Nervous System Complications of Systemic Viral Infections

Enteroviruses

Enteroviruses are unenveloped single-stranded RNA viruses forming a genus in the family picornavirus. They account for 60 to 80 percent of cases of viral meningitis in which an agent is identified. Enteroviruses survive well in water and sewage, are transmitted by fecal–oral or hand–mouth routes, and replicate initially in the gastrointestinal tract. Enteroviruses were previously subdivided into three groups: polioviruses, echoviruses, and coxsackieviruses. Newer isolated enteroviruses have been assigned numbers (e.g., enterovirus 71 or EV71). Coxsackievirus A9 and echoviruses E7, E9, E11, E19, and E30 have accounted for 70 percent of all cultured isolates from cerebrospinal fluid (CSF) in cases of enteroviral meningitis. Polioviruses have been largely eradicated, persisting only in Nigeria, Pakistan, and Afghanistan. Other enteroviruses have a worldwide distribution, and although cases of enteroviral meningitis occur throughout the year, infection is most likely to occur during summer and early fall months when conditions of sanitation are most lax. Acute enterovirus infection is usually asymptomatic or may result in mild gastroenteritis or pharyngitis; less than 5 percent of patients will develop meningitis or encephalitis.

Enteroviral CNS infection typically causes meningitis rather than encephalitis, with fever, headache, and stiff neck. These symptoms commonly last for 1 to 3 weeks in older children and adults. In occasional patients, enteroviruses may cause encephalitis or rarely a paralytic disease similar to polioviruses (see below) and may cause protracted, atypical infection in immunocompromised patients.

Herpes Simplex Virus Type 2

HSV-2 is a double-stranded DNA virus that is universal in human populations. HSV-2 is usually transmitted sexually, with antiviral antibodies first appearing in adolescence or early adult life. Following acute infection, the virus persists predominantly in spinal sensory ganglia and is subject to periodic reactivation, often without cutaneous or mucosal signs of infection. HSV-2 accounts for up to 10 to 20 percent of isolates in adults with viral meningitis and is roughly twice as common among women. HSV-2 as a cause of viral meningitis should be considered, particularly in young, sexually active adults. Older data suggested that up to 36 percent of women and 11 percent of men had headache, fever, or nuchal rigidity at the time of their first attack of genital herpes. Some patients with HSV-2 meningitis following genital herpes may have focal lumbosacral symptoms including urinary retention suggesting nerve root infection, and the virus may also be associated with myelitis. HSV-2 DNA can frequently be detected in CSF by amplification using the polymerase chain reaction (PCR). Approximately 20 percent of individuals with acute HSV-2 meningitis may subsequently develop recurrent episodes of meningitis (Mollaret meningitis). Many individuals with recurrent meningitis have no history of genital herpes and lack genital lesions during attacks of meningitis.

Patients with HSV-2 meningitis usually recover without treatment. Although successful treatment with acyclovir has been described in individual cases, the efficacy of antiviral therapy in acute or recurrent HSV-2 meningitis is uncertain. In one clinical trial, suppressive treatment with valacyclovir did not prevent recurrence of HSV-2 meningitis.

Varicella Zoster Virus

VZV is a herpesvirus typically associated with chicken pox during acute infection and with cutaneous zoster (shingles) during reactivated infection. Like HSV-2, VZV is thought to account for 10 to 20 percent of identified cases of viral meningitis. Meningitis may occur during either primary or reactivated infection and may do so in the absence of rash. In contrast to many other viruses, VZV meningitis may result in significant CSF hypoglychorrachia and may be accompanied by a CSF pleocytosis characterized by atypical lymphocytes. As with HSV-2 meningitis, most immunocompetent patients with VZV meningitis recover without treatment. VZV infection may also produce a wide variety of other neurologic conditions, which are discussed in greater detail below.

Less Common Causes of Viral Meningitis

The arthropod-borne agents—WNV, St. Louis encephalitis virus, California encephalitis virus, Powassan virus, Jamestown Canyon virus, and Colorado tick fever virus—are most commonly associated with encephalitis, but may also cause meningitis. WNV, St. Louis encephalitis virus, Jamestown Canyon virus, and California encephalitis virus are transmitted by mosquitoes and tend to be more common in summer and early autumn months. The tick-borne agents Powassan virus and Colorado tick fever virus can cause a rash and most frequently occur during spring and early summer months. An important diagnostic consideration in patients with suspected Colorado tick fever is the tick-borne rickettsial illness Rocky Mountain spotted fever, which also has a peak incidence in spring and summer, usually has a rash, and requires antibiotic treatment.

