Arthropod-borne encephalitis: an overview for the clinician and emerging considerations

Abstract

The rapid spread of arboviral infections in recent years has continually established arthropod-borne encephalitis to be a pressing global health concern. Causing a wide range of clinical presentations ranging from asymptomatic infection to fulminant neurological disease, the hallmark features of arboviral infection are important to clinically recognise. Arboviral infections may cause severe neurological presentations such as meningoencephalitis, epilepsy, acute flaccid paralysis and stroke. While the pathogenesis of arboviral infections is still being investigated, shared neuroanatomical pathways among these viruses may give insight into future therapeutic targets. The shifting infection transmission patterns and evolving distribution of arboviral vectors are heavily influenced by global climate change and human environmental disruption, therefore it is of utmost importance to consider this potential aetiology when assessing patients with encephalitic presentations.

Introduction

Arthropods are a diverse group of invertebrate animals that are characterised by hallmark features such as a chitin exoskeleton, segmented body with bilateral symmetry, jointed appendages with specialised functions and open circulatory system [1]. Several prominent infections are transmitted to vertebrate hosts from bites from arthropod organisms such as mosquitoes, ticks and sandflies, [2] and may cause a variety of systematic manifestations. The global impact of arboviral infections is significant, with dramatic re-emergence and extended geographic spread of epidemic arboviral diseases over the past 50 years [3, 4]. Several arboviral infections invade the nervous system and can cause life-threatening complications including meningitis and encephalitis. In this review, we discuss significant pathogens and clinical considerations for arthropod-borne encephalitis, and explore emerging threats associated with these potentially fatal diseases.

Learning objectives

• To review current understanding of pathogenesis and virulence factors associated with neurological arboviral infections.

• To understand the current clinical approaches to diagnosis, treatment and prevention of arboviral encephalitis.

• To highlight the re-emergence of certain arboviral infections and discuss concerns regarding the global spread of these fatal diseases.

Neurological involvement of arboviruses

Arboviral infections lead to a variety of presentations, ranging from asymptomatic infection, to mild febrile illness, to fulminant neurological disease. The arthropod viral families most commonly known to infect the nervous system include Togaviridae, Flaviviridae, Bunyaviridae and Reoviridae [5]. A majority of arboviruses are RNA viruses (Alphavirus, Flavivirus, Orthobunyavirus, Nairovirus, Phlebovirus, Orbivirus, Vesiculovirus and Thogotovirus), and the only known DNA arbovirus is African swine fever virus [6, 7]. Some prominent neuroinvasive arboviruses that cause meningoencephalitic symptoms include West Nile virus (WNV), Japanese encephalitis virus (JEV), tick-borne encephalitis virus (TBEV), Powassan virus, dengue virus (DENV), chikungunya virus (CHIKV), Venezuelan Equine Encephalitis virus (VEEV), Eastern equine encephalitis virus (EEEV), La Crosse Encephalitis virus and Colorado tick fever.

Pathogenesis

Arboviral infections are primarily transmitted via an enzootic cycle between invertebrate arthropod vectors (mosquitoes, ticks, etc) and amplifying vertebrate hosts (birds, rodents, horses, non-human primates etc). Some of the most well-known arboviral transmitting vectors include Aedes aegypti mosquitos A. albopictus mosquitos, Culex mosquitos and Ixodes ticks [8]. The arthropod vectors initially become infected after taking a blood meal from a highly viremic host, causing the viral pathogen to replicate within tissue and eventually travel to the vector salivary glands. The infected arthropod vector then transmits the infection to a new vertebral reservoir host for further amplification, thereby completing the transmission cycle. Some arthropod vectors such as mosquitos can further spread infection through vertical and venereal transmission [9, 10]. Transmission patterns are also highly dependent on climate, with tropical areas having consistent viral cycling year long, and temperate climates having viral circulation concentrated more in warmer months and weaning in colder months [11].

Humans become infected after being bitten by an infected vector; however, humans typically serve as dead end hosts and do not contribute to the transmission cycle, as they usually do not harbour adequate levels of viremia to infect vectors. However, in recent years, there has been concern that humans increasingly contribute to the primary disease amplification cycle for viruses such as CHIKV and DENV in urban settings [12]. This is thought to be the result of multiple factors including human encroachment onto enzootic foci of natural arboviral cycles, urbanisation and environmental alteration leading to amplification of vector breeding, modern travel enhancing the spread of infective species and climate change causing variations in vector–host dynamics [13–15].

Neuroinvasiveness, neurotropism and neurovirulence

It is important to recognise the difference between neuroinvasiveness, neurotropism and neurovirulence before exploring these characteristics of encephalitic arboviruses. Neuroinvasiveness relates to the virus’ ability to invade the central nervous system (CNS) or peripheral nervous system (PNS) after virus transmission, while neurotropism is the capability of virus to replication within nervous system cells. Neurovirulence is defined as the independent ability of the virus to establish a productive infection of the CNS [16]. Each of these elements have an important interplay in neurological arboviral infection.

Major neuroinvasive arboviruses causing encephalitis have been identified as members of the Flaviviridae, Alphaviridae and Bunyaviridae RNA viral families. Flaviviruses are single-stranded, spherical, enveloped RNA viruses that produce both structural and non-structural mature viral proteins. Composing the majority of identified arboviruses including JEV, and WNV, flaviviruses enter CNS cells via receptor-mediated endocytosis [17]. It has been suggested that JEV specifically enters the CNS through the olfactory bulb or choroid plexus, [18] and viral entry may be highly mediated by the JEV envelope protein [19]. Meanwhile, WNV is theorised to invade via direct infection of endothelial cells in the CNS microvasculature, spread to the olfactory bulb or retrograde axonal transport from PNS neurons [20]. The Flavivirus non-structural protein 1 (NS1) has been established to play an important role in both viral replication and immune response generation [21]. Intracellular dimeric NS1 has been shown to be essential for neurotropic replication of the viral genome inside host cells, while hexameric membrane-bound NS1 that is secreted plays a role in evading the immune system [22 23]. Additionally, toll-like receptor 3 (TLR3) has been reported to play variable roles in WNV neuroinvasion. Some studies suggest it provides a protection against neural infection, [24] while others report that higher TLR3 activity may contribute to increased blood brain barrier (BBB) permeability, [25] and recent studies suggest that TLR3 may not have any significant role in neuroinvasion [26].

Alphaviruses are positive single-stranded enveloped viruses that have two open reading frames that encode four structural proteins and three envelope glycoproteins. Notable neuroinvasive alphaviruses include VEEV, EEEV and CHIKV [17]. Experiments have proposed that VEEV invades neurons via haematogenous spread from the capillary beds underlying the olfactory sensory neurons, or through invasion of the trigeminal nerve [27]. Meanwhile, EEEV is thought to invade the nervous system through passive transfer across the blood–brain barrier or transfer of infected leucocytes into the CNS [28]. Alphavirus NS1 functions as a major determinant of genome replication, [29] while NS2 contributes to neurovirulence by inhibiting host transcription and diminishing host immune response [30]. Furthermore, transmembrane alphavirus glycoproteins E1 and E2 also play important roles in neurotropism, allowing for binding of host cell receptors and membrane fusion. These proteins have also shown to contribute to neurovirulence, as enhanced viremia was shown to be mediated by E2 in CHIKV [31] and mutations in E1/E2 have been linked to increased neurovirulence [32, 33].

Bunyaviruses are negative sense RNA viruses made up of three segments, classified as large, medium and small. Each segment encodes specific viral elements including a viral polymerase, glycoproteins and non-structural proteins [34]. LACV is an important encephalitic arbovirus whose neuroinvasiveness depends on generating high viremia in striated muscle before disseminating across the BBB [35]. It is thought that LACV glycoproteins (Gn and Gc) allow for viral attachment and mainly contribute to neuroinvasion [36].

