CHAPTER 92 VIRAL MENINGITIS AND ENCEPHALITIS
Acute viral infections of the central nervous system (CNS) are normally classified into two clinical syndromes, meningitis and encephalitis, which reflects the anatomical localization of the infection. They are inflammatory conditions of the leptomeninges and brain, respectively. In general, both are caused by the same viral agents, although there is often a propensity for an agent to be more associated with one condition than with the other. Many of these infections are related to neuroinvasion during the course a systemic infection (e.g., arbovirus and enterovirus infections), and only a small subset of patients with the infection actually develops either meningitis or encephalitis. In contrast, rabies virus produces encephalomyelitis and does not cause systemic infection.
EPIDEMIOLOGY
Viral Meningitis
The incidence of aseptic meningitis has been estimated at 10.9 per 100,000 people per year.1 Viral meningitis is more common in men and boys, with a male-to-female ratio of at least 1.5. For reasons that are unclear, the disease is relatively uncommon among people older than 40. There is a striking seasonal incidence, with peak incidence during the months of July, August, and September, which reflects the dissemination of both enteroviruses and arboviruses (see the following sections).
Specific Viral Etiologies
Enteroviruses are ubiquitous, infect individuals of all ages, and cause a wide spectrum of clinical illnesses. Humans are infected by multiple enteroviruses during their lifetime. There is a predominance of enterovirus infections during the summer and fall, although sporadic cases occur all year. Enteroviruses belong to the family Picornaviridae and include the polioviruses, coxsackieviruses, echoviruses, and the numbered human enteroviruses 68 to 71. The enteroviruses are the most common cause of viral meningitis and are responsible for more than 80% of cases in which a specific etiology can be identified.2 Less commonly, enteroviruses cause encephalitis. The enteroviruses replicate in the gastrointestinal tract and are transmitted via the fecal-oral route. Most enteroviral infections are asymptomatic, and gastrointestinal symptoms are usually absent. Recognized cases of viral meningitis represent only a small fraction of enteroviral infections.3 Patients with agammaglobulinemia may develop chronic enterovirus meningitis, and therapy with intravenous immunoglobulin has proved useful in these patients.4,5
Mumps virus was at one time responsible for more cases of viral meningitis than any other single virus. Mumps virus is transmitted via the respiratory route. Outbreaks of mumps peak in the late winter and early spring in northern temperate climates, and major outbreaks traditionally occur at intervals of 2 to 7 years. Mumps virus infection confers lifelong immunity. Mumps virus infection may be associated with parotiditis, orchitis, and deafness. In mumps meningitis, mumps virus may frequently be isolated from the cerebrospinal fluid (CSF). Mumps meningitis has become much less common in the United States since the introduction of live attenuated mumps vaccine in the late 1960s. The Jeryl-Lynn strain of mumps vaccine, which is in trivalent vaccines currently used in the United States, has not been associated with neurological complications. However, the Urabe strain of mumps vaccine, which has been used in other countries, is associated with occasional cases of meningitis.6
Lymphocytic choriomeningitis virus is an arenavirus that causes inapparent infection in rodents and is present in their excreta, and direct contact may result in human infection. In humans, a biphasic illness is common: a mild systemic illness with fever, malaise, and myalgias that improves before the onset of meningitis. Lymphocytic choriomeningitis infection may be associated with severe respiratory symptoms, with pulmonary infiltrates, parotitis, orchitis, or rash.7 Although most cases of lymphocytic choriomeningitis virus infection manifest with meningitis, encephalitis may also occur.
Herpes simplex virus (HSV) type 2 is associated with viral meningitis, particularly at the time of an initial episode of genital herpes infection and especially in girls and women. Meningitis may be preceded by genital or pelvic pain. A minority of these patients go on to have recurrent episodes of meningitis, which may meet the criteria for Mollaret’s meningitis, in which the virus usually cannot be cultured from CSF, but HSV type 2 (occasionally type 1) DNA can often be detected in CSF with polymerase chain reaction (PCR) amplification.8,9
With regard to other viruses, viral meningitis is associated with primary infection with human immunodeficiency virus (HIV) in 5% to 10% of patients, which usually occurs just before the time of seroconversion. Cranial nerve palsies, particularly involving cranial nerves V, VII, and VIII, are more common in HIV meningitis than in viral meningitis with other causes.10 Varicella-zoster virus (VZV) may produce meningitis associated with chickenpox or shingles and rash may not be associated.11,12 PCR amplification is useful in the diagnosis of varicella-zoster virus CNS infections.
Viral Encephalitis
Although many of the same viruses cause viral meningitis and encephalitis, the relative frequencies of the two conditions are different. The incidence of encephalitis has been estimated at 7.4 per 100,000 people per year.1 More than 100 viruses are known to cause acute viral encephalitis, and specific etiological viral agents vary in frequency from year to year13 (Table 92-1). After thorough investigation, one study demonstrated a confirmed or probable viral agent in only 9% of cases of encephalitis, which included those with nonviral causes.14
TABLE 92-1 Significant Causes of Viral Encephalitis in the United States
Adapted from Griffin DE, Inouye RT: Acute viral encephalitis. In Schlossberg D, ed: Current Therapy of Infectious Disease, 2nd ed. St. Louis: Mosby, 2001, pp 270-276.
