Handbook of Clinical Neurology, Vol. 123 (3rd series) Neurovirology A.C. Tselis and J. Booss, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 20

West Nile and St. Louis encephalitis viruses 1

RYAN J. OYER1, J. DAVID BECKHAM1,2,3, AND KENNETH L. TYLER1,2,3* Division of Infectious Diseases, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA 2

Department of Neurology, University of Colorado School of Medicine, Aurora, CO, USA

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Department of Microbiology, University of Colorado School of Medicine, Aurora, CO, USA

INTRODUCTION West Nile virus (WNV) and St. Louis encephalitis virus (SLEV) are arthropod-borne flaviviruses that belong to the Japanese encephalitis virus (JEV) antigenic complex. SLEV transmission is limited to North and South America, whereas WNV infection occurs on six continents. WNV is now the most common cause of epidemic viral meningoencephalitis in the United States and greater than 39000 human cases have been reported since its emergence in New York City in 1999. Both viruses are maintained in the natural environment in a cycle between mosquitoes and birds. Human infection is an incidental, non-amplifying, dead-end occurrence in the natural history of these viruses and neither WNV nor SLEV is naturally transmitted from person to person. The majority of infections are asymptomatic (80%) and most clinical illness manifests as a selflimited, febrile, flu-like syndrome. However, a small percentage of individuals (99.8% homologous) to a 1998 Israeli WNV strain likely brought to the United States by migrating birds, the importation of illegal birds or unintentional introduction of virus-infected mosquitoes (Lanciotti et al., 1999; Rappole et al., 2000). Ultimately 59 cases of encephalitis and seven deaths from WNV were confirmed (Nash et al., 2001). WNV is generally transmitted via bite from infected mosquitoes. While many species of mosquito are capable of acquiring WNV after feeding on infected vertebrate amplifying hosts – most often birds – the most important species in the United States are from the Culex genus (C. pipiens, C. restuans, C. salinarius, C. tarsalis) (Girard et al., 2004). Following a blood meal, WNV penetrates the mosquito gut and replicates in multiple tissues, including the nervous system and salivary glands, producing infection that lasts the lifetime of the mosquito (Girard et al., 2005). An infected Culex pipens mosquito injects about 104 plaque-forming units (pfu) per milliliter of WNV into its host during a blood meal (Vanlandingham et al., 2004). Among mosquitoes, the virus is transmitted from females transovarianly to their offspring and overwinters in hibernating female mosquitoes, continuing its persistence in a particular location (Nasci et al., 2001; Dohm et al., 2002). Mosquitoes transmit WNV to over 150 species of birds and at least 30 other vertebrates (van der Meulen et al., 2005). Passerine birds, including corvids (crows, magpies, and jays), house sparrows, finches, and grackles appear to be the most competent and efficient WNV reservoirs and amplifying hosts. Viremia titers >1010 pfu/mL have been measured in infected American crows, well above the >105 pfu required for reservoir competency. Titers at this level correlate to transmission of WNV infection to 80% of biting mosquitoes (Komar et al., 2003). Further, because high viremia titers are positively correlated with mortality, this level of viremia may decimate non-immune avian populations; some populations of American crows were decreased by 90% during WNV epidemics in the United States. Notably, avian mortality had not generally been a hallmark of WNV infection until an outbreak in Israel in 1998 where high mortality rates were seen in domestic goslings and migrating white storks (Malkinson et al., 2002). Humans (and other mammals, notably horses) are not competent WNV reservoirs and are incidental, dead-end

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Fig. 20.2. Factors known or postulated to be involved in the life cycle of West Nile virus and epidemics of human disease (Reproduced with permission from Solomon et al., 2003).