Approach for the clinician

Clinical presentation

Patients with neuroinvasive arboviral disease can present with a wide range of symptoms with varying severity. Symptoms that often precede the development of neurological deficits in the days following the arthropod bite include fever, headache, altered mental status, vomiting, nausea and overall malaise [2]. Some hallmark encephalitic signs that may present with neuroinvasive disease are memory difficulties, dizziness, lethargy, increased sleepiness, trouble with concentration, tremors, photophobia, dysarthria, dysphagia, weakness, paresthesia and trouble balancing [37]. Additionally, some viruses may present with other systemic manifestations such as maculopapular rash and chorioretinitis [38].

While some neurological symptoms such as seizures are commonly shared across several encephalitic arboviruses, others are specifically associated with certain viral agents [39–44] (table 1).

Table 1.

Neurological presentations specific to certain arboviruses.

Neurological presentation	Causative arboviruses
Epilepsy	JEV LCEV TBEV
Stroke	JEV EEEV
Parkinsonism	WNV JEV SLEV EEEV
Peripheral neuropathy	DEV JEV WNV TBEV
Acute flaccid paralysis	WNV DEV SLEV POW EEEV
Coma	EEEV SLEV

DEV, dengue virus; EEEV, Eastern equine encephalitis virus; JEV, Japanese encephalitis virus; LCEV, La Crosse encephalitis virus; POW, Powassan virus; SLEV, St. Louis encephalitis virus; TBEV, tick-borne encephalitis virus; WNV, West Nile virus.

Laboratory testing

Eliciting a thorough history and physical exam is of particular significance in diagnosis of arboviral encephalitis because routine hospital laboratory testing may be negative depending on the stage of disease. Blood tests of suspected cases may show mild leucocytosis, and in more serious infections leucopaenia and thrombocytopaenia may arise. Additional laboratory abnormalities that can occur include hyponatraemia as a result of syndrome of inappropriate antidiuretic hormone secretion (EEV, WNV, St. Louis encephalitis virus (SLEV)), elevated aspartate aminotransferase and alanine aminotransferase levels, elevated creatinine phosphokinase and mild anaemia [5].

As long as there are no contraindications, all patients with suspected arboviral encephalitis typically receive a lumbar puncture. CSF findings typically include a normal or elevated opening pressure, and white blood cell pleocytosis that may only appear after 1–2 days of infection [5]. Additionally, CSF glucose is typically normal, CSF protein is normal to slightly elevated and oligoclonal bands may be detected in postinfectious patients. There is typically lymphocytic predominance, though some viruses, particularly WNV, may exhibit neutrophil predominance [45].

Diagnosis is confirmed by detection of virus-specific serological antibodies in CSF or serum. A definitive case of neuroinvasive arbovirus infection is usually made by the presence of IgM against the specific arbovirus in either CSF or serum [46]. It is important to note that there is significant evidence demonstrating serological cross-reactivity between various arboviral species, especially within flaviviruses such as DENV and WNV [47, 48]. Additionally, this cross-reactivity may be enhanced in individuals with previous vaccination against arboviral targets [49]. Therefore, in areas where multiple flaviviruses coexist, it is especially necessary to further contextualise and verify the results of these assays.

Neuroimaging

Imaging findings for arboviral encephalitis can range from non-specific and normal in early infection to presence of signal abnormalities in CNS structures including the basal ganglia, thalamus, brainstem and spinal cord [37, 41]. MRI is typically the imaging modality of choice to visualise abnormalities [50].

