Viral encephalitis implies infection of the brain parenchyma by a virus. Seasonal, geographical and immunological factors are all important when differentiating between numerous viral pathogens in the differential diagnosis. Clinical presentation involves the triad of fever, altered consciousness and headache, whereas seizures and various neurological deficits may be encountered. The diagnosis is made through clinical, imaging, laboratory and microbiological findings. Empiric antiviral therapy is the mainstay.
The clinical presentation of patients suffering from encephalitis encompasses the triad of headaches, altered level of consciousness and fever. In addition, focal neurological deficits that may range from fronto-temporal signs and aphasia to personality changes can also be seen together with seizures . Cranial nerve deficits, hemiparesis and pyramidal signs may also be encountered . These symptoms are used to distinguish encephalitis from other similar conditions such as ADEM, in which visual disturbances and signs of spinal cord involvement are frequent, and encephalopathy, where fever and focal neurological deficits are rarely present . Additionally, a skin rash may be present in VZV infection, while mucosal lesions are hallmarks of herpes virus encephalitis .
Whenever patients present with the mentioned triad of symptoms, immediate diagnostic protocols to exclude or confirm viral encephalitis should be instated. Patient history should be fully obtained, including information regarding recent travel, exposure to animals and mosquitoes,as well as presence of comorbidities that may present as a risk factor (such as HIV infection), followed by a thorough physical examination and neuroimaging studies. MRI is recommended over CT , but both are useful in initial evaluation. The importance of brain imaging lies in excluding conditions that may contraindicate lumbar puncture, such as increased intracranial pressure and risk of herniation. Additionally, some MRI findings can point to the underlying cause, such as unilateral frontotemporal changes in herpes simplex encephalitis or thalamic hemorrhage in Japanese encephalitis . Disseminated lesions in the brainstem and basal ganglia are considered as hallmarks of Eastern Equine encephalitis . Once imaging studies have determined that lumbar puncture can be safely performed, CSF examination should be carried out. A high protein and normal glucose content is seen in viral infections of the CNS, together with lymphocytic pleiocytosis . However, neutrophils may predominate in the case of WNV infection and can often mislead the physician toward a bacterial pathogen . For these reasons, the use of all accessible microbiological tests should be advocated, including serology for herpesviruses, Japanese encephalitis virus and arboviruses, whereas polymerase chain reaction (PCR) is a more specific method of viral DNA detection that can be used for virtually all pathogens . Despite the availability of these tests, however, the pathogen remains undiagnosed in up to 60% of patients and the diagnosis, as well as treatment, remains on clinical criteria  . Electroencephalography (EEG) and brain biopsy may be performed for further differentiation between causes.
Symptomatic management is the primary form of therapy for patients with suspected viral encephalitis, because antiviral therapy is available only against herpes viruses, influenza and CMV. Nevertheless, it is recommended to start patients on intravenous acyclovir as soon as a high suspicion toward encephalitis is made . The recommended dosage is 10mg/kg q8h for 2-3 weeks for adults and 20 mg/kg for children under 12 years , and it is important to infuse the drug over 1 hour or even more to reduce nephrotoxicity. For CMV infection, valganciclovir 900 mg PO q12h for 2-3 weeks is indicated for milder cases, while ganciclovir 5 mg/kg IV q12h for 2-3 weeks is used in severe cases . Supportive care includes antiepileptic therapy, management of brain edema through administration of mannitol and ensuring adequate tissue oxygenation through assisted ventilation , as many patients are in severely comatose states.
The most important factor in determining the prognosis is the causative agent of encephalitis, but in general, fatal outcomes are not uncommon. Mortality rates for WNV are estimated to be around 12%, whereas Japanese encephalitis mortality rates are between 20-30% . Untreated herpes simplex encephalitis has a mortality rate of 70% (compared to 20-30% with therapy) and less than 3% of patients who do survive return to normal daily life, indicating that an early diagnosis may be of life-saving magnitude in some patients  . Regardless of the etiology, long-term neurological and psychiatric complications are common, while respiratory failure, coma and status epilepticus may ensue despite adequate supportive care . All of these facts emphasize the striking danger viral encephalitis poses to individuals.