hosts that do not generally transmit WNV to other humans or mosquitoes (Fig. 20.2). Thus, transmission is necessary for continued viral propagation. This is in contrast to other clinically important flaviviruses such as dengue and chikungunya, which can be transmitted from person to person, but similar to JEV and yellow fever (YFV), which also require enzoonotic passage. The intensity of WNV transmission to humans is dictated by seasonal feeding behavior and numbers of mosquitoes, as well as by local ecologic determinants of human exposure (Hayes and Gubler, 2006). WNV epidemics exhibit a seasonal variation in the United States, with most cases observed in the summer and early fall (June through October). WNV transmission has also been documented following organ transplantation of WNV-infected organs (Iwamoto et al., 2003), breastfeeding (CDC, 2002; Hinckley et al., 2007), blood transfusions (Pealer et al., 2003), and needlestick (Venter et al., 2009). Additionally, possible vertical transmission from mother to fetus has been reported (CDC, 2002), as has possible transmission from infected hemodialysis machines (CDC, 2004). The speed and completeness of the spread of WNV across the United States has been remarkable. In 2003, 4 years after the emergence of WNV in New York City, the largest epidemic of WNV ever reported occurred in the United States, when 9862 cases of West Nile infection, 2860 (29%) cases of neuroinvasive disease (meningitis, encephalitis, and myelitis) and 264 deaths occurred. The highest concentration of cases was reported in Colorado, although all contiguous US states except Washington and Oregon reported confirmed WNV cases. In 2010, 41 states reported WNV diagnoses and 981 total cases were documented in the United States. Sixty-one percent of cases were reported as neuroinvasive and there were 45 deaths (Fig. 20.1B). These numbers

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reflect significant sample bias, and a considerable underestimation of the incidence of WNV infection in the United States, as most WNV cases are asymptomatic and unlikely to be reported; the more severe cases, including West Nile neuroinvasive disease (WNND), are more likely to be hospitalized and documented. In the United States seroprevalence of neutralizing WNV antibody is estimated at 1–6% in endemic areas and is much higher during epidemic activity, for example, reaching 20% in certain areas during the 2003 WNV epidemic (Mostashari et al., 2001; Freifeld et al., 2010; Planitzer et al., 2009). What is clear is that WNV is now endemic in many areas in the United States and the diagnosis of WNV infection should be considered in any patient presenting with an unknown febrile illness, meningitis, encephalitis, or acute flaccid paralysis (AFP) in an endemic area with ongoing mosquito activity.

Virology WNV is an RNA virus in the family Flaviviridae (genus Flavivirus). It is an enveloped, icosahedral virus containing a single strand of positive-sense RNA; an 11 kilobase RNA that encodes three structural proteins: capsid (C), envelope (E), and premembrane (prM) protein, and seven non-structural proteins (Campbell et al., 2002, Mukhopadhyay et al., 2003). E protein is the major antigenic determinant, and neutralizing antibodies (IgG and IgM) directed at E protein epitopes confer immunity and are thought to play a major role in postinfection containment and clearance of WNV (Samuel and Diamond, 2006). WNV is antigenically related to several important flaviviruses, including dengue, JEV, SLEV, and YFV, and is further classified into the JEV serogroup with JEV, SLEV, and Murray Valley encephalitis virus. There are two main genetic WNV lineages: one which is widely dispersed globally and causes significant human disease; and a second one, in Africa (Weaver and Reisen, 2010) (Fig. 20.1A).

Pathogenesis In humans, following a bite from an infected mosquito, WNV replicates in the local tissue and lymph nodes, resulting in a primary viremia that disseminates virus to the reticuloendothelial system and other sites (Gyure, 2009). Continued replication results in a secondary viremia that can disseminate virus to the central nervous system (CNS) and other organs. The ability of WNV to invade the CNS (“neuroinvasiveness”) is determined by multiple viral and host factors (Lustig et al., 1999). Proposed routes of WNV CNS entry include penetration of the cerebral microvasculature following infection of endothelial cells or diapedesis of infected leukocytes, penetration of the choroid plexus, and

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axonal transport in olfactory or other neurons (Verma et al., 2009), although a CNS viral receptor has not been identified. Animal studies have shown that host cellular proteins such as matrix metalloproteinase 9 and intracellular adhesion molecule-1 play important roles in the ability of WNV to cross the blood–brain barrier (BBB) (Dai et al., 2008; Wang et al., 2008). Additionally, Toll-like receptor 3 induces production of tumor necrosis factor-a that likely increases BBB permeability facilitating viral CNS entry during viremia (Wang et al., 2004). Once it has penetrated the BBB, WNV can directly infect and cause death of neurons. Several studies have shown that apoptosis is an important mechanism of WNV neuron and CNS injury (Parquet et al., 2001; Michaelis et al., 2007; Samuel et al., 2007). Clearance of WNV from the brain and other organs appears to be primarily antibody-mediated, but CD8 þ cytotoxic T cells directed against peptide determinants derived from WNV proteins also participate (Diamond et al., 2003a; Wang et al., 2003; Shrestha and Diamond, 2004). Polymorphonuclear leukocytes may have a biphasic response to WNV infection, serving as a reservoir for replication and dissemination in early infection and later contributing to viral clearance (Bai et al., 2010).