Certain viruses have been studied to have potential affinity for specific areas of the brain. In WNV neuroinvasive disease, CNS involvement on MRI correlates to the severity of infection, with imaging abnormalities in the cerebral cortex seen in the least severe cases, followed by basal ganglia, thalamus, brainstem and eventually spinal cord involvement in the most severe instances. Evidence of brain injury has also been suggested to correlate to disease severity for TBEV, which has an increased tendency to affect the thalamus [51]. For JEV, imaging abnormalities are identified most commonly in the thalamus, substantia nigra, basal ganglia and pons [45]. Similarly, patients with EEV encephalitis typically exhibit T2-Fluid Attenuated Inversion Recovery Sequence (T2-FLAIR) hyperintense signal in bilateral basal ganglia, thalami and mesial temporal lobes on MRI [52]. DENV is classically characterised by T2 hyperintense lesions in the cortical grey matter, subcortical/deep white matter, basal ganglia and thalamus, along with areas of restricted diffusion representing microhaemorrhages [53, 54]. The substantia nigra has been shown to be particularly affected by SLEV encephalitis, with MRI showing oedema and symmetric T2 hyperintensity selectively focused in that region [55, 56].

Compared with other arboviral pathogens, CHIKV encephalitis tends to have a predilection for white matter, with imaging showing scattered punctate T2 hyperintense regions in the periventricular white matter in conjunction with restricted diffusion and T1 shortening on MRI. Additionally, CHIKV myelitis can present with short demyelinating-like T2 hyperintense lesions, along with longitudinal T2 hyperintense lesions spreading to the cervical spinal cord [57]. Across all viruses, imaging abnormalities are likely to be increased in the 2–4 weeks following infection onset compared with the acute phase [5].

Neuropathology

Histologic brain examination of patients affected by arboviral encephalitis often reveal diffuse reactive cellular infiltration, cellular necrosis and neuronal degeneration. Features often representative of viral encephalitis include perivascular inflammatory cell infiltration, microglial nodules, lymphocytic or neutrophilic cuffing, leptomeningeal cellular infiltration, focal demyelination and neuronophagia [58–60].

Autoimmune encephalitis (AE), which is a common differential diagnosis in cases of arboviral encephalitis, presents with more non-specific histological findings such as inflammatory infiltrates and microglial activation [61]. Specific AEs such as NMDAR encephalitis have been noted to lack neuronal degeneration and complement activation, while Voltage gated potassium channel (VGKCs) encephalitis exhibit more neuronal destruction [62]. Additionally, studies have shown there may be varying CD4:CD8 ratios when comparing viral and AE, with autoimmune aetiologies containing greater proportions of CD20 B cells and marked B cell cuffing around brain vessels [63, 64].

Treatment

There is currently no definitive treatment for arthropod-borne encephalitis. The current mainstay of treatment is supportive care, including fluid maintenance, bed rest and antipyretic agents. Aspirin and NSAIDs are typically avoided in these patients to lower the potential risk of coagulation dysfunction. Patients with encephalitis are typically hospitalised to monitor risk of severe complications such as cerebral oedema, seizures and respiratory failure [5].

There are several experimental treatments that have shown potential efficacy against arboviral infection. IV immunoglobulin (IVIg) has been studied in treatment for certain arboviruses, showing potential efficacy as an adjunctive therapy for patients with EEE and JEV [52, 65]. However, in a trial assessing the efficacy of Ig with high titers of anti-WNV antibodies (Omr-IgG-am) for treatment of neuroinvasive WNV, no increased effectiveness was noted in patient receiving the experimental IVIg compared patients receiving to standard IVIg or normal saline [66]. Additionally, neutralising monoclonal antibodies against viral envelope proteins and against NS1 have shown therapeutic promise within in vitro studies [67–69]. While limited drugs have shown effectiveness against arboviral infections, some small-molecule antiviral agents that have shown potential efficacy against early viral infection include sofosbuvir, suramin, ribavirin, interferon, and niclosamide [70–74].

Contemporary considerations

While arboviral infections have been a major health concern for decades, the impact of human behaviours and climate change on the re-emergence and evolution of various arboviral infections in recent years has further established them as a significant global health threat [75]. The dramatic burden of disease imposed by arboviruses led the WHO to launch the Global Arbovirus Initiative in March 2022 to discuss current threats and preventative strategies to mitigate the effects of these devastating illnesses [76].

