Viral encephalitis is an inflammation of the brain parenchyma caused by a virus. It is the most common type of encephalitis and often coexists with viral meningitis. Viruses invade the host outside the central nervous system (CNS) and then reach the spinal cord and brain hematogenously or in a retrograde manner from nerve endings.
Infectious encephalitis can be viral, bacterial, fungal, protozoal, or helminthic in etiology. The etiology of many cases of encephalitis remains unknown despite extensive workup. Viruses are the most prevalent identified cause, accounting for about 70% of confirmed cases of encephalitis. In the United States, the most common causes of viral encephalitis are herpes simplex virus (HSV), West Nile virus, and the enteroviruses. Some of the other viral etiologic agents include varicella-zoster virus, Epstein-Barr virus (EBV), cytomegalovirus (CMV), human herpesvirus type 6 and 7, measles virus, mumps virus, rubella virus, St. Louis virus, eastern equine virus, western equine virus, dengue virus, and rabies virus.
The incidence of viral encephalitis is 3.5 to 7.5 per 100,000 people, with the highest incidence in the young and elderly. The epidemiology of certain viral causes of encephalitis has changed through time. For example, vaccination has led to a decrease in the incidence of encephalitis due to mumps and measles. On the other hand, EBV and CMV encephalitis are seen more frequently now because they occur in immunocompromised individuals, such as AIDS, transplant, and chemotherapy patients. Other important epidemiologic factors include time of the year, geography, and animal or insect exposure. For instance, arboviruses (i.e., eastern equine, western equine, St. Louis, Venezuelan equine, Zika, and West Nile) cause disease during the summer months when mosquitos are active. St. Louis encephalitis is primarily seen in the Midwest and South, whereas tick-borne encephalitis occurs mainly in the north central and Northeastern United States.
Viruses invade the host at a site outside the CNS and replicate. Most then reach the spinal cord and brain hematogenously. HSV, rabies, and herpes zoster virus are important exceptions to this. They travel to the CNS from nerve endings in a retrograde manner. Once in the brain, the virus and the host’s inflammatory response disrupt neural cell function.
Brain histology of individuals with viral encephalitis shows dead neurons with nuclear dissolution and hypereosinophilia within the cytoplasm on light microscopy. Because encephalitis is an inflammatory process, perivascular inflammatory cells such as microglia, macrophages, and lymphocytes are also seen. Virions within neurons can be visualized with electron microscopy, which allows for much greater magnification than light microscopy.
As mentioned above, the cause of many cases of encephalitis remains unknown despite extensive testing. Thus, history and physical exam play a vital role in making the diagnosis of viral encephalitis. Important elements of history include immune status, exposure to insects or animals, travel history, vaccination history, geography, and time of year. The most common sign and symptoms are fever, headache, seizures, and altered mental status. Neuropsychiatric features such as behavioral changes, hallucinations, and/or cognitive decline are often seen. Patients may also have other symptoms or exam findings that are more specific to a given virus. For example, rash and skin vesicles are seen with herpes zoster encephalitis, whereas lymphadenopathy and splenomegaly are usually associated with EBV. HSV encephalitis involves the temporal and frontal lobes, so it is often characterized by psychiatric features, memory deficits, and aphasia. On the other hand, motor symptoms such as choreoathetosis and parkinsonian movements are seen with some arboviruses because they predominately affect the basal ganglia.
Neuroimaging and lumbar puncture (LP) are essential initial diagnostic studies for evaluating patients with viral encephalitis. Computed tomography (CT) or magnetic resonance imaging (MRI) help exclude increased intracranial pressure and the risk of uncal herniation prior to performing an LP. MRI is also the most sensitive imaging modality for showing findings consistent with HSV encephalitis, such as temporal and frontal lobe involvement. Cerebrospinal fluid (CSF) should be analyzed for opening pressure, cell counts, glucose, and protein. CSF evaluation should also include polymerase chain reaction (PCR) testing for HSV-1, HSV-2, and enteroviruses. Additional testing, such as serology for arboviruses and HIV testing, may also be done based on history and clinical presentation. Brain biopsy and body fluid specimen cultures and PCR may also be helpful in establishing the etiology in some cases.
The treatment of viral encephalitis is primarily supportive as there is no specific medical therapy for most central nervous system viral infections. A very important exception to this is HSV encephalitis. When started early, acyclovir has been shown to significantly decrease mortality and morbidity and limit the severity of long-term behavioral and cognitive impairment of HSV encephalitis. Therefore, empirically, it is recommended that physicians start all patients with suspected encephalitis on acyclovir. The recommended dose is 10 mg/kg intravenously (IV) every 8 hours for 14 to 21 days. Although not as effective as it is with HSV, nucleoside analogues are used for other herpesviruses as well. Acyclovir 10 to 15 mg/kg IV every 8 hours for 10 to 14 days, with possible adjunctive corticosteroids in immunocompetent patients, is recommended for varicella zoster virus. The recommended treatment for CMV encephalitis is a combination of ganciclovir 5 mg/kg IV every 12 hours and foscarnet 60 mg/kg IV every 8 hours or 90 mg/kg IV every 12 hours for 21 days.
Another important component of the management of patients with viral encephalitis is serial intracranial pressure (ICP) monitoring. Elevated ICP is associated with a poor prognosis. Although there is limited data on their efficacy in viral encephalitis, steroids and mannitol can be given to relieve increased ICP.
A broad differential diagnosis, both infectious and noninfectious, should be considered for encephalitis. These alternatives include malignancy, autoimmune or paraneoplastic diseases (e.g., anti-NMDA receptor encephalitis), brain abscess, tuberculosis or drug-induced delirium, neurosyphilis, or bacterial, fungal, protozoal, or helminthic encephalitis.
Most patients with viral encephalitis recover without sequelae. Those who remain symptomatic have difficulties in concentration, behavioral and speech disorders, and/or memory loss. In rare cases, patients may remain in a vegetative state.
Patients with viral encephalitis should be admitted to the hospital for supportive care and IV antiviral therapy. They may require intensive care for frequent neurologic exams and/or respiratory support. Early initiation of medical therapy is essential for HSV, the most common cause of viral encephalitis, so all patients with suspected encephalitis should be started empirically on acyclovir as soon as possible.
Viral encephalitis is a serious disorder, and the morbidity and mortality depend on the type of virus and the severity of the infection. Viral encephalitis may primarily involve the brain but has repercussions in many other organs; hence a multidisciplinary approach in management is key. It has been estimated that a single bout of viral encephalitis can cost upwards of $2 million to the healthcare system. For patients who are untreated, mortality rates can be high. Mortality after herpes encephalitis can range more than 50%, and after western equine encephalitis, children may develop marked behavior changes and seizures. The eastern equine encephalitis can also have crippling effects on children including paralysis, seizures and mental retardation. The recent Zika virus epidemic has resulted in microcephaly in newborn infants. However, mortality is low with the La Crosse and the Venezuelan equine virus. Recent data reveal that the tick-borne encephalitis from the Orient is far more dangerous than the central European tick-borne encephalitis. Patients who acquire the Asian tick-borne encephalitis often have residual seizures for a long time.
The key to the viral encephalitis is prevention. Surveillance of mosquitoes must be done to assess the risk of infectivity. Travelers should wear protective garments to prevent mosquito bite and sleep under a mosquito net. One should also avoid outdoor activities where the risk of tick-borne infections is high. The public has to remove containers of stagnant water from the home surroundings, and insecticide spraying may help. Vaccines are available against the EEE, WEE and VEE. However, their effectiveness is not 100%.
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