Viral encephalitis.

Abstract

Upon completion of this article, readers should be able to:Viral infections of the central nervous system (CNS), with a few exceptions, are difficult to diagnose. However, the advent of antiviral therapy has resulted in increased attention to the prompt and specific diagnosis and treatment of such infections of the CNS as herpes simplex encephalitis (HSE). This review focuses on the pathogenesis and general diagnostic approach to patients who have presumed CNS viral infections.Encephalitis is an unusual complication of common viral infections. Thus, there is a high ratio of individuals who have systemic viral infection compared with a very few who develop clinical CNS disease. Most viral infections cause either meningeal involvement, namely aseptic meningitis, or a mild clinical syndrome of meningoencephalitis rather than the alarming forms of encephalitis. In general, viral encephalitis can be subdivided into categories based on etiology and pathogenesis: 1) acute encephalitis,2) postinfectious encephalomyelitis,3) slow viral infections of the CNS,and 4) chronic degenerative diseases of the CNS of presumed viral etiology. This review does not detail slow viral infections but highlights acute viral encephalitis and postinfectious encephalomyelitis.A virus gains access to the CNS generally by one of two routes:hematogenous or neuronal. Hematogenous spread is most common and is exemplified by arthropod-borne viral disease. Following an insect bite and local replication of virus at a skin site, transient viremia may ensue, with seeding of the reticuloendothelial system,particularly liver, spleen, lymph nodes, and sometimes muscle. With continued viral replication, secondary viremia leads to seeding of other organs,including the CNS. In acute viral encephalitis, capillary and endothelial inflammation of cortical vessels is a striking pathologic finding that is seen primarily in the gray matter or at the gray-white junction. Perivascular lymphocytic infiltration results either from passive transfer of virus across the endothelium at pinocytotic junctions of the choroid plexus or active replication of virus in capillary endothelial cells. Lymphocytic infiltration in the gray matter and neuronophagia can be found. As the disease progresses,astrocytosis and gliosis become prominent histopathologic findings. Unique histopathologic features include Cowdry type A intranuclear inclusions and Negri bodies associated with herpesviruses and rabies infections, respectively.Alternatively, virus can gain access to the nervous system intraneuronally, as occurs with herpes simplex virus (HSV) invasion from peripheral sites. Another example of intraneuronal transmission of virus to the CNS is rabies, which ultimately involves the limbic system. Once virus has reached the brain,subsequent replication can remain intraneuronally or can result in either cell-to-cell or extracellular transmission.Postinfectious encephalomyelitis is thought to be an autoimmune phenomenon that is initiated by the viral pathogen. An apparent latent phase exists between acute illness and the onset of neurologic symptoms. Histopathologic evaluation demonstrates perivascular inflammation and demyelination.Many human viral pathogens cause CNS infections. The Centers for Disease Control and Prevention suggest that approximately 20,000 cases of encephalitis occur in the United States each year, with most being mild. The two endemic causes of encephalitis in the United States are HSV and rabies virus. Rabies virus causes only encephalitis and is more common in developing countries. HSV accounts for approximately 10% of all cases of encephalitis in the United States.Japanese encephalitis probably is the most common epidemic infection of the CNS outside of North America. In China alone, more than 10,000 cases occur annually despite childhood immunization. The development of effective vaccines for control of diseases such as measles,mumps, rubella, and yellow fever has decreased the incidence of both acute encephalitis and the complication of postinfectious encephalomyelitis. Control of poliomyelitis through vaccination has decreased significantly the incidence of poliovirus infections of the CNS. A few sporadic cases do occur as a consequence of vaccine-associated infection. Other members of the picornavirus family clearly have the potential to invade the brain,including enteroviruses, coxsackieviruses,and echoviruses, although these latter agents usually cause a benign aseptic meningitis.The arthropod-borne viruses, such as St. Louis encephalitis, Eastern equine encephalitis, Venezuelan equine encephalitis, and La Crosse virus, cause sporadic and epidemic CNS viral infection in the United States. Early identification and recognition of the specific infection may lead to intervention strategies to prevent burgeoning mosquito populations that serve as vectors for transmission of infection.In the United States,postinfectious encephalomyelitis has been associated with upper respiratory tract infections, particularly influenza. In countries where the administration of vaccine is not routine,measles is a major cause of postinfectious encephalomeylitis,accounting for as many as 100,000 cases worldwide.The hallmark of viral encephalitis is the acute onset of a febrile illness. Clinical findings common to most viral encephalitides include headache, fever, altered consciousness,disorientation, and behavioral and speech disturbances. Although the neurologic signs may be focal, more