Viral encephalitis can be caused by numerous pathogens   :
Epidemiological studies suggest that the incidence rate of viral encephalitis (based on clinical criteria only) ranges between 3.5-7.4 per 100,000 patients per year, but significant variations exist . In the United States, isolated reports are closer to the upper border of 7.4 per 100,000 individuals per year,and approximately 20 000 cases are reported on an annual basis , whereas research conducted in England showed an incidence rate of 1.5 per 100 000 individuals per year . Numerous studies have determined a much higher incidence rate in children, up to 22.5 per 100 000 individuals per year, indicating that young age is a significant risk factor for this form of infection . On the other hand, a second peak in the elderly has been observed, especially for WNV . Across all studies, however, the reports seem to underestimate the actual number of patients who suffered from viral encephalitis, primarily due to lack of confirmation   . In the lack of diagnostic tools to determine the exact viral pathogen, epidemiological information regarding recent travel, vector exposure, immune status and seasonal development of infection are considered to be of vital importance. Exposure to specific mosquito species (for ex. Aedes sp.) puts the patient at significant risk for contraction of WNV, equine encephalitis viruses and Japanese encephalitis, which is estimated to cause infection in almost 70,000 individuals every year . Rodents (tick-borne encephalitis, LCMV), horses (several equine encephalitis viruses), woodchucks (Powassan virus), bats, dogs, skunks (all carrying rabies) and birds are all vectors of transmission and direct contact with these animals significantly increases the risk of contracting the viruses they respectfully carry . Some viruses are endemic for certain regions of the world (Africa is endemic for Rift Valley fever virus, whereas Japanse and tick-borne encephalitis are restricted primarily to Asia). On the other hand, WNV is distributed through practically all parts of the globe . Finally, immunodeficiency either by HIV, corticosteroid therapy due to organ transplantation or malignancy has shown to be a risk factor for encephalitis caused by HSV or VZV .
The pathogenesis model significantly varies across different pathogens, as various modes of replication and further dissemination into host central nervous tissue has been established. Viruses that cause encephalitis are neurotropic, meaning that they invade and replicate within the nervous system. They exhibit variations in potency of CNS invasion , meaning that not all virions are equally dangerous and harmful for the human host. Routes include hematogenous and direct invasion of the neural network, which is the case of herpes viruses . Viruses can pass through the blood-brain barrier, usually being situated inside macrophages and other leukocytes and trigger their replication once they reach the CNS. In addition to viral replication, significant damage on the parenchyma of the brain occurs as a result of severe pro-inflammatory events, the primary reason why patients often suffer from severe and long-term consequences of this disease.
Prevention measures may include avoiding exposure and direct contact to mosquitoes and animals that are known to be vectors of transmission as well as management of underlying immunocompromised conditions that puts the patient at increased risk for infection. Many patients who contract some of the viruses that cause encephalitis remain asymptomatic, however, presumably due to strong immune responses, which is why ensuring a strong immune system through regular exercise, as well-balanced diet and reduced contact with harmful vectors could be the optimal strategy for prevention.
Encephalitis is a term encompassing inflammation of the brain parenchyma that may occur due to infectious, autoimmune and paraneoplastic causes . Viral pathogens, however, are hypothesized to be one of the most common causes of this syndrome. A myriad of viruses have been described as potential causes, depending on factors such as geographical location, season and immune status of the individual. Herpes simplex 1 and 2 (HSV-1 and HSV-2) viruses, as well as Varicella zoster virus (VZV) are considered to be one of the most frequently confirmed viral pathogens when it comes to encephalitis , whereas numerous arboviruses (including West Nile virus (WNV), Venezuelan and Japanese encephalitis viruses, as well as several other), Human herpesvirus type 6 (HHV-6), Rabies virus, Lymhpocytic choriomeningitis virus (LCM), cytomegalovirus (CMV), but also tick borne-encephalitis, influenza and several other are listed as potential causes . Risk factors are geographical presence, level of virulence, but also immune status of the individual, since immunocompromised patients, for ex. those suffering from human immunodeficiency virus (HIV) infection, are at a significantly higher risk for infection by HSV and CMV . Transmission of viruses that cause encephalitis usually requires the presence of a vector, with mosquitoes being responsible in the majority of cases . Other vectors, however, are rodents, horses, skunks, swine, birds and bats , each being responsible for transmission of one or more viruses. Depending on the geographical region and distribution of vectors, different pathogens may be encountered at various parts of the globe. For example, Japanese encephalitis virus is one of the most important causative agents of encephalitis in Asia with more than 15000 deaths every year, whereas St. Louis encephalitis virus is restricted to the central and eastern part