Global climate change has had a significant impact on vector–host interactions, transmission cycles and amplification of these infectious diseases. Given that viral replication within mosquitos has been studied to be more effective at increased temperatures, rising global temperatures have allowed for enhanced infection and transmission cycles for several arboviral pathogens [77 78]. The extrinsic incubation period of certain arboviruses such as DENV and WNV has also been studied to be inversely associated with rising temperatures, thus alterations to typical temperature patterns may lead to increased vector infectivity [79 80]. Life cycles of arboviral vectors such as A. aegypti and A. albopictus are highly dependent on climate factors, and changes such as increased temperatures, rising precipitation levels and rising humidity are associated with enhanced survival of these species [81]. Several models predict that the spread of A. aegypti and A. albopictus will dramatically widen in the upcoming years, with spread into typically unaffected regions and up to a 13% increase in habitable vector regions, thus heightening potential human–vector contact [82 83]. Additionally, dramatic shifts in geographic distribution of arboviruses have occurred because of human activities such as population growth, increased urbanisation and international travel [84]. The combination of these forces has concurrently increased human exposure to vector populations through encroachment of natural habitats, created more favourable living environments for breeding vector populations and spread potential pathogens to areas typically not inhabited by them [85 86].

Here, we briefly outline some recent arbovirus outbreaks that demonstrate the effect of these shifting viral patterns.

Australian JEV outbreak (March 2022)

In early March 2022, JEV was declared a communicable disease incident of national significance in Australia after more than 70 pig farms were detected to have evidence of the virus. According to the WHO, only 15 cases of JEV have been reported in Australia within the last 10 years, and a majority of these were acquired from overseas travel [87]. As of 25 May 2022, there have been 42 confirmed human cases of JEV and 5 deaths [88]. The unprecedented spread of JEV in Australia has been attributed to the effects of climate, specifically given the context of record flooding levels in Northeast Australia in February and March 2022, which may have allowed for enhanced travel of infectious Culex mosquito vectors [89].

DENV and WNV outbreak in malaria-endemic area in Nigeria (2016)

Mohammed et al described a concurrent outbreak of DENV and WNV occurring in Sokoto, Nigeria, a known malaria-endemic region. From 3 October to 11 November 2016, 1477 cases of febrile illness were reported in Sokoto. Laboratory analysis of infected patients revealed evidence of DENV, WNV and malaria. Significantly, factors that were associated with increased infection included densely populated urban areas, bushy landscapes and having uncovered waste bins and water containers in the home [90]. This outbreak demonstrates the increasing ability of pathogenic arboviral vectors to both breed in areas previously endemic to other infectious vectors, and the impact of human urbanisation on the growth of these species.

Yellow fever outbreaks in Angola and the Democratic Republic of the Congo (2016)

Yellow fever has been a significant arboviral threat since the beginning of its detection. Although there were large-scale vaccination efforts in the mid-1900s, viral mutations, lack of global access to vaccinations and decreasing population immunity have contributed to its re-emergence in several endemic regions in recent years [91]. Of note, a yellow fever epidemic was noted in Angola and the Democratic Republic of the Congo, where from December 2015 to November 2016 more than 7300 suspected cases and 393 deaths were reported [92]. Along with the re-emergence of yellow fever in these endemic regions, this outbreak was particularly significant because it marked the first reported cases of yellow fever in Asia, after travellers from Angola to China spread the virus into previously a previously unaffected region [93].

Conclusion

Arthropod-borne encephalitis remains a significant global health concern and may pose a significant growing threat as the impact of climate change and human behaviour alters the transmission cycles of infectious pathogens.

Main messages

• Arthropod-borne encephalitides are a major public health threat, with significant risks associated with environmental changes and population growth.

• While a large class of pathogens transmitted by mosquitoes and ticks can cause encephalitis, significant clinicoradiographic similarities exist suggesting common mechanistic pathways.

• Evidence of host and pathogen-specific factors associated with neurovirulence, with potential therapeutic targets.

