Activation of the innate signaling molecule MAVS by bunyavirus infection upregulates the adaptor protein SARM1, leading to neuronal death.

La Crosse virus (LACV), a zoonotic Bunyavirus, is a major cause of pediatric viral encephalitis in the United States. A hallmark of neurological diseases caused by LACV and other encephalitic viruses is the induction of neuronal cell death. Innate immune responses have been implicated in neuronal damage, but no mechanism has been elucidated. By using in vitro studies in primary neurons and in vivo studies in mice, we have shown that LACV infection induced the RNA helicase, RIG-I, and mitochondrial antiviral signaling protein (MAVS) signaling pathway, resulting in upregulation of the sterile alpha and TIR-containing motif 1 (SARM1), an adaptor molecule that we found to be directly involved in neuronal damage. SARM1-mediated cell death was associated with induced oxidative stress response and mitochondrial damage. These studies provide an innate-immune signaling mechanism for virus-induced neuronal death and reveal potential targets for development of therapeutics to treat encephalitic viral infections.

Human Jamestown canyon virus infection --- Montana, 2009.

Jamestown Canyon virus (JCV) is a mosquito-borne zoonotic pathogen belonging to the California serogroup of bunyaviruses. Although JCV is widely distributed throughout temperate North America, reports of human JCV infection in the United States are rare. This is the first report of human JCV infection detected in Montana, one of only 15 cases reported in the United States since 2004, when JCV became reportable. On May 26, 2009, a man aged 51 years with no travel history outside of Montana went to a local emergency department immediately following onset of fever, severe frontal headache, dizziness, left-sided numbness, and tingling. His blood pressure was elevated. Stroke was ruled out, oxygen was administered, medication was prescribed for hypertension, and the patient was sent home. One week later, the patient visited his primary-care physician complaining of continued neurologic symptoms consistent with acute febrile encephalitis and recent mosquito bites. Although West Nile virus (WNV) disease was diagnosed based on detection of WNV-immunoglobulin M (IgM) and G (IgG) antibodies, subsequent testing indicated that the WNV antibodies were from a past infection and that his illness was caused by JCV. The final diagnosis of JCV infection was based on positive JCV-specific IgM enzyme-linked immunosorbent assay (ELISA) results and a fourfold rise in paired sample JCV plaque reduction neutralization test (PRNT) titers. This finding represents a previously unrecognized risk for JCV infection in Montana; clinicians should consider JCV infection when assessing patients for suspected arboviral infections.

Periodic lateralized epileptiform discharges in La Crosse encephalitis, a worrisome subgroup: clinical presentation, electroencephalogram (EEG) patterns, and long-term neurologic outcome.

La Crosse virus encephalitis is the most common mosquito-borne virus in children in the United States. La Crosse virus encephalitis has emerged as a significant health concern due to its potential for acute morbidity, including seizures, alterations in mental status, and, in rare cases, death, as well as the potential for chronic morbidity, including, epilepsy and cognitive and behavioral disorders. The aim of this study is to provide a clinical description of the largest series of children reported with periodic lateralizing epileptiform discharges (PLEDS) associated with La Cross virus encephalitis with reference to their clinical course, seizure type, electroencephalogram (EEG) patterns, and 2- and 10-year long-term neurologic outcome. In addition, to evaluate whether this subset of children may indeed have more severe disease than children with La Crosse virus encephalitis without PLEDS, comparisons are made between the 2 groups on specific variables. All patients presented with fever and disorientation; 6 of the 9 (66%) presented with seizures. PLEDS localized to the temporal lobe in 7 patients (77%). The children with PLEDS had longer intensive care unit stays (6.5 +/- 2.4 vs 3.2 +/- 1.9; P < .0001), a higher rate of intubation (88% vs 20%; P < .001), and a higher rate of cerebral herniation (1%; P < .05) than children with La Crosse virus encephalitis without PLEDS. Follow-up data on the subset with PLEDS also suggest a relatively high rate of epilepsy and behavioral difficulties with hyperactivity symptoms, memory deficits, and school difficulties. The implications for recognition, management, and follow-up of this worrisome subset of patients with La Crosse virus encephalitis are discussed.