commonly they are diffuse and include such findings as hemiparesis or seizures. These clinical findings distinguish a patient who has encephalitis from one who has viral meningitis, which is characterized by only nuchal rigidity and fever. Clinical findings reflect disease progression and the cells of the CNS that are infected. The trophism of a variety of viruses for different cell types illustrates this point. For example, the predisposition of HSV for the temporal lobe leads to clinical findings of aphasia, anosmia,temporal lobe seizures, and focal neurologic findings.Diagnosing specific viral infections of the CNS is difficult. The history may reveal a characteristic epidemiology that suggests a specific etiology. History of a bite from a potentially rabid animal, the season of year, and prevalent diseases within the community may provide clues. Enteroviral infections are encountered most commonly in late summer and early fall in temperate climates. Similarly, mosquito propagation may enhance the likelihood of arthropod-borne viruses in communities in damp climates and during warm summer months.Although physical examination of a patient usually does not lead to an etiologic diagnosis, the distinction between generalized and focal neurologic findings is important. The most common cause of focal encephalopathic findings is HSV. However, viruses that usually are responsible for diffuse encephalitic diseases occasionally can localize to one area of the brain, thereby mimicking HSE. Patients enrolled in antiviral studies of the treatment of HSE conducted by the National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group required a positive brain biopsy for HSV. However,55% of patients undergoing brain biopsy were found not to have HSV. Causes of these nonHSV diseases from patients who had negative HSV biopsies are listed in Table 1. A distinction must be made between viral encephalitis and postinfectious encephalomyelitis, an entity that develops days to weeks after the onset of acute viral illness. Postinfectious encephalomyelitis generally follows a vague viral syndrome, usually of the respiratory tract, and is most common among children. Neurologic findings vary and reflect the areas of the brain involved. Demyelination is a prominent pathologic finding. The distinction between postinfectious encephalomyelitis and acute viral encephalitis is crucial because the outcome is often different.Evaluation of the cerebrospinal fluid(CSF) is essential unless its collection is contraindicated because of marked increased intracranial pressure. Assessment of CSF indices is helpful, with findings generally including a predominately mononuclear cell pleocytosis and elevated levels of protein. Changes in glucose concentration usually are less helpful in suggesting a specific viral etiology for the encephalitis. A small percentage of patients(approximately 3% to 5%) who have severe viral infections of the CNS,such as HSE, have completely normal CSF, including both white blood cell count and protein concentrations. In these patients, even serial sampling of CSF fails to reveal any abnormalities. Unfortunately, cultures of CSF are of little value in isolating the virus except under unusual circumstances.Neurodiagnostic tests, including electroencephalography (EEG),computed tomography (CT), technetium brain scans, and magnetic resonance imaging (MRI), all can provide useful information in the evaluation of patients who have altered mentation and fever. As demonstrated in Table 1,some individuals have tumors or abscesses of the CNS that are not recognized immediately by CT imaging technology. It is possible that MRI will improve diagnostic capabilities. The EEG is of value,particularly for patients who have HSE in which periodic high-voltage spike wave activity emanating from the temporal regions and slow wave complexes at 2- to 3-second intervals are highly suggestive of HSV infection of the brain. These findings alone have prompted many physicians to institute antiviral chemotherapy, presuming the diagnosis to be HSE.Laboratory confirmation of the etiology of brain infections is of limited therapeutic value, but always is of prognostic value. For most diseases,antibodies identified in the CSF are not useful diagnostically unless evaluated sequentially. Routine evaluation of acute and convalescent sera to demonstrate either seroconversion or seroboosting is of no practical value in the decision to institute therapy for viral infections of the brain. Nevertheless, such studies may be helpful retrospectively to clarify the etiology of infection, as has been done for HSE.The development of new diagnostic assays that use CSF can accelerate diagnosis of viral infections of the brain. For example, an enzyme-linked immunosorbent assay(ELISA) that detects immunoglobulin M (IgM) antibodies in the CSF from patients who presumably have Japanese encephalitis is sensitive and specific. Most patients have IgM antibodies at the time of hospitalization, and virtually all acquire them by the third day of illness.The application of polymerase chain reaction (PCR) to amplify DNA is the diagnostic method of choice for HSV, cytomegalovirus(CMV), human herpesvirus 6(HHV-6), and enterovirus infections. The verification of the sensitivity and specificity has been studied best for HSE, where it is 99% and 94%,respectively. Notably, the CSF remains PCR-positive for HSV DNA in more than 80% of cases even 1 week after the initiation of antiviral therapy in cases of HSE. However, it is important