WEST NILE FEVER Clinical features Eighty percent of WNV infection is asymptomatic. Approximately 20% of infected individuals develop an acute, self-limited, flu-like illness, called West Nile fever (WNF). WNF is by far the most common presentation of clinically significant WNV infection (95%), the remaining 5% of cases representing WNND (meningitis, encephalitis, and AFP). The incubation period ranges from 3 to 14 days but may be longer (up to 17 days) in immunocompromised individuals (Petersen and Marfin, 2002; Iwamoto et al., 2003). WNF is characterized by the abrupt onset of fever (80–90%), headache (55%), fatigue, anorexia, nausea and diarrhea (25–33%), myalgia (50%), and lymphadenopathy. An erythematous, maculopapular rash involving the trunk and limbs, occasionally accompanied by dysesthesia and pruritis, occurs in 25–50% about 5 days after symptoms begin, particularly in younger patients, and lasts about a week (Fig. 20.3) (Watson et al., 2004; Ferguson et al., 2005; Huhn and Dworkin, 2006). Other symptoms reported include eye pain, pharyngitis, and abdominal pain. Generally the symptoms of WNF resolve spontaneously within 3–6 days, although long-term sequelae, including fatigue (lasting up to 2 months), muscle

Fig. 20.3. Four patients with West Nile virus fever and erythematous, maculopapular rashes on the back (A), flank (B), posterior thigh (C), and back (D). (Figure adapted with permission from Ferguson et al., 2005.)

WEST NILE AND ST. LOUIS ENCEPHALITIS VIRUSES weakness, tremor and abnormalities in motor skills and executive functions, and difficulty concentrating, have been reported (Watson et al., 2004; Carson et al., 2006).

WEST NILE NEUROINVASIVE DISEASE Less than 1% of WNV-infected individuals develop WNND, which encompasses the syndromes of meningitis, encephalitis, and AFP/poliomyelitis (Bode et al., 2006; Davis et al., 2006; Debiasi and Tyler, 2006; Kramer et al., 2007). Clinically there is often a large degree of overlap between symptoms among these three entities (Table 20.1) and, while the Centers for Disease Control and Prevention (CDC) do not further Table 20.1 Clinical features seen in West Nile neuroinvasive disease Signs Fever (>38 C)

Symptoms

Generalized non-focal weakness Anorexia Trouble walking Nausea/vomiting Numbness in limb or body Fatigue Tremors Headache Myalgias Trouble concentrating Blurry vision Memory problems Myoclonic jerks Confusion, delirium, Marked sleepiness lethargy Stiff neck or neck pains Less common Chills Focal sensory loss (5–50%) Dizziness Sensitivity to light Imbalance Non-pruritic maculopapular rash Back pains Dysphagia Somnolence Nystagmus Slurred speech Babinski sign Diarrhea Stupor Arthralgias Uncoordinated gait/ ataxia Focal arm or leg Joint pains weakness Paresthesias in limbs Uncommon Seizure/status Paraplegia or (1–4%) epilepticus quadriplegia Lymphadenopathy Urinary/fecal incontinence Pharyngitis Parkinsonism Conjunctivitis Monocular visual loss Coma Diplopia Facial palsy Marked chorioretinitis

Common (>50%)

Reproduced from Davis et al. (2006).

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categorize WNND, it has been estimated that 30–40% of patients with neuroinvasive WNV infection develop meningitis, 50–60% develop encephalitis, and 5–10% develop AFP (Sejvar et al., 2003a, b). Age is the most important risk factor for developing neuroinvasive disease and most cases occur in individuals older than 60. In one study the odds ratio (95% confidence interval) of developing encephalitis was 2.2 (1.6–3.1) in those older than 64 years of age (Jean et al., 2007). It is relatively rare for patients < 30 years old to develop WNND, although >300 cases have been reported in patients 5 cells/mm3) in 97% of patients with WNM and 95% of patients with WNE (Tyler et al., 2006). There is typically a pleocytosis of 10–300 white blood cells (WBC)/mm3 (227 cells/mm3 mean), but the CSF occasionally may lack WBCs early in the first 1–2 days of the encephalitis. In general, lymphocytes predominate, but in one-third of cases neutrophils predominate early in the illness. Neutrophil predominance and persistence are more common with WNV infection than

