption of signal transmission at neuromuscular junction. We aimed to search about a newly reported association between MG and West Nile Virus (WNV) infection. We searched WNV IgG by ELISA in serum samples of 50 available MG patients and 38 controls. None of the samples gave positive results for past WNV infection. No evidence of past WNV infection was found in our study population of MG patients. This may have been because MG has been showed to be related with neuroinvasive WNV, which none of our study subjects seem to have had based on their stories. New multicentre studies focusing on immunological mechanisms and held with larger groups or especially neuroinvasive disease patients can cast light onto the answer of this question.

DIFFUSE ALVEOLAR HEMORRHAGE: STEROIDS AND TRANEXAMIC ACID FOR AN UNUSUAL MANIFESTATION OF WEST NILE VIRUS

Arboviruses (arthropod-borne-viruses) are an emerging global health threat that are rapidly spreading as climate change, international business transport, and landscape fragmentation impact local ecologies. Since its initial detection in 1999, West Nile virus has shifted from being a novel to an established arbovirus in the United States of America. Subsequently, more than 25,000 cases of West Nile neuro-invasive disease have been diagnosed, cementing West Nile virus as an arbovirus of public health importance. Given its novelty in the United States of America, high-risk ecologies are largely underdefined making targeted population-level public health interventions challenging. Using the Centers for Disease Control and Prevention ArboNET neuroinvasive West Nile virus data from 2000-2021, this study aimed to predict neuroinvasive West Nile virus human cases at the county level for the contiguous USA using a spatio-temporal Bayesian negative binomial regression model. The model includes environmental, climatic, and demographic factors, as well as the distribution of host species. An integrated nested Laplace approximation approach was used to fit our model. To assess model prediction accuracy, annual counts were withheld, forecasted, and compared to observed values. The validated models were then fit to the entire dataset for 2022 predictions. This proof-of-concept mathematical, geospatial modelling approach has proven utility for national health agencies seeking to allocate funding and other resources for local vector control agencies tackling West Nile virus and other notifiable arboviral agents.

Case seriesPatients: Male, 34-year-old • Female, 57-year-oldFinal Diagnosis: West Nile virus myeloradiculitis • West Nile virus opsoclonus myoclonus ataxia syndromeSymptoms: Confusion • lower extremity weakness • opsoclonus-myoclonus-ataxiaMedication: —Clinical Procedure: Lumbar punctureSpecialty: Infectious Diseases • NeurologyObjective:Unusual clinical courseBackground:West Nile virus (WNv) is the leading cause of epidemic arbovirus encephalitis in the continental United States. Movement disorders (MDs) have been reported in 20% to 40% of patients with WNv and about 37% of patients with WNv encephalitis have changes on magnetic resonance imaging (MRI). We report 2 unusual cases of neuroinvasive WNv in patients with unusual MDs and unreported MRI findings.Case Reports:In the first case, a 34-year-old man presented with a 1-week history of disinhibition, agitation, opsoclonus-myoclonus and ataxia syndrome (OMAS), tremor, and facial agnosia. Evaluation of his cerebrospinal fluid (CSF) revealed elevated immunoglobulin (Ig)M against WNv, a high level of protein (98 mg/dL), and an elevated white blood cell (WBC) count (134, 37% lymphocytes). An MRI of the brain showed an area of diffusion restriction in the splenium of the corpus callosum. The patient’s MRI findings and OMA improved significantly after 2 treatments with i.v. IG (IVIG).In the second case, a 57-year-old woman presented with fever, headaches, psychosis, and ataxia; she was subsequently intubated for airway protection. Analysis of her CSF showed elevated IgM against WNv, a high level of protein (79 mg/dL), and elevated WBC count (106, 90% lymphocytes). One week after the onset of symptoms, the patient experienced facial dyskinesia. Later, she developed proximal bilateral lower extremity weakness. An MRI of her lumbar spine showed evidence of myeloradiculitis with contrast enhancement of the conus medullaris and ventral nerve roots. After a single treatment with IVIG, she had partial improvement in weakness.Conclusions:MDs and changes on MRI have been reported in patients with neuroinvasive WNv disease. Our patient with OMAS also had transient splenial diffusion restriction on imaging, which, to the best of our knowledge, has not been previously reported with WNv infection. In both patients, treatment with IVIG resulted in improvement in symptoms.

In Georgia, most individuals reported with West Nile virus (WNV) disease have been diagnosed with West Nile neuroinvasive disease (WNND). Relatively few cases of West Nile Fever (WNF) are reported, and the burden of illness due to WNV is likely underestimated. From July through October 2003, WNV serologic testing was performed on enrolled patients>or=18 years of age with fever admitted to a large, urban hospital in Atlanta, Georgia through the emergency department (ED). Patients' history, clinical, and laboratory data were recorded. Residual blood drawn in the ED was tested to determine the presence of WNV IgG and IgM antibodies. Of 254 patients tested for WNV, four (1.6%) patients were positive for WNV IgM and IgG antibodies, and had a clinical illness compatible with WNV. None of the four positive patients were clinically suspected of having WNV infection; discharge diagnoses included pneumonia, migraine, stroke, and gout. These four patients accounted for 80% of all WNV diagnosed in this hospital, 44% of all cases in Fulton County, and 7% of all cases reported in Georgia in 2003. The occurrence of WNV disease may be substantially greater than currently reflected in disease statistics in Georgia and many other states. When indicators of WNV activity are present and patients are likely to have had intensive mosquito exposure, WNV should be considered in the differential diagnosis of seriously ill, febrile patients.