to note that these results were achieved in a highly skilled research laboratory. Extrapolation to other PCR assays cannot necessarily be made at this time. Each clinician should determine the reliability, sensitivity, and specificity of his or her own commercially available assays.Following are the unique characteristics of some encephalitic syndromes of interest in the United States, emphasizing those for which efficacious therapy is available.HSV infection of the CNS occurs primarily in two circumstances:1) the newborn, and 2) encephalitis of older children and adults (HSE). Notably, however, HSV also can cause aseptic meningitis,predominately among patients who have primary genital HSV disease. The outcome in these cases is excellent,even without antiviral therapy. HSV infection of the brain is the only viral CNS infection for which therapy has been proved useful in rigorous controlled trials. Successful therapy depends on a high index of suspicion of HSV disease and early institution of therapy. However,clinical diagnosis often is based presumptively on evidence of focality on physical or neurodiagnostic evaluation. In the best interest of patient care, pleocytosis and elevated protein concentrations in the CSF of those who have encephalopathy but no identified pathogens should be considered to be caused by HSV until proven otherwise.Neonatal HSV infections of the CNS occur in approximately 50% of infants who have herpetic disease during the newborn period. The route of HSV type 2 to the brain in infants who have multiorgan disseminated infection is likely the blood and is associated with a diffuse encephalitic process that results in generalized encephalomalacia. When disease involves only the CNS and is not disseminated, neuronal transmission of virus to the CNS tends to result in initial unitemporal involvement, with subsequent bitemporal disease as illness progresses. Virus can be isolated by culture from the CSF in approximately 25% to 35%of babies who have encephalitis or disseminated disease. Given this relatively low yield, detection of the HSV DNA by PCR has become the gold standard for diagnosing HSV CNS disease in the neonate.No difference in morbidity or mortality was detected for vidarabine and acyclovir when compared directly for treatment of neonatal HSV infection. Morbidity and mortality of neonatal HSV disease involving the CNS depends on whether the infant has isolated involvement of the CNS (CNS disease) or involvement of other visceral organs such as the lungs or liver (disseminated disease). In the preantiviral era, mortality from disseminated neonatal HSV disease was 85%. Antiviral therapy has decreased this mortality rate to 60%. Among survivors, the likelihood of subsequent neurologic impairment has decreased only slightly, from 50% in the preantiviral era to approximately 40% now. The impact of antiviral therapy on the mortality from CNS disease (without dissemination to other visceral organs) is more pronounced, with a decrease from 50% in the preantiviral era to 15% or less today. Unfortunately,antiviral therapy has had essentially no impact on morbidity among survivors of CNS disease;approximately two thirds suffer neurologic impairment despite the use of antiviral agents during the period of acute CNS infection. Interestingly, babies who have HSV-1 infection of the CNS have a significantly better neurologic outcome than those who have HSV-2 infection of the brain. Because of the ease of administration and relative absence of toxicity,acyclovir is the medication of choice for treatment of neonatal HSV infection. The currently approved dosage is 30 mg/kg per day given intravenously in three divided doses. However, some experts recommend increasing the total daily dose to 45 to 60 mg/kg per day administered every 8 hours. The duration of therapy ranges from 14 to 21 days,depending on the severity of disease.HSE is the most common cause of nonepidemic, sporadic, acute focal encephalitis in the United States. The estimated occurrence is approximately 1 in 250,000 to 500,000 individuals annually. Occurring throughout the year, approximately one third of the cases of HSE develop in patients who are younger than 20 years of age, and 50% of individuals who have HSE are older than age 50. In the absence of antiviral therapy, the mortality for HSE exceeds 70%, with only approximately 2.5%of individuals returning to normal function. Infection is the consequence of HSV-1 in the overwhelming majority of cases. Interestingly,HSV-2, which is the most common cause of genital herpes and, not infrequently, viral meningitis, results in encephalitis only very rarely. Diagnosis is achieved by detection of HSV DNA by PCR in the CSF.Acyclovir is the treatment of choice for HSE (10 mg/kg per dose administered every 8 h for 14 to 21 d). Importantly, the age of the patient, level of consciousness, and duration of disease all influence the outcome of therapy. If the level of consciousness, as measured by the Glasgow Coma Score, is 6 or less, a poor therapeutic outcome is uniform,irrespective of the age of the patient. If the duration of disease prior to the institution of antiviral therapy is 4 days or less, survival increases from 72% to 92% at the 18 months following treatment. On long-term evaluation, 30% of acyclovir recipients are judged to be normal or have mild impairment, 9% have moderate sequelae, and 53% are dead or have severe impairment. Thus, the need for improved therapy is obvious.As identified in Table 1, other herpesviruses can