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Table 20.2 Criteria for clinical and definite diagnosis of West Nile neuroinvasive disease Possible clinical diagnosis of West Nile neuroinvasive disease (before serology results are available) Requirements: 1, 2, 3 (A, B, or C), five with four supportive New onset of: 1. Fever >38 C or subjective fever by patient when temperature never taken 2. Acute systemic symptoms (>1 lasting >48 hours) Headache Nausea or vomiting Myalgias Transient erythematosus maculopapular rash 3. Acute neurologic signs and symptoms (A, B, or C required) A. Altered mental status for >48 hours (>1 below are required) Marked lethargy that often incapacitates the individual Delirium or agitation Marked disorientation or confusion that often incapacitates the individual Profound sleepiness (sleeping all day for >2 days) Stupor or coma B. Brainstem or spinal cord signs that persist >48 hours (>1 below are required) Cranial nerve palsies Myelitis i. New focal weakness in one or more limbs that is not due to arthritis or limb pains lasting >48 hours ii. Respiratory failure requiring intubation that is not solely due to pneumonia iii. Electromyographic evidence of recent denervation in more than one nerve root C. Cerebrospinal fluid (CSF) all required if examined Pleocytosis (rarely may be absent if lumbar puncture performed within first 2 days of central nervous system symptoms) CSF immunoglobulin M (IgM) antibody for West Nile virus (WNV) Negative cultures for bacteria and negative Gram stain (if mycobacterial, fungal, or viral cultures were done they should be negative) 4. Supportive criteria A. Focal neurologic signs of acute onset (1 desired but not required) Hemiparesis Visual field loss or chorioretinitis Hyperactive deep tendon reflexes or Babinski sign Seizure Tremor or myoclonus Bradykinesia, spasticity, or rigidity Photophobia Severe generalized weakness and fatigue that keep patient in bed B. Mosquitoes as vector (1 desired unless patient received transfusion or transplant organ) Positive WNV mosquito pools or infected horses in region within past 3 weeks or Recent cases of acute WNV infection in region or Travel within past 3 weeks to regions with positive WNV mosquito pools or cases of WNV infection 5. Exclusion criteria (required) Underlying dementia, congestive heart failure, or chronic obstructive pulmonary disease that could cause altered mental status and no known other neurologic disease that could cause the neurologic signs Definite or confirmed diagnosis of West Nile neuroinvasive disease Above criteria plus WNV serology/virology (A and B plus/or C or D) A. Demonstration of WNV IgM antibody in serum without vaccination with yellow fever or Japanese B viral vaccines in past 5 years or recent infection with other flavivirus, such as St. Louis encephalitis virus. Note: If WNV has occurred in region in prior years, criterion B is needed because previously infected individuals may have prolonged persistence of IgM in serum B. Fourfold or greater increase in serum WNV IgG or IgM antibody titer between acute and convalescent samples taken 10–28 days apart C. Demonstration of WNV IgM antibody in CSF D. Identification of WNV in CSF by viral culture or of WNV nucleic acid by polymerase chain reaction Reproduced from Davis et al. (2006).

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Fig. 20.4. Schematic of typical time course for development of West Nile virus (WNV) immunoglobulin G (IgG) and IgM antibodies in humans after WNV infection. (Courtesy of CDC’s Arbovirus Disease Branch, Diagnostic and Reference Laboratory, Fort Collins, CO; Davis et al., 2006.)

ganglia, mesial temporal structures, cerebellum, and brainstem, and, less commonly, deep white matter (Ali et al., 2005; Petropoulou et al., 2005) (Fig. 20.5). One study suggests that patients with no MRI abnormalities or abnormalities only on diffusion-weighted images, compared to abnormalities on T2-weighted or nonenhanced fluid attenuated inversion recovery (FLAIR) images, have the best prognosis (Ali et al., 2005). In contrast, computed tomography is almost always normal in patients with WNND (Nash et al., 2001; Jeha et al., 2003; Sejvar et al., 2003a). Patients with AFP can have enhancing spinal lesions, especially in the conus medullaris and spinal nerve roots, although normal studies are frequently noted (Sejvar et al., 2003b; Ali et al., 2005; Petropoulou et al., 2005). MRI of the spinal cord may show increased signal in the anterior horns on T2 and FLAIR sequences (Ali et al., 2005; Petropoulou et al., 2005).

