ETIOLOGY

Encephalitis is an inflammatory process of the brain parenchyma leading to cerebral dysfunction. It is usually an acute process but may be a postinfectious encephalomyelitis, a chronic degenerative disease, or a slow viral infection. Encephalitis may be diffuse or localized. Organisms cause encephalitis by one of two mechanisms: (1) direct infection of the brain parenchyma or (2) an apparent immune-mediated response in the central nervous system that usually begins several days after the appearance of extraneural manifestations of the infection.

Viruses are the principal causes of acute infectious encephalitis (Table 101-1). The most common viral causes of encephalitis in the United States are the arboviruses, enteroviruses, and herpesviruses. Human immunodeficiency virus (HIV) is an important cause of subacute encephalitis in children and adolescents and may present as an acute febrile illness but more commonly is insidious in onset (see Chapter 125). Other causes of subacute encephalitis include measles, slow viruses (e.g., JC virus), and prion-associated diseases (e.g., Creutzfeldt-Jakob disease). Encephalitis also may result from metabolic, toxic, and neoplastic disorders.

TABLE 101-1 Viral Causes of Acute Encephalitis

* Frequency of occurrence of encephalitis as a component of infection.

Adapted from Cherry JD, Shields WD: Encephalitis and meningoencephalitis. In Feigin RD, Cherry JD, Demmler GJ, et al: Textbook of Pediatric Infectious Diseases, 5th ed, Philadelphia, 2004, Saunders.

Acute disseminated encephalomyelitis (ADEM) is the abrupt development of multiple neurologic signs related to an inflammatory, demyelinating disorder of the brain and spinal cord. ADEM follows childhood viral infections such as measles and chickenpox or vaccinations and resembles multiple sclerosis clinically.

EPIDEMIOLOGY

Arboviral and enteroviral encephalitides characteristically appear in clusters or epidemics that occur from midsummer to early fall, although sporadic cases of enteroviral encephalitis occur throughout the year. Herpesviruses and other infectious agents account for additional sporadic cases throughout the year.

Arboviruses tend to be limited to certain geographic areas, reflecting the reservoir and mosquito vector. St. Louis encephalitis virus is present throughout the United States in birds. California encephalitis virus, common in the Midwest, is carried by rodents and spread by mosquitoes. Eastern equine encephalitis virus is limited to the East Coast in birds. Western equine encephalitis virus is present throughout the Midwest and West in birds. West Nile virus infection occurs worldwide and causes outbreaks of summer encephalitis in North America. The principal vector for West Nile virus is the Culex pipiens mosquito, but the organism can be isolated in nature from a wide variety of Culex and Aedes species. A broad range of birds serves as the major reservoir for West Nile virus.

CLINICAL MANIFESTATIONS

Acute infectious encephalitis usually is preceded by a prodrome of several days of nonspecific symptoms such as cough, sore throat, fever, headache, and abdominal complaints followed by the characteristic symptoms of progressive lethargy, behavioral changes, and neurologic deficits. Seizures are common at presentation. Children with encephalitis also may have a maculopapular rash and severe complications such as fulminant coma, transverse myelitis, anterior horn cell disease, or peripheral neuropathy.

West Nile encephalitis produces a broad spectrum of illness from asymptomatic infection to death. Severity of disease increases with advancing age. Most children are asymptomatic. Typical symptoms include mild, nonspecific extraneurologic illness characterized by fever, rash, arthralgias, lymphadenopathy, gastrointestinal complaints, and conjunctivitis.

LABORATORY AND IMAGING STUDIES

The diagnosis of viral encephalitis is supported by examination of the cerebrospinal fluid (CSF), which typically shows a lymphocytic pleocytosis, slight elevation in protein content, and normal glucose level. The CSF occasionally may be normal. Extreme elevations of protein and reductions of glucose suggest tuberculosis, cryptococcal infection, or meningeal carcinomatosis. The electroencephalogram (EEG) is the definitive test and shows diffuse, slow wave activity, although focal changes may be present. Neuroimaging studies may be normal or may show diffuse cerebral swelling of the parenchyma or focal abnormalities. A temporal lobe focus on EEG or brain imaging is the characteristic feature of herpes simplex virus (HSV) infection.