cause acute encephalitic syndromes, including CMV and Epstein-Barr virus. The occurrence of focal encephalopathic disease caused by Epstein-Barr virus is of particular interest because recovery is complete. Varicella-zoster virus also can result in CNS disease. Cerebellar ataxia is a common clinical finding in association with chickenpox that usually is benign. In older individuals, zoster encephalitis and granulomatous arteritis can occur. The latter condition has been reported following zoster ophthalmicus.HHV-6 recently was identified as a pathogen of the CNS and has been associated with cases of meningitis and encephalitis in both children and adults. Encephalitis due to HHV-6 can be focal and mimic HSE. No specific findings distinguish encephalitis or meningitis caused by HHV-6 from that of other viral etiologies. Indeed, the full extent of neurotropism of HHV-6 remains to be elucidated, and the role of antiviral treatment in this disease is unknown. Of considerable interest are several recent reports suggesting that HHV-6 may play a role in the pathogenesis of multiple sclerosis.Herpes B virus has been reported recently as causing several cases of severe and fatal encephalitis. The virus is transmitted by monkey bite and can be prevented by proper animal handling precautions. Acyclovir or ganciclovir may be of value in therapy of CNS disease, but the therapeutic experience is limited. Because of the high fatality rate associated with B virus disease of the CNS, therapy should be attempted.Rabies is increasing in the United States because of the changing epidemiology of infection in animal populations. In the southeastern United States, raccoons, foxes, and bats most often are infected with rabies virus; in California, the skunk most frequently is infected. In South and Central America, dogs and cattle are the primary carriers of rabies virus. Infection is transmitted by the bite of a rabid animal. The incubation period varies, ranging from days to months. Not all individuals bitten by a rabid animal develop infection, but if infection does occur, it invariably is fatal. The best medical management is prevention of infection by use of postexposure vaccine and immune serum,particularly in individuals bitten by an unprovoked animal. Vaccine should be administered to animal handlers at risk. Recent vaccine advances using rabies virus glycoproteins produced by vaccine vectors may be a better prophylactic approach. Attempts to administer vaccine to wild animals to decrease transmission in the animal community have been attempted in Europe and North America with some degree of success.The diagnosis of rabies sometimes can be made by staining of corneal smears, but only approximately 50% are positive by immunofluorescence. Biopsy of the skin at the nape of the neck or of buccal mucosa provides a lower diagnostic yield. Brain biopsy can lead to positive identification by immunofluorescence within a short period of time. An old technique of inoculating brain tissue from the presumed rabid animal into susceptible animals who then are monitored for illness remains in use as a diagnostic tool.Arthropod-borne viruses can be a common cause of sporadic and epidemic encephalitis in the United States. These viruses replicate in both vertebrate and nonvertebrate species and include members of the alpha-, flavi-, and bunyavirus families. These agents are transmitted by mosquitoes and ticks. Among the alphaviruses are those that cause Eastern, Western, and Venezuelan equine encephalitis. The flaviviruses cause either mosquito- or tick-borne encephalitis. Examples of the former include Japanese, St. Louis, Rocio,Murray Valley, and West Nile encephalitis. Examples of tick-borne diseases are Kyasuma Forest and Powassan encephalitis. The bunyavirus family includes the most common causes of arboviral disease in the United States, La Crosse virus,as well as Jamestown Canyon and California encephalitis viruses.Japanese encephalitis is a major medical problem in China, Southeast Asia, and India, where as many as 20,000 cases per year have been reported. The major vector for Japanese encephalitis in humans appears to be the colicine mosquito, which breeds in large numbers in rice fields. Incubation in the mosquito,known as the gestational incubation period or the interval between ingestion of infected blood and spread from the mid-gut to the salivary glands, is inoculum- and temperature-dependent. Once the human is infected, the resultant pathology is similar for mice or humans, with hematogenous spread to the brain that frequently involves the basal ganglia. A predictive factor for outcome is the rapid appearance of antibodies directed against Japanese encephalitis in the CSF, which ameliorate the severity of disease.A summary of common clinical characteristics and outcomes for arboviral infections of the United States appears in Table 2. Most of these viruses are transmitted by mosquitos from a host, such as wild birds, to horses or humans in whom clinical symptomatology develops. Outbreaks appear in the United States periodically, as occurred with St. Louis encephalitis in the Ohio and Mississippi River basins in the early 1980s. St. Louis encephalitis is the second most common arthropod-borne encephalitis in this country. As with other infections of the brain, the ratio of apparent to inapparent infection is high, varying from 1 in 1,000 to 1 in 100. Encephalitis due to St. Louis encephalitis virus has a fatality rate of 10% to 20%, with most deaths occurring in young children