EEG and EMG in other arbovirus neuroinvasive disease (Tyler et al., 2006). CSF glucose is almost always normal. Opening pressure and protein are normal or elevated. Oligoclonal bands are rare in CSF obtained at onset of illness but may be seen in convalescent specimens (Tyler et al., 2006). Patients with WNF do not have viral neuroinvasion, and thus have normal CSF studies.

Chemistry and Hematology Patients with WNV infection generally have a normal complete blood count or mild leukocytosis (Davis et al., 2008). Thrombocytopenia occurs in 15% of cases (Chowers et al., 2001) and prolonged lymphocytopenia has been reported (Cunha et al., 2000). One study reported a modestly higher leukocytosis in patients with meningitis than either encephalitis or AFP (Sejvar et al., 2003a). Hyponatremia is seen in 33–50% of WNND patients, and liver function test abnormalities occur in up to 24% of patients (Chowers et al., 2001; Weiss et al., 2001). Additionally, elevated creatine kinase and lipase have been reported (Jeha et al., 2003; Batuello et al., 2005).

Imaging Neuroimaging, particularly magnetic resonance imaging (MRI), may be helpful in the diagnosis of neuroinvasive WNV infection. However, in contrast to herpes simplex virus encephalitis, MRI is abnormal in only 20–70% of WNND cases, with the frequency depending on the timing of the studies and the imaging sequences used (Sejvar et al., 2003a; Ali et al., 2005; Petropoulou et al., 2005). When present, MRI abnormalities are non-specific but typically involve the thalami, basal

Seizure occurs in a small (10%) proportion of WNND cases, likely reflecting viral predilection for deep rather than cortical structures (Nash et al., 2001; Jeha et al., 2003; Sejvar et al., 2003a; Brilla et al., 2004). Nevertheless, abnormal EEG findings have been reported in up to 86% of patients in some series. Generalized slowing with anterior more than temporal predominance has been seen most frequently (Gandelman-Marton et al., 2003, Sejvar et al., 2003a). Patients with WNV-associated poliomyelitis/AFP often have abnormal EMG (Leis et al., 2003; Li et al., 2003; Al-Shekhlee and Katirji, 2004). Electric studies obtained acutely show reduction in amplitude or absence of compound muscle action potentials with relatively preserved sensory nerve action potentials. EMG studies obtained 2–3 weeks after onset show characteristic features of denervation, including increased insertional activity and fasciculations. In contrast to Guillain–Barre´ there is no evidence of significant demyelination (slowed conduction velocities, conduction block).

Treatment There is no specific therapy of proven benefit for WNV infection. Supportive care, often including intensive care unit observation and mechanical ventilation in severe neuroinvasive WNV infection, is the standard. Nevertheless, multiple treatment modalities have been investigated. Passive immunization with WNV-specific antibody has shown promise in vitro and in animal models, but clinical results are less clear (Diamond et al., 2003a, b). Isolated case reports and small series describe benefit as well as lack of effect from intravenous immune globulin (IVIG) containing high-titer

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Fig. 20.5. Magnetic resonance images of West Nile encephalitis. (A) Diffusion-weighted image showing increased signal intensity in bilateral posterior limbs of internal capsule. (B) Fluid attenuated inversion recovery (FLAIR) image corresponding to A, notably without abnormality. (C) FLAIR image showing abnormal signal intensity in bilateral cerebellum and left occipital lobe. (D) T2WI image showing increased signal intensity in bilateral thalami. (Reproduced with permission from Tyler, 2004; Ali et al., 2005; Petropoulou et al., 2005.

anti-WNV antibodies (Shimoni et al., 2001; Hamdan et al., 2002; Haley et al., 2003; Saquib et al., 2008; Ben-Nathan et al., 2009). A randomized, controlled multicenter trial of high-titer anti-WNV IVIG preparation (Omr-IgG-am) was recently conducted by the Collaborative Antiviral Studies Group (NCT00069316), but results are not available at this time. Phase II trials evaluating the safety and efficacy of a humanized monoclonal antibody (MGAWN1) directed against an epitope on the WNV envelope glycoprotein (NCT00515385). Isolated reports of use of corticosteroids in patients with WNV AFP and brainstem disease do not permit any conclusions about efficacy (Pyrgos and Younus, 2004). Ribavirin is a broad-spectrum antiviral that has activity against multiple viruses, including some RNA viruses. Its clinical efficacy in WNV infection

