**5. Treatment of arboviral infections**

ing cognitive biological processes. In order to differentiate the evasion strategies employed, animal models are required. Currently, there are only a limited number of animal models available for a few arboviruses; JEV [59], EEEV [75], LACV [71], WNV [76] and CHIKV [72]. However, the cardinal features of human clinical encephalitis induced by these arboviruses are hardly reproduced in these models. Therefore, what the exact mechanisms by which ar‐ boviruses cross the BBB remains poorly understood, as well as the precise mechanisms by which circulating peripheral pathogens induce the inflammation of the brain remain largely

Nevertheless, the best systems available that have been used to characterize the biological properties of arboviruses in animal models are the WNV [76, 77], LACV [71], EEEV [75], and CHIKV [72, 78]. Results revealed that viral strain variations, in addition to the host age and immune conditions, contribute a significantly to neuroinvasiveness and neurovirulence. In‐ fection of the mice intradermally or subcutaneously leads to the robust replication of WNV, LACV, and CHIKV in the brain, particularly in newborn mice. But the mechanisms contri‐ buting to neurotropism of other viruses are less clear since suitable models are not available. When viruses enter the CNS, a variety of cells are permissive for infection [46, 79]; some cells may be more susceptible than others, and the viruses may have their differential prefer‐ ences [74, 75, 78, 80]. Regardless, the net consequence is the activation and/or damage to res‐ idential cells. This results in the recruitment of defense cells with immune system functions to the damaged site. An inflammatory response occurs due to the presence of an overpro‐ duction of multiple functional cytokines from the infiltrating cells [81-83]. The nature of the privileged environment of the brain bestows it with characteristics that make restoration to the default normal status far more complicated than other parts of the body. The most sali‐ ent feature of the brain is that a large proportion of the cells are terminally differentiated. These cells are very difficult to renew and replace. Therefore, affected encephalitic patients suffer long-term neurological impairment as a result from the infection [18, 28]. These symp‐ toms include short-term or long-term memory loss, seizures, and impaired judgment [28, 84, 85]. A neurological exam is performed to evaluate the mental status, detect neurological problems, such as motor dysfunction and seizures, and help determine which area of the

The causes of the dysfunctional circuitry in neurons are likely different among the arbovi‐ ruses. Some viruses have the capacity of direct engagement with neurons by infection, while others may induce cell death or apoptosis in nearby cells, which shed releasates, likely trig‐ gering a cascade of events that damages the neuronal tissue [81, 82]. This may be why some viruses can be recovered from the CNS easier than others in autopsy specimens. For those viruses capable of infecting small animals, results also suggest the observed scenarios. In contrast, for the viruses with limited capacity to replicate in animal models, the actual caus‐

The initial symptoms of the arbovirus infections that induced encephalitis are very similar, especially for those mild cases of encephalitis, which makes the correct diagnosis a challenge to physicians. In order for accurate diagnosis, in addition to the routine examination on the physical performance, specific tests are required, such as electroencephalogram, brain mag‐

unknown.

82 Encephalitis

brain is affected [18].

es of neurological symptoms are less clear.

*Currently used drugs to treat arboviral encephalitis.* There is no cure for arboviral encephalitis and treatment is generally supportive, with maintenance of respiratory and circulatory sys‐ tems while the infection runs its course. The purpose of the palliative care is to reduce the malfunctioning of critical organs and to relieve symptoms, while the body fights the infec‐ tion. The priority of the treatment is to ensure the alleviation of pain, as well as to mitigate the swelling in the brain, reduce the fever and prevent dehydration and other chemical im‐ balances by administration of intravenous fluids. As a whole, the treatment for arboviral en‐ cephalitis depends on the cause. Some clinical cases of arboviral encephalitis can be mitigated successfully if medication is started as soon as possible. A number of therapeutic drugs specific to arboviral infections are under investigation for their potential antiviral and neuroprotective effects: minocycline and curcumin for JEV and other arboviruses [87-89], ribavirin for LACV [90], interferon (Omr-IgG-aM) and humanized monoclonal antibody (Mab E16) as a potential candidate for WNV treatment [61, 91, 92]. However, currently there is limited information available on the effectiveness of these therapeutic modalities in the clinical setting. Additionally, there are a number of reliable medicines that are commonly prescribed to treat the symptoms mentioned above; administration of benzodiazepines (*e.g.*, lorazepam [Ativan®) to prevent seizure, diuretics drugs (*e.g.*, furosemide or mannitol) to re‐ duce brain swelling, sedatives to relieve irritability, antibiotics to prevent secondary infec‐ tions, and acetaminophen to control fever and headache. For those patients whose brain functions may be severely affected, interventions like physical therapy and speech therapy may be needed after the illness is controlled.