or the elderly. Other encephalitides transmitted by arthropods have either similar mortality rates, such as Venezuelan equine encephalitis found in the southern United States, or higher mortality rates, such as Eastern equine encephalitis, a fortunately rare disease that occurs along the Gulf and Atlantic coasts. Western equine encephalitis is associated with a high overall rate of infection in the population but a low incidence of both overt disease and mortality (3% to 7%). The California group of viruses, including the La Crosse virus, is the most significant cause of brain infection in the upper midwestern United States.Enteroviruses can produce both meningitis and encephalitis in infected persons. The degree of involvement within the CNS depends on the person’s age and immune status. Infection in the neonatal period can be life-threatening,with severe disease commonly including meningitis or meningoencephalitis as a component. Among infants beyond the neonatal period,however, severe disease or poor outcome is rare. The incidence of enteroviral meningitis is highest during the first two months of life. In one study of aseptic meningitis in infants younger than 2 years of age,64% of the children were 8 weeks of age or younger and 85% were younger than 16 weeks of age. Approximately 10% of infants hospitalized with aseptic meningitis experience acute CNS complications, such as seizures, obtundation,or increased intracranial pressure. However, recent large prospective studies of long-term outcome have failed to identify any long-term adverse neurologic sequelae following enteroviral meningitis, including among infants who had neurologic findings during the acute illness.Enteroviral encephalitis is well-described but significantly less common than enteroviral meningitis. Following a prodromal period of fever and upper respiratory tract symptoms, there usually is an abrupt onset of such neurologic findings as confusion, altered level of consciousness, and irritability. Unlike the focal encephalitis seen in HSE,enteroviral encephalitis usually is global, with generalized neurologic manifestations.Finally, in patients who have agammaglobulinemia, enteroviral infections of the CNS can be chronic over many years. This highlights the importance of the humoral arm of the immune system in the containment and clearance of enteroviral infections.Human T-lymphotropic viruses(HTLV) are known causes of CNS disease. HTLV type I has been associated with spastic pareses in Japan and Hawaii. Human immunodeficiency virus (HIV) causes dementia in nearly all patients by the time of death and especially among children who fail antiretroviral therapy. For HIV-infected children, CNS involvement initially is characterized by the loss of developmental milestones. Likely, HIV encephalopathy will become the most common cause of CNS viral infection worldwide. Therapy may benefit CNS disease as it does other systemic manifestations of infection.Other viruses can cause CNS disease and are reviewed briefly. Two paramyxoviruses, mumps and measles, commonly caused CNS disease in the prevaccine era, but immunization programs in the United States have nearly eliminated this problem. The arenaviruses, lymphocytic choriomeningitis and Lassa viruses, are rare causes of CNS disease. Ribavirin, an antiviral licensed for therapy of respiratory syncytial virus infection of infants, has been reported efficacious in the treatment of Lassa fever.In the United States, postinfectious encephalomyelitis most commonly is associated with the occurrence of varicella and upper respiratory tract infections, particularly influenza. Worldwide, however, measles is a more important cause of postinfectious encephalomeylitis, accounting for as many as 100,000 cases. In what appears to be the consequence of a perturbation of the immune response, individuals who have postinfectious encephalomyelitis suffer from an invariably irreversible demyelinating syndrome. Why only certain individuals develop postinfectious encephalomyelitis remains to be explained.Patients who develop postinfectious encephalomyelitis due to measles typically have an abrupt onset of new fever, neurologic symptoms,and multifocal signs, including altered mental status, during recovery from measles. Approximately 50% of patients have seizures. Onset of these symptoms is usually 2 to 7 days after the initial appearance of the measles rash. Fatality rates have been estimated to be as high as 25%. Neurologic sequelae occur in the majority of survivors and may be severe. CSF findings range from normal to a mononuclear pleocytosis, with moderate elevations in protein concentration in some patients. EEG reveals diffuse slowing.Understanding the spectrum of disease produced by viral infections of the CNS has increased exponentially in recent decades. Along with this increased knowledge base, effective antiviral therapies have emerged for some of the offending pathogens. To date, antiviral therapies have been reserved mostly for more severe CNS infections, primarily encephalitis. Despite these advances,significant obstacles remain. Specifically,standardized, commercially available, rapid diagnostic tests that can reliably diagnose individual viral CNS diseases are needed in greater number. Additionally, antiviral agents that are effective against such scourges as Japanese encephalitis virus, the arthropod-borne viruses,and rabies are needed. With these advances, the overall care during the acute illness as well as during recovery likely will improve.