is unproven, with one uncontrolled study even showing a higher than expected mortality rate in treatment compared to untreated individuals (Chowers et al., 2001). Interferon-a plays an important role in innate immune defense against viral infection. Further, it has activity against WNV in vitro (in addition to hepatitis C and JEV) (Anderson and Rahal, 2002). Its use in the treatment of hepatitis C virus infection is well documented, but its efficacy is unknown in WNV infection. A limited number of published cases using interferona to treat human WNE show both benefit and lack of efficacy (Sayao et al., 2004; Kalil et al., 2005; Lewis and Amsden, 2007). A small, unblinded, preliminary trial of interferon-a use in patients with St. Louis encephalitis virus, a flavivirus related to WNV, showed

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some benefit (Rahal et al., 2004). However, in Vietnam, a double-blinded, randomized placebo-controlled trial involving over 1000 patients failed to show any significant benefit of interferon-a use in the treatment of Japanese encephalitis (Solomon et al., 2003). Several other antiviral strategies for treatment of WNV infection are in various stages of research and development, and clinical trials including small inhibitory RNA, antisense oligomers and peptides (Bai et al., 2005, 2007; Deas et al., 2007; Diamond, 2009). However, all are likely years away from clinical use. Development of a human WNV vaccine continues to be at the forefront of prevention. Other flavivirus vaccines already exist, including effective vaccines to the closely related JEV and YFV. At least four equine WNV vaccines have been licensed already in the United States but no human vaccine has yet obtained licensure. ChimeriVax-WN02 is a novel live-attenuated WNV vaccine that has recently finished phase II clinical trials with promising results (Monath et al., 2006; Biedenbender et al., 2011; Smith et al., 2011). Despite the expected poor cost-effectiveness of large-scale WNV vaccination, and asymptomatic nature of most infections, there are likely populations, the elderly and immunocompromised for example, that would benefit greatly from vaccination. Currently, the best WNV prevention strategies include mosquito population control, insect repellent use, and avoidance of exposure to mosquitoes.

Prognosis There are no significant long-term sequelae in the vast majority of WNV infections. Indeed, 80% of infections are completely asymptomatic during both acute and convalescent stages. For those with clinical disease, however, significant morbidity and mortality can occur. Mortality from WNND is approximately 12–30%, and occurs almost exclusively in the subsets of patients with severe encephalitis or severe AFP. While age is clearly a risk factor for contracting neuroinvasive WNV infection, the risk factors associated with poor outcome are less clearly defined. In a retrospective chart review of more than 100 WNE cases the major predictors of progression from encephalitis to death were lack of CSF pleocytosis, renal insufficiency, need for intubation and mechanical ventilation, loss of consciousness, and presence of myoclonus and tremors (Murray et al., 2008). Another study found the need for vasopressor support, history of solid-organ cancer, hypertension, previous stroke, or immunosuppression to be important risk factors for poor outcome after WNE (Bode et al., 2006). The overall mortality for severe WNND has consistently been around 12–30%.

The frequency and severity of sequelae from WNV infection are still not well understood (Klee et al., 2004). Forty percent of patients with movement disorders such as myoclonus, parkinsonism, or tremors have residual symptoms 6 months after the acute infection, and 20% have ongoing symptoms at 18 months of follow-up (Sejvar, 2007). Further, 50% of WNE survivors report cognitive problems, decreased motor speed, and diminished dexterity 3 months after the initial infection (Sejvar, 2007). Surprisingly, one study that compared long-term outcome in hospitalized patients (WNF and WNND) to that in non-hospitalized patients (non-WNND) found the severity of disease did not correlate to a patient’s risk of long-term “adverse outcomes.” Indeed, complaints of memory problems, extremity weakness, word-finding difficulty, and headache were similar in both groups and nearly half of all patients reported fatigue, and 20% new tremor. More recent data suggest long-term sequelae are common as well. In one previous study of 214 persons infected with WNV  6 months, 53% reported one or more persistent symptoms, including fatigue, muscle aches, decreased activity, difficulty with memory, and difficulty concentrating. Persons with neuroinvasive disease, hypertension or diabetes were significantly more likely to report persistent symptoms, whereas age, sex, and time since infection were not associated with persistent symptoms (Cook et al., 2010). Another recent study found that physical and mental function, as well as mood and fatigue, seemed to return to normal within 1 year of symptom onset for those with either WNF or WNND. Further, although patients with neuroinvasive disease took slightly longer to recover, there was no difference between patients diagnosed with WNM and WNE. Lack of pre-existing comorbid conditions was associated with faster recovery of physical function, whereas lack of comorbid conditions and male sex were associated with faster recovery of mental function (Loeb et al., 2008).