LCMV is an arenavirus whose natural host is mice but which can cause meningitis and, less frequently, encephalitis in humans. The virus is present in mouse urine and is acquired by the respiratory route. At one time, it was thought to account for roughly 4 percent of diagnosed cases of viral meningitis, but in recent years it has become much less common, for unknown reasons. LCMV infections are classically most common in autumn and winter. Occasional outbreaks of infection have been associated with exposure to mice in animal facilities or to pet hamsters or guinea pigs. The meningitis associated with LCMV may be accompanied by low CSF glucose levels, which may persist over weeks to months in cases with prolonged recovery. In neonates, LCMV may cause a fatal systemic and CNS infection. Outbreaks of severe infection with high mortality have also been reported in which LCMV has been transmitted by organ transplantation. Reliable antiviral therapy for LCMV infection is not available; one patient with transplant-acquired LCMV infection recovered after reduction of the patient’s immunosuppressive regimen and treatment with ribavirin.

Mumps virus, once a major cause of meningitis worldwide, is now rare in developed countries but remains a significant cause of meningitis in areas where mumps immunization is not practiced. The virus has also caused occasional epidemics in Western countries in unvaccinated populations exposed to individuals who have visited areas where mumps is still prevalent.

Human Immunodeficiency Virus

CNS invasion occurs early in the course of primary HIV infection, and meningitis due directly to HIV occurs in 9 to 24 percent of patients (see Chapter 43 ). The meningitis usually develops near the time of seroconversion and often occurs in the setting of an acute, mononucleosis-like retroviral syndrome characterized by fever, pharyngitis, and cervical lymphadenopathy; CNS findings of disorientation, confusion, or psychosis accompany this syndrome in some patients. Primary HIV meningitis should be considered in young adults with meningitis, particularly when they have HIV risk factors or a co-existent mononucleosis-like syndrome. The symptoms of meningitis are usually not severe and resolve in most but not all cases; in some patients, HIV meningitis becomes chronic. The CSF typically reveals a mild lymphocytic pleocytosis, mildly elevated protein content, and normal glucose level. HIV meningitis may be the initial presentation of HIV infection and may also occur early enough that standard serologic tests for HIV (as well as tests for home use) have not yet become positive. Initial diagnostic testing, per CDC recommendations, ideally involves a combined HIV-1/2 antigen/antibody assay; this should be repeated in 45 days if the assay is negative but there is high suspicion of HIV. Individuals testing positive should be assayed for viral load in serum and CSF. Treatment of HIV is with antiretroviral therapy, and follow-up assay for antiviral antibodies is used to confirm the diagnosis. In approaching patients with suspected HIV meningitis, it must be kept in mind that lymphocytic meningitis in patients with HIV infection may be caused by a wide variety of other agents, many of which are treatable.

Approach to Patients With Viral Meningitis

Bacterial meningitis is the primary concern in any patient presenting with acute meningitis. If the patient is severely ill, bacterial meningitis should be suspected and presumptive antibiotic therapy should be initiated immediately, usually along with corticosteroids. Similarly, acyclovir should be initiated if HSV encephalitis is a significant diagnostic concern. Antibiotics and acyclovir can be discontinued once CSF studies are negative. In general, patients presenting with viral meningitis are less severely ill, and antibiotic and acyclovir treatment may often be deferred.

The diagnosis of viral meningitis is made by lumbar puncture and CSF analysis. In acute bacterial meningitis, there is often an elevated opening pressure and typically a marked neutrophilic pleocytosis, with significantly elevated protein and depressed glucose concentrations. In contrast, in viral meningitis the opening pressure is usually normal or mildly elevated, and the CSF white cell count is usually in the range of 50 to 2000/mL. Although viral meningitis typically produces a lymphocytic pleocytosis, polymorphonuclear leukocytes may constitute over 50 percent of the cells during the first 24 to 36 hours of the infection and may occasionally remain the predominant cell type for longer periods of time. Protein is usually elevated in the range of 50 to 100 mg/dL but is sometimes higher. The CSF glucose level in viral meningitis is usually greater than 50 percent of blood glucose; the absence of CSF hypoglychorrachia is an important consideration in differentiating viral from bacterial meningitis. Depression of glucose to levels approaching those of bacterial meningitis may occasionally occur in meningitis caused by HSV-2, VZV, mumps, and LