Murray Valley Encephalitis Virus

Introduction

Murray Valley encephalitis virus (MVEV) is one of several mosquito-borne flaviviruses of the Japanese encephalitis virus complex that causes severe disease in humans. It is restricted to a small region of Oceania and, with the exception of travel-related cases, has been exclusively reported in Australia and Papua New Guinea. It is endemic in tropical portions of the Northern Territory and Kimberley region of Western Australia, found periodically in Central Australia and occasionally in southeastern regions of the continent. Kunjin virus is another mosquito-borne encephalitic flavivirus found in Australia and is a subset of West Nile virus (WNV). WNV and Kunjin virus are the subject of separate chapters.

Although relatively rarely reported, Murray Valley encephalitis (MVE) has a high mortality rate and almost half of the survivors have long-term or permanent neurological disease. Disease occurs primarily during times of mosquito activity during the wet season (December–June), especially in years with above-average amounts of rainfall or flooding.

Given the remoteness of some of the areas in which MVE is found and its presence among Aboriginal populations, disease incidence is most likely underreported. MVE may also be misdiagnosed as infection with Kunjin virus. Due to its high morbidity and mortality rates and its propensity to cause outbreaks, MVEV is a potential threat to not only Australia and Papua New Guinea, but also other, surrounding regions of Oceania. Fortunately, infections in sentinel chickens often are detected prior to human cases and may provide important warning of impending outbreaks, especially if these affected regions experience increased rainfall. These factors suggest that MVEV is an excellent candidate for study by the One Health Initiative.

History

During the summers of 1917–18, 1922, and 1950–51, outbreaks of severe, highly lethal encephalitis were reported in eastern Australia. The first case of this disease, originally named Australian X disease, was reported in October 1916 in New South Wales. Over the next 17 months, 184 additional cases were reported, most of which were from the Murray Valley region or in Queensland. During the 1922 outbreak, at least 75 cases were reported throughout Queensland. Fatality rates for these epidemics averaged 68% and were most frequent in children under the age of 15 years. Infections in males were more common than in females. Another major epidemic of 45 encephalitis cases occurred in the Murray Valley region during the summers of 1950–51 with similar characteristics. This disease was subsequently named Murray Valley encephalitis and is believed to be identical to Australian X encephalitis.

MVEV was first isolated during the 1951 epidemic in southeast Australia. Previously, MVE cases were present in large outbreaks in eastern Australia. The disease was first reported in Papua New Guinea in 1956. The next major epidemic of 58 cases occurred in 1974, with early cases widely scattered along the Murray Valley. This outbreak was preceded by the detection of antibodies against MVEV in domestic fowl in the beginning of February 1974, prior to the first human case being reported in Queensland. Antibodies to MVEV in sentinel chickens were also found prior to human cases in a 1993 outbreak, suggesting the potential usefulness of sentinel chickens to warn about potential outbreaks in both endemic and nonendemic regions, and appear to have a greater predictive value in rural than in urban areas. Since 1974, most symptomatic human infections moved across the continent and are being reported in Western Australia, primarily as outbreaks after heavy rainfall events, notably in 2011. The correlation between heavy rainfall or flooding and the seroconversion of sentinel chickens may be the most useful predictive model of subsequent human infections in a region; however, this model is not absolute. Another factor that may play an important role in human infections by MVEV is the ability of virus to survive the dry season, due to the desiccation-resistance of Aedes mosquito species eggs. While Culex species remain the major MVEV vectors, several Aedes species serve as MVEV vectors.

MVEV and the Kunjin type of WNV underwent a 26-year absence from Central Australia between 1976 and March and April of 2000, when five laboratory- confirmed cases of flavivirus-associated encephalitis were reported in Aboriginal populations from remote communities in the normally dry inland region near Alice Springs, the largest township in Central Australia and a major tourist center. This was preceded or accompanied by seroconversion of sentinel chickens in northern Western Australia in early January, in the Northern Territory in late February, in Tennant Creek in early March, and in Alice Springs in late March. The appearance of these cases followed unusually high amounts of rainfall from a tropical cyclone. These conditions led to a sharp rise in the numbers of the common banded mosquito ( Culex annulirostris ), another MVEV vector, at multiple rural sites in Central Australia, beginning in January 2000 and remaining high to very high until early April. More MVE cases were reported during the following wet season in both Aboriginals and Caucasians in the urban Alice Springs. Interestingly, most of the Aboriginal cases were among children. The low incidence of disease in Aboriginal adults may result from high infection rates during childhood, rendering the adults resistant to WNV infection. After the year 2000, disease incidence has shifted more toward non-Aboriginal populations, perhaps due to increased mining, agriculture, and tourism in northern Australia.

In 2011, after record high levels of rainfall, MVEV activity was present in all mainland states of Australia and caused 17 human encephalitis and numerous equine disease cases. In the 2011 epidemic, unlike earlier outbreaks, the majority of cases were non-Aboriginal adults. This may be indicative of a change in the demographics of MVE cases and suggests a risk of the virus expanding its range to include the heavily populated areas of southeastern Australia.