ST. LOUIS ENCEPHALITIS SLEV has been an important cause of arboviral encephalitis in the United States since the 1930s and was the most important neuroinvasive flavivirus in North America until the emergence of WNV (Davis et al., 2008). St. Louis encephalitis was first recognized as a human disease after an outbreak of encephalitis in Paris, Illinois, in 1932. The following year SLEV was isolated from human brain tissue after a similar but larger outbreak involving more than 1000 cases in St. Louis, Missouri and its surrounding counties (Muckenfuss, 1934). SLEV belongs to the Japanese encephalitis serocomplex and is closely related to WNV. It is found in a broad range from Canada and the United States to Central

WEST NILE AND ST. LOUIS ENCEPHALITIS VIRUSES and South America. SLEV incidence in the United States has decreased threefold since the introduction of WNV to the United States in 1999 (Reimann et al., 2008). Indeed, WNV appears to have displaced SLEV in many areas, although both viruses coexist in others (Reimann et al., 2008; Ciota et al., 2011). Transmission to humans in the western United States is primarily via Culex tarsalis, whereas in the eastern United States it is through Culex pipiens, C. quinquefasciatus, and C. nigripalpus. The incidence rates for SLEV encephalitis in the United States range from 0.003 to 0.752 per 100 000 (Monath et al., 2002). From 1964 through 2008, an average of 108 cases were reported annually (range 2–1967) (http://www. cdc.gov/sle/technical/epi.html) (Fig. 20.6). In 1975, the largest outbreak recorded in the United States involved 2800 cases in 31 states. In 2010, eight cases of SLEV were reported to the CDC, mainly located in the lower Mississippi river basin (http://diseasemaps.usgs.gov/ sle_us_human.html). Following the bite of an infected mosquito, an incubation period of 4–21 days precedes the onset of clinical symptoms. In adults, symptomatic infection occurs in 1 of 300 individuals exposed to virus (Davis et al., 2008). These patients develop a flu-like illness characterized by fever, myalgias, and headaches as well as other nonspecific symptoms, including nausea, vomiting, cough, and sore throat. In patients below the age of 20 years, 40% develop meningitis and 50% develop encephalitis (Brinker and Monath, 1980). In patients over the age of

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60 years, over 90% develop encephalitis. Common manifestations of SLEV encephalitis include reduced level of consciousness with lethargy, coma, tremors, myoclonic jerks, opsoclonus, nystagmus, and ataxia. Mortality of SLEV infections ranges from 4% to 27%, seizures develop in 47% of patients, and AFP has been associated with 6% of encephalitis cases (Southern et al., 1969; Brinker and Monath, 1980; Wasay et al., 2000). MRI is often normal but may show high T2 signal intensity of the substantia nigra, thalamus, and basal ganglia. In a case series of 11 patients, CSF studies revealed a lymphocytic pleocytosis in all patients (mean 107 cells/ mm3, range 5–446), elevated protein (mean 67 mg/dL) in 7 patients, and normal CSF glucose (Wasay et al., 2000). EEG is almost invariably abnormal, with the most common finding being generalized slowing. Severely affected patients may have seizures or periodic lateralized epileptiform discharges. General laboratory studies can reveal a peripheral leukocytosis, hyponatremia, mild transaminitis, and sterile pyuria (Southern et al., 1969). Diagnosis is based on demonstration of anti-SLEV IgM antibodies in the serum or CSF (Monath et al., 1984). A fourfold increase in neutralizing antibody titers in the serum during the acute and convalescent phases of disease can also be used to establish a diagnosis. There is no therapy for SLEV encephalitis of proven efficacy, although therapy with interferon-2a may be considered (C-III) (Tunkel et al., 2008). An open-label, nonrandomized study of interferon-a2b suggested that therapy improved outcome (Rahal et al., 2004).

Fig. 20.6. Cumulative cases of St. Louis encephalitis virus neuroinvasive disease in the United States since 1964, reported by state of residence. (Courtesy of http://www.cdc.gov/sle/resources/SLEmap.pdf.)

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