• Neuroanatomical distribution of lesions across motor pathways suggests axonal transport once in the central nervous system for several arthropod-associated encephalitides.

Current research questions

• What are the major factors for emerging of neurotropic arthropod infections?

• What are the host and pathogen associated factors associated with emergence of arthropod-associated encephalitis?

• How do arthropod-borne viruses impact cellular populations in the nervous system?

Key references

• Morens DM, Fauci AS. Emerging Pandemic Diseases: How We Got to COVID-19 [published correction appears in Cell. 2020 Oct 29;183(3):837]. Cell. 2020;182(5):1077–1092. doi:10.1016 /j.cell.2020.08.021

• Salimi H, Cain MD, Klein RS. Encephalitic Arboviruses: Emergence, Clinical Presentation, and Neuropathogenesis. Neurotherapeutics. 2016;13(3):514–534. doi:10.1007 /s13311-016-0443-5

• Wasay M, Khatri IA, Abd-Allah F. Arbovirus infections of the nervous system: current trends and future threats. Neurology. 2015;84(4):421–423. doi:10.1212/WNL.0000000000001177*

• Kraemer, Moritz UG, et al. “Past and future spread of the arbovirus vectors Aedes aegypti and Aedes albopictus.” Nature microbiology 4.5 (2019): 854–863

• Tajudeen YA, Oladunjoye IO, Mustapha MO, Mustapha ST, Ajide-Bamigboye NT. Tackling the global health threat of arboviruses: An appraisal of the three holistic approaches to health. Health Promot Perspect. 2021;11(4):371–381. Published 2021 Dec 19. doi:10.34172/hpp.2021.48

Self-assessment questions

1. What are examples of arthropod species associated with encephalitis?

2. What are common neuroradiological patterns seen in arthropod-associated encephalitis?

3. How does climate change impact risk of arthropod associated encephalitis?

4. What was the main driver of the recent Australian outbreak of Japanese encephalitis?

Answers

1. • Togaviridae (Eastern Equine virus, Western Equine virus, Venezuelan Equine Encephalitis virus)

   • Flaviviridae (Dengue Virus, Japanese Encephalitis Virus, Murray Valley Encephalitis virus)

   • Bunyaviridae (La Crosse Virus, California Encephalitis Virus)

   • Reoviridae (Colorado Tick Fever Virus)

2. • Several viruses have predilection for and exhibit T2 hyperintensities in gray matter structures (basal ganglia, thalamus, brainstem). Spinal cord involvement can be seen in the most severe infections.

3. • Rising global temperatures allow for increasing viral replication cycles of infectious species leading to enhanced transmission cycles and prolonged life cycles of disease-spreading pathogens

   • Human activities such as uncontrolled population growth, increased urbanization, and migration have allowed for the spread of several arboviral species into a wider range of landscapes including previously unaffected regions, and created more favorable living environments for these species to amplify disease.

4. • Unprecedented flooding levels facilitated the spread of infectious Culex mosquitoes by allowing for enhanced breeding environments and long-distance travel of vectors to previously uninhabited regions within Australia. This led to the disease being detected in over 40 pig farms across the nation and eventually in humans, signaling intensified amplification of JEV in the context of ongoing climate change.

Twitter

Abhilasha Pankaj Boruah @abhilashaboruah and Kiran T Thakur @ kiranthakurmd

Contributors

APB contributed to the writing, editing and review of this manuscript. KT contributed to the development, writing, editing and review of this manuscript.

Funding

KT is supported by NIH K23 (1K23NS105935-01), Centers for Disease Control and Prevention Funding, Biomerieux Company.

Competing interests

KT has the following competing interests: External Consultant, WHO, External Consultant, Centers for Disease Control and Prevention Clinical Immunization Safety Assessment Group.

Provenance and peer review

Not commissioned; externally peer reviewed.

Ethics statements

Patient consent for publication

Not applicable.

Ethics approval

Not applicable.