of the United States . Although viral pathogens are widely distributed throughout the world and exposure cannot be avoided, not all patients suffer from a symptomatic infection. In fact, only a very small number of individuals develop some form of illness and a fraction of these individuals develop severe brain infection. An example includes the estimation that up to 1 million people in the United States have contracted WNV, but only about 20,000-30,000 cases have been documented  . The clinical presentation comprises the triad of fever, altered consciousness and headache, while accompanying features that distinguish viral encephalitis from other similar conditions such as acute disseminated encephalomyelitis (ADEM) and encephalopathy are neurological deficits and differences in cerebrospinal fluid (CSF) findings . Whenever this triad is confirmed in patients, all attempts to obtain a detailed patient history regarding recent travel and exposure to potential vectors should be made. Prior to obtaining a lumbar puncture and performing CSF analysis, computed tomography (CT) or magnetic resonance imaging (MRI) should be done first to rule out the presence of tumors or brain herniation, as lumbar puncture can cause further deterioration of the patient under such circumstances. In the case of viral encephalitis, CSF panel shows lymphocytic pleocytosis (although neutrophils may be present in WNV and several other) , normal glucose and elevated protein levels, together with negative cultures . Various serological and molecular tests exist for identifying viral pathogens, but studies have determined that the diagnosis is not confirmed in up to 60% of patients . For these reasons, the importance of empiric therapy is detrimental and should be based on on patient history and laboratory results. Unfortunately, scarce options exist when it comes to antiviral therapy, and the empiric regimen consists of acyclovir, primarily used for herpes encephalitis . In immunocompromised patients, gancyclovir may be given due to strong suspicion toward CMV, while oseltamivir can be effective against influenza but only if administered during the first few days  . Otherwise, symptomatic therapy that often mandates severe intensive care is necessary, as coma, status epilepticus, respiratory failure and brain edema are not uncommon . The prognosis can be fatal despite all therapeutic measures and mortality rates range from 20-70%, depending on the pathogen and attempted treatment.
Viral encephalitis is a term that implies infection of the brain by a virus. Most important viral agents include the herpes virus family (herpes simplex type 1 and 2, varicella zoster virus and cytomegalovirus), West Nile virus (WNV) and several other arthropod-borne viruses (or arboviruses, named after the fact that mosquitoes transmit viruses to humans) and a myriad of other pathogens (such as influenza, measles, rabies, etc.). Their occurrence may significantly depend on geography and presence of animals that transmit the particular virus, such as Japanese encephalitis, which is exclusively seen in Asia, or Eastern Equine encephalitis virus, as its presence is restricted to southern and eastern parts of the United States. Numerous animals, in addition to mosquitos, have been established as potential vectors - bats, skunks, dogs, woodchucks, horses and rodents, making direct contact with these animals a risk factor for this infection. Age extremes (less than 10 years and more than 65 years of age) are shown to possess highest rates of infection, whereas travel to endemic areas and an immunocompromised status (such as human immunodeficiency virus - HIV infection or corticosteroid therapy) are also established risk factors. Patients usually present with a triad of headache, altered consciousness and fever, while additional signs include seizures and various neurological deficits. To make the diagnosis, imaging studies such as magnetic resonance imaging (MRI) or computed tomography (CT scan) are initially performed to investigate the presence of brain lesions that may suggest the causative agent, but also to ensure that a lumbar puncture may be performed. This procedure comprises drawing a sample of cerebrospinal fluid (CSF) from the spine and its subsequent examination. Changes in content of the CSF can indicate whether the infection is of viral, bacterial or some other origin, but more importantly, microbiological investigation of this material may provide valuable results in determining the exact virus that caused symptoms. Despite numerous advances in techniques used for confirmation, however, the final diagnosis is not made in up to 60% of patients, and clinical criteria are used for initiation of treatment. Unfortunately, antiviral therapy currently exists for only herpes viruses and a few other, shifting the focus of treatment on symptomatic measures. The prognosis of patients suffering from viral encephalitis is not good, as up to a third of patients do not survive infections by West Nile virus and Japanese encephalitis virus. Similar mortality rates are observed with herpes viruses, but the percentage rises to 70% in untreated patients, which is why administration of acyclovir is indicated in those in whom viral encephalitis is suspected, in the attempt to reduce mortality rates. However, only 3% of individuals return to their normal function and many develop long-term neurological and psychiatric complications. These facts show that viral encephalitis is a devastating and often life-threatening disease that necessitates improvement in diagnostic and therapeutic fields in order to reduce very high mortality rates.