Serologic studies should be obtained for arboviruses (including West Nile virus), Epstein-Barr virus, Mycoplasma pneumoniae, cat-scratch disease, and Lyme disease. Additional serologic testing for less common pathogens should be performed as indicated by the travel, social, or medical history. In addition to serologic testing, viral cultures of CSF and stool and a nasopharyngeal swab should be obtained. In most cases of viral encephalitis, the virus is difficult to isolate from the CSF. Polymerase chain reaction tests for HSV, enteroviruses, West Nile virus, and other viruses are available and should be sent if no specific cause is found. Even with extensive testing and the use of polymerase chain reaction assays, the cause of encephalitis remains undetermined in one third of cases.

Brain biopsy is seldom performed but may be useful in patients with focal neurologic findings. It may be appropriate for patients with severe encephalopathy who show no clinical improvement if the diagnosis remains obscure. Rabies encephalitis and prion-related diseases (Creutzfeldt-Jakob disease and kuru) may be routinely diagnosed by culture or pathologic examination of brain biopsy tissue. Brain biopsy may be helpful to identify arbovirus and enterovirus infections, tuberculosis, fungal infections, and noninfectious illnesses, particularly primary central nervous system vasculopathies and malignancies.

DIFFERENTIAL DIAGNOSIS

The diagnosis is established presumptively by the presence of characteristic neurologic signs, typical epidemiology findings, and evidence of infection by CSF analysis, EEG, and brain imaging techniques. Encephalitis may result from infections with bacteria, Mycoplasma, Rickettsia, fungi, and parasites and from many noninfectious diseases, including metabolic diseases (encephalopathy) such as Reye syndrome, hypoglycemia, collagen vascular disorders, drugs, hypertension, and malignancies.

TREATMENT

With the exception of HSV, varicella-zoster virus, cytomegalovirus, and HIV, there is no specific therapy for viral encephalitis. Management is supportive and frequently requires intensive care unit admission to facilitate aggressive therapy for seizures, timely detection of electrolyte abnormalities, and, when necessary, airway monitoring and protection or reduction of increased intracranial pressure and maintenance of adequate cerebral perfusion pressure.

Intravenous acyclovir is the treatment of choice for HSV and varicella-zoster virus infections. Cytomegalovirus infection is treated with ganciclovir. HIV infections may be treated with a combination of antiretroviral agents. M. pneumoniae infections may be treated with doxycycline, erythromycin, azithromycin, or clarithromycin, although the clinical value of treating encephalitis associated with mycoplasmal disease is uncertain.

ADEM has been treated with high-dose intravenous corticosteroids, but it is unclear whether the improved outcome with corticosteroids reflects milder cases recognized by magnetic resonance imaging, fewer cases of ADEM caused by measles (which causes severe ADEM), or improved supportive care.

COMPLICATIONS AND PROGNOSIS

Among survivors, symptoms usually resolve over several days to 2 to 3 weeks. Although most patients with epidemic forms of infectious encephalitis (St. Louis, California, West Nile and enterovirus infections) in the United States recover without sequelae, severe cases leading to death or substantial neurologic sequelae can occur with virtually any of these neurotropic viruses. About two thirds of patients recover fully before being discharged from the hospital. The remainder show clinically significant residua, including paresis or spasticity, cognitive impairment, weakness, ataxia, and recurrent seizures. Most patients with neurologic sequelae of infectious encephalitis at the time of hospital discharge gradually recover some or all of their function. The overall mortality for infectious encephalitis is approximately 5%.

Disease caused by HSV, Eastern equine encephalitis, or M. pneumoniae is associated with a worse prognosis. The prognosis may be worse for encephalitis in children younger than 1 year of age or with coma. Rabies is, with very rare exceptions, fatal.

Relapses of ADEM occur in 14%, usually within 1 year with the same or new clinical signs. Recurrences of ADEM may represent onset of multiple sclerosis in childhood.

PREVENTION

The best prevention for arboviral encephalitis is to avoid mosquito-borne or tick-borne exposures and to remove ticks carefully (see Chapter 122). There are no vaccines in use in the United States for prevention of arboviral infection or for enteroviruses except for poliomyelitis. There are no specific preventive measures for HSV encephalitis except for cesarean section for mothers with active genital lesions (see Chapter 65). Rabies can be prevented by pre-exposure or postexposure vaccination. Influenza encephalitis can be prevented by use of influenza vaccination. Reye syndrome can be prevented by avoiding use of aspirin or aspirin-containing compounds for children with fever as well as use of varicella and influenza vaccines.