Clinical comparisons of La Crosse encephalitis and enteroviral central nervous system infections in a pediatric population: 2001 surveillance in East Tennessee.

BACKGROUND: La Crosse encephalitis (LAC) is a mosquito-borne illness that primarily affects children. In 1997, an initial cluster of cases was identified by the regional pediatric referral center in East Tennessee. Since that time, public health officials, pediatric infectious disease physicians, infection control nurses, laboratory personnel, entomologists, and Centers for Disease Control and Prevention consultants have collaborated to provide ongoing surveillance activities. Studies comparing LAC cases with non-LAC (no etiologic diagnosis) central nervous system infections have yielded no statistical significance in signs and symptoms or laboratory values. OBJECTIVE: To determine any differences in signs, symptoms, and/or diagnostic laboratory values between LAC cases and enteroviral central nervous system (EV-CNS) infections. METHODS: In 2001, descriptive public health surveillance for LAC was performed concurrent with an outbreak investigation of EV-CNS infections at a pediatric referral center in East Tennessee. All patients being evaluated for suspected meningitis and/or encephalitis were interviewed for signs and symptoms of illness. Patients with positive test results for LAC and negative results for EV or positive results for EV and negative results for LAC were included in the study. RESULTS: Compared with patients with EV-CNS infection, patients with LAC were significantly more likely to have aphasia (P=.001), loss of consciousness (P=.0003), seizure (P=.0003), and admission to the pediatric intensive care unit (P=.02). Presence of fever, headache, vomiting, stiff neck (subjective), photophobia, behavioral changes, confusion, need for mechanical ventilation, age, and sex showed no statistical significance (P>.05). Statistical differences were not demonstrated in cerebrospinal fluid laboratory values (P>.05). CONCLUSION: Patients with LAC demonstrated more severe symptoms on presentation to the hospital than did patients with EV-CNS infection. A possible advantage of identifying specific viral etiologic factors of pediatric CNS disease by clinical characteristics may be the ability to take advantage of emerging antiviral therapies.

La Crosse encephalitis in children.

BACKGROUND: La Crosse encephalitis is a mosquito-borne disease that can be mistaken for herpes simplex encephalitis. It has been reported in 28 states but may be underrecognized. METHODS: We investigated the manifestations and clinical course of La Crosse encephalitis in 127 patients hospitalized from 1987 through 1996. The diagnosis was established by serologic testing for IgM and IgG antibodies to La Crosse virus. Data were collected by chart review. RESULTS: Most of the patients were school-aged children (mean [+/-SD] age, 7.8+/-3.5 years; range, 0.5 to 15.0). Symptoms included headache, fever, and vomiting (each in 70 percent or more of the patients), seizures (in 46 percent), and disorientation (in 42 percent). Thirteen percent had aseptic meningitis. Hyponatremia developed in 21 percent, and there were signs of increased intracranial pressure in 13 percent. Six patients, including three with cerebral herniation, underwent intracranial-pressure monitoring. The 13 patients (11 percent) whose condition deteriorated in the hospital had decreases in serum sodium levels (P=0.007), and increases in body temperature (P=0.003) at the time of deterioration. At admission, these patients more often had a history of vomiting (P=0.047) and a score of 12 or lower on the Glasgow Coma Scale (P=0.02) than the others; a trend toward a greater prevalence of seizures at admission was also evident in this group (P=0.07). All the patients survived, but 15 of them (12 percent) had neurologic deficits at discharge. Follow-up assessments, performed in 28 children, suggested an increase in cognitive and behavioral deficits 10 to 18 months after the episode of encephalitis. CONCLUSIONS: La Crosse virus infection should be considered in children who present with aseptic meningitis or encephalitis. Hyponatremia and increasing body temperature may be related to clinical deterioration.

Severe La Crosse encephalitis with significant neurologic sequelae.