The first reported case of MVE in Europe was in a young German male who had visited the Northern Territory of Australia prior to his return to Europe in May of 2001. Despite severe illness, he fully recovered after 2 months. The 2011 epidemic in Australia caused at least one travel-associated case, in a healthy 19-year-old Canadian woman who visited, among other places, Darwin, in the tropical region of Top End in the Northern Territory, and Alice Springs in Central Australia. Upon her return to Canada, she was drowsy, confused, and febrile. Despite administration of high-dose intravenous ceftriaxone, vancomycin, and acyclovir, she continued to experience progressive neurological deterioration. Despite the absence of MVEV in cultures of blood, urine, cerebrospinal fluid (CSF), and respiratory secretions, her condition continued to decline and she became deeply comatose with progressively worsening seizures that were refractory to treatment prior to her death. Upon autopsy, she was found to have had lymphocytic myocarditis, pulmonary edema, and acute tubular necrosis of the kidney as well as congestion of the liver and spleen. These two travel- related cases demonstrate the possibility of acquiring severe or fatal MVE when visiting endemic areas of Australia, even though both patients were young and previously healthy. It is imperative, therefore, to include recent travel in the diagnosis of patients with encephalitis. It should also be noted that travel-related infections may be much more common than realized, since MVEV infections are typically asymptomatic, as discussed below.

The Diseases

Human infections with MVEV are usually asymptomatic, with only a small number of those infected developing clinical disease, including fever with headache, irritability, seizures, altered state of consciousness, or encephalitis. The latter is associated with high mortality and morbidity. Outcomes have included cognitive impairment, hypotonia, and quadriplegia. The CSF often contains proteins, as well as neutrophils and monocytes. Other symptoms of infection include respiratory failure resulting from brain stem involvement and respiratory muscle paralysis, requiring supportive ventilation. Seizures are the predominant manifestations in children, while adults usually present with more typical encephalitic symptoms. Cranial nerve palsies, especially those involving the seventh nerve, are found in 50% of cases. Movement disorders are significant in 40% of patients and include choreiform movements, Parkinsonism and other tremors, as well as flaccid paralysis. Necrosis of white matter, the thalamus, and the cerebellar cortex can occur later in the course of the disease.

Only 0.1%–0.2% of MVEV infections result in encephalitis; however, approximately 20% of those cases are fatal and permanent neurological sequelae are seen in about half of the survivors. Encephalitis is reported primarily among Aboriginal children, tourists, and newcomers to the region. Disease clusters have been present sporadically in Australia for the past 100 years. These outbreaks are reported every few years and are seasonal, occurring during or following the wet season of February to May. Approximately one-third of MVE patients completely recover. Fatalities are most common in infants less than 2 years of age and those over the age of 60.

In the CNS, MVEV only infects neurons and has not been found in glial cells, the ependyma, the choroid plexus, or meninges. Microscopic analysis of the brains of MVEV-infected mice reveals necrosis in the olfactory bulb and hippocampus neurons by 5 days postinfection, proliferation of the endoplasmic reticulum (ER) and Golgi apparatus membranes, and abnormal membrane-bound tubular and spherical vesicles structures in the ER cisternae similar to those present in other flaviviruses. After 7–8 days, apoptotic neurons are seen, particularly in the hippocampus and, late in the course of infection, apoptotic immune cells are also prominent. Mortality rate in these infected mice correlates with the presence of inflammatory cells, especially neutrophils, but also includes some lymphocytes and macrophages.

In a 2007–2011 study of nine encephalitis patients with altered mental state and seizures, tremor, weakness, or paralysis, all of the patients had elevated levels of C-reactive protein in the blood and most patients developed peripheral neutrophilia and thrombocytosis, as well as acute liver injury with raised ALT and creatine kinase levels. Bilateral cerebral peduncle involvement was also detected by early magnetic resonance imaging (MRI); however, only one patient had an abnormal CT scan early during the illness. T1-weighted MRIs reveal bilateral, symmetrical, thalamic hypointensity with prominence of the ventricles. Thalamic hyperintensity may also be seen with involvement of the red nucleus, substantia nigra, and cervical cord; however, T2-weighted MRIs of patients with MVE are similar to those present during infection with JEV, while other related flaviviruses have a lower propensity to involve the thalamus. Patients without MRI hyperintensity during acute illness had better neurological outcomes, whether or not they had leptomeningeal enhancement. In contrast, patients with widespread abnormalities involving the thalamus, midbrain, and cerebral cortex or cerebellum typically had severe neurological outcomes. Of note: in a 2005 case report, a man living in the Northwest Territory who had recently camped in northeastern Kimberley presented with symptoms clinically and radiologically characteristic of herpes simplex encephalitis, with MRI temporal lobe changes indicative of herpes infection, rather than MVEV. Serological findings demonstrated the presence of anti- MVEV IgM, however, as well as a hemagglutination inhibition antibody titer of 1:1280.

In a 2016 report of 39 survivors of MVEV infection, the long-term sequelae include paralysis or paresis in nine patients, which was more common and severe in those under the age of 5 years, requiring lengthy hospitalization. This differs from WNV encephalitis in which children typically have less severe disease. Two of these patients died due to complications of quadriplegia. Two patients who were discharged with neurological sequelae required no further hospitalizations but reported ongoing cognitive dysfunction and inability to work. This is similar to findings in long-term survivors of WNV infection, who also report cognitive dysfunction, memory loss, and poor physical health lasting up to 8 years, especially in those people initially presenting with neuroinvasive disease.

Inborn resistance to flaviviruses in wild mice and in some laboratory strains of mice is conferred by the chromosome 5 locus flv , while some susceptible mouse strains have a nonsense mutation in this gene. Strains of MVE-susceptible mice harbor a high viral RNA load in their brains. Viral load was reduced in the cortex, olfactory bulb, thalamus, and hypothalamus of congenic resistant mice with an active flv gene. Low amounts of MVEV RNA from resistant mice carrying the flv gene were confined to the cerebral cortex, thalamus, and olfactory tuberculum. No viral RNA was detected in the hippocampus, pons, medulla oblongata, or cerebellum of resistant mice. The brains of resistance mice also had only mild inflammation, with lower numbers of inflammatory cells, and lower induction of the IFN I/II and TNF-α genes than in mice lacking functional flv.

The Virus