Specific Viral Etiologies
HSV type 1 is the most common cause of sporadic encephalitis and herpes simplex encephalitis has been identified in about 5% to 10% of cases of acute viral encephalitis in the United States15 with an estimated incidence of about 1 per 250,000 to 500,000 people per year.16 There is no seasonal preponderance or gender predilection. There is a bimodal age distribution in which about one third of cases occur in patients younger than 20 and one half in patients older than 50; this may reflect the occurrence of primary infections in younger individuals and reactivation of latent infections in older patients.17,18 About 90% of cases of herpes simplex encephalitis are caused by HSV type 1, and 10%are caused by HSV type 2.19 Familial herpes simplex encephalitis has been reported infrequently.20
Arboviral infections have a seasonal (usually in the summer and early fall) and geographical distribution that depends on complex ecological cycles between arthropod vectors (mosquitoes and ticks) and their natural hosts. The arboviruses are a biological classification of viruses based on transmission by hematophagous arthropod vectors, and they include viruses in different families, including togaviruses, flaviviruses, bunyaviruses, and reoviruses. Most arboviral infections produce a subclinical or mild clinical illness and go undiagnosed. A minority of patients develop a febrile illness, and a much smaller minority develop encephalitis or, less commonly, meningitis. Epidemics of eastern equine encephalitis are relatively small, with fewer than 35 human cases, and they usually occur in the coastal regions of the eastern United States. Western equine encephalitis occurs in the western United States and in Canada. Venezuelan equine encephalitis has occurred in large outbreaks in Central and South America, and in 1971, a large epidemic in Mexico crossed the Texas border.21 In Venezuelan equine encephalitis, horses are important amplifying hosts, whereas in eastern and western equine encephalitis, horses, like humans, are dead-end hosts. St. Louis encephalitis occurs in both urban and rural outbreaks, and it is an important cause of epidemic encephalitis in North America. In 1975, an epidemic of St. Louis encephalitis included cases in 30 states and in Canada.22 About 25 sporadic cases of Powassan encephalitis have occurred in the northern United States and Canada (Ontario and Quebec).23,24 Powassan virus is transmitted by Ixodes ticks. Most cases of California serogroup encephalitis are caused by La Crosse virus and occur in the central United States. Japanese encephalitis is the most common cause of epidemic encephalitis in the world. Large summer epidemics and endemic disease in Asia are responsible for an estimated 50,000 cases and 15,000 deaths annually.25 Japanese encephalitis virus is transmitted by the mosquito Culex tritaeniorhychnus that breeds in rice fields. Water birds are natural hosts, and pigs may be important amplifying hosts in many countries. In 1999, West Nile virus was responsible for an outbreak of encephalitis in New York City and neighboring counties. The mechanism of introduction of the virus into North America is unknown. The virus has quickly moved across the North American continent. In the United States during 2003, there were 2866 cases of West Nile virus infection causing meningitis or encephalitis and 264 deaths26 (Fig. 92-1). Elderly and immunosuppressed patients are particularly at risk for disease and a fatal outcome. Transmission of West Nile virus may also occur by organ transplantation, infected blood products, and breast milk.
Figure 92-1 Distribution of human cases of West Nile virus infection by state in the United States during 2003 and 2004.
(From the Centers for Disease Control and Prevention, http://www.cdc.gov/ncidod/dvbid/westnilel)
Nipah virus was associated with an epidemic of encephalitis in pig farmers and abattoir workers in Malaysia in 1998 and 1999, which affected 265 people and killed 105.27 Two species of large fruit bats (flying foxes) are the natural hosts of the virus.28 Infected pigs developed respiratory disease and transmitted the virus to humans via the respiratory route, but subsequent outbreaks of Nipah virus encephalitis in Bangladesh and India have not been traced to pig infections.
CLINICAL FEATURES AND INVESTIGATIONS
The diagnosis of viral meningitis or encephalitis can often be made on the basis of the clinical evaluation without specific laboratory or imaging investigations. Patients with viral meningitis have fever, headache, and neck stiffness and rigidity. There is an inflammatory response involving proinflammatory cytokines that play a role in producing fever. The leptomeninges are pain-sensitive structures that account for headache and neck pain and stiffness. Patients may have mild drowsiness, but the level of consciousness is not severely altered, and there are no seizures, focal neurological signs, or other clinical evidence of involvement of the brain parenchyma. In contrast, patients with viral encephalitis have one or more of these features. Some patients with encephalitis have prominent focal features, including hemiparesis or aphasia, whereas others have diffuse brain involvement with depression in the level of consciousness without lateralizing signs. Specific arboviruses are associated with regional involvement of the CNS, including the basal ganglia with Japanese encephalitis virus, the rhombencephalon with West Nile virus, and the spinal cord with tickborne encephalitis virus and West Nile virus.
Examination of the CSF is the mainstay of diagnosis in viral meningitis and encephalitis. In viral meningitis, there is typically mild mononuclear pleocytosis, a normal or mildly elevated protein concentration, and a normal or mildly decreased glucose concentration. In meningitis arising from mumps and lymphocytic choriomeningitis virus infections, the CSF cell counts may be in the thousands. Polymorphonuclear leukocytes may predominate in the CSF, particularly early in the illness. In this case, a repeat examination several hours later usually shows a shift to mononuclear cells.29 Viruses may be cultured from the CSF, or nucleic acids may be detected with PCR amplification techniques. Serological testing may also be helpful for making a specific etiological diagnosis in viral meningitis. Patients with encephalitis should also undergo brain imaging, preferably magnetic resonance imaging (MRI), and CSF examination if there is no concern about brain herniation or other contraindications to lumbar puncture.
Specific Clinical Syndromes
Enteroviral meningitis manifests with fever, headache, and nuchal rigidity, and nausea, vomiting, and photophobia are common. Young children or neonates may exhibit irritability and nonspecific findings. Exanthemata, hand-foot-and-mouth disease, herpangina, pleurodynia, myocarditis, pericarditis, and hemorrhagic conjunctivitis are associated with enterovirus infections. The duration of illness is usually about 1 week, but some symptoms may persist for several weeks, particularly in adults. Serological testing is of only very limited value in enteroviral meningitis because of the large number of enteroviral serotypes. Enteroviruses may be cultured from the oropharynx and stool and also in blood, CSF, urine, and tissues. However, viral growth in culture may take 4 to 8 days, and some enterovirus serotypes grow poorly.30 PCR amplification on CSF for enteroviruses has proved diagnostically superior to viral cultures and has an important effect in reducing the use of antibiotics and in shortening hospitalizations.31 Enteroviruses can also cause encephalitis. In 1998 there was an enterovirus 71 epidemic in Taiwan with many cases of rhombencephalitis.32
Epstein-Barr virus meningitis may occur with or without an infectious mononucleosis syndrome, and meningitis is the most common neurological manifestation of Epstein-Barr virus infection. Encephalitis is less common, and its prognosis is fairly good. Atypical lymphocytes may be present in peripheral blood specimens or in CSF. Epstein-Barr virus is rarely cultured from CSF. PCR amplification may reveal Epstein-Barr virus DNA in the CSF, but the sensitivity and specificity of the test have not yet been determined.33 Serological tests may show evidence of acute Epstein-Barr virus infection with immunoglobulin M (IgM) antibody to viral capsid antigen or with antibody to the diffuse component of the early antigen in association with the absence of antibody to nuclear antigen.34
Herpes simplex encephalitis is characterized by headache, fever, and alteration of consciousness, which may develop over a period of hours or more slowly, over days. Headache is usually a prominent early symptom, and fever is almost always present. Focal neurological features are frequently present, including aphasia, hemiparesis, and visual field defects (superior quadrant). Focal or generalized seizures and olfactory or gustatory hallucinations may occur as well. Behavioral disturbances (sometimes bizarre), personality changes, or psychotic features may occur and be prominent, and psychiatric disease is sometimes suspected. Signs of autonomic dysfunction are also often present. Papilledema is present in a minority of patients. Mild or atypical forms of herpes simplex encephalitis have been recognized without focal features, and they have been associated with both HSV types 1 and 2 infections, immunosuppression with corticosteroids or coexisting HIV infection, or disease predominantly involving the nondominant temporal lobe.35,36 Herpes simplex encephalitis may occur with unusual clinical features, including the anterior opercular syndrome.37
Focal electroencephalographic abnormalities are present in about 80% of cases of herpes simplex encephalitis.38 Sharp- and slow-wave activity is usually localized to the temporal region, and periodic complexes may be present.39 Brain imaging studies, particularly MRI, usually reveal abnormalities in involved areas, including the frontal and temporal lobes, although rare patients with normal MRI studies have been reported.40 Computed tomography reveals hypodense lesions in the temporal lobe and orbitofrontal region, which may demonstrate mass effect, regions of hemorrhage, and irregular contrast enhancement. On MRI, hyperintense signal intensities are typically seen on T2-weighted images in typical sites (Fig. 92-2A), including one or both inferomedial temporal lobes, insular cortex, inferior frontal lobes, cingulate gyrus, and thalamus, with foci of hemorrhage caused by the presence of degradation products of hemoglobin, whereas T1-weighted images show hypointense signal in the same areas, and meningeal enhancement may be demonstrated after administration of gadolinium.41 Fluid-attenuated inversion recovery imaging sequences demonstrate superior definition of temporal lobe abnormalities in comparison with standard T1- and T2-weighted images36 (see Fig. 92-2B). Diffusion MRI studies may also be useful for early detection of lesions.42,43