La Crosse encephalitis, a member of the California arbovirus group, is the most common cause of reported mosquito-borne illness in the United States. Approximately 70 cases of La Crosse encephalitis are reported each year. The principal vector is the mosquito Aedes triseriatus. During the summer the virus is amplified horizontally in a cycle among small mammals such as chipmunks and squirrels. Infected female A. triseriatus deposit eggs in the basal holes of hardwood trees, although man-made containers and old tires containing water also supply a suitable breeding site. Some of these eggs infected with La Crosse virus hatch the next spring and give rise to infected adult A. triseriatus, and the host-vector cycle is renewed. Only a minority of children infected with the virus become ill. Clinical disease caused by La Crosse is usually mild, and neurologic sequelae are relatively uncommon. In this report we describe six patients with severe La Crosse meningoencephalitis diagnosed within a 4-week period. All patients required intensive care management, and there was a high rate of neurologic sequelae, suggesting that La Crosse is not necessarily a benign meningoencephalitis.

Ovine fetal malformations induced by in utero inoculation with Main Drain, San Angelo, and LaCrosse viruses.

The teratogenic potential of three bunyaviruses, two California serogroup bunyaviruses, LaCrosse virus and San Angelo virus, and a Bunyamwera serogroup member, Main Drain virus, in sheep was studied following in utero inoculation of ewes in early gestation. Although Main Drain virus appeared to be most teratogenic, all three viruses induced a range of lesions including arthrogryposis, hydrocephalus, fetal death, axial skeletal deviations, anasarca, and oligohydramnios. The teratogenic effects of these viruses are identical to those described in ovine infections by Cache Valley and Akabane viruses. Demonstration of a common bunyaviral tropism for fetal tissue infection that results in congenital brain and musculoskeletal malformations provides evidence that human in utero infection by bunyaviruses could result in similar malformations in human infants.

Infarction of basal ganglia associated with California encephalitis virus.

A child developed acute hemiparesis due to infarction of basal ganglia and internal capsule. Pleocytosis of cerebrospinal fluid and elevated immunoglobulin M antibodies suggest that California encephalitis virus infection caused the stroke.

Clinical aspects of La Crosse encephalitis: neurological and psychological sequelae.

Only rarely will a child continue to have focal neurologic findings, such as paresis, for as long as 8 years after LAC encephalitis. Most of the other focal neurologic findings, such as Babinski reflexes, pathologic reflexes, aphasias, choreas, dysarthrias and ataxias, resolve completely. Abnormal electroencephalographic findings during the acute period were note in 86-100% of the cases. On 1-8 year follow-up, EEG abnormalities were noted in approximately 33% of the subjects tested. Seizures are present at high frequency during acute illness and recurrent seizures may occur in 6-13% of the cases 1-8 years after infection. The cognitive and intellectual functioning of children following LAC encephalitis is not significantly different from that of the normal population. As a group, LAC encephalitis victims also function in the normal range in terms of their academic performances. There are individuals, however, who will have suffered permanent destructive lesions resulting in lowered IQ and lowered school performance. Behavioral abnormalities are difficult to measure and when present, difficult to ascribe to a definitive cause.

Relationship of California group virus infection and mental retardation: seroepidemiological observations.

A plaque reduction neutralisation test was utilised to determine the prevalence of antibodies to California group virus (LaCrosse subtype) among 612 moderately to profoundly retarded subjects resident in two Wisconsin state institutions. Neutralising antibodies were detected in the sera of fifty-one (8 per cent) of the subjects tested. Age and sex differences in antibody distribution were not significant. When sero-logical data correlated with clinical case history records, antibody was found in the sera of 13 per cent (24/188) of a group in which mental retardation (MR) was attributed to "presumed psychological causes" and in 8 per cent (12/158) of a group for which the aetiology of MR was "encephalopathy". In a group of 254 subjects with MR of unknown aetiology, none of the sixty subjects with cranial anomaly and only two of the ninety-five (2.1 per cent) subjects with Down's syndrome were positive for antibody to CEV, while thirteen of ninety-nine (13.1 per cent) subjects diagnosed as "other cerebral defects" had CEV antibody. In a majority of the subjects with CEV neutralising antibody, MR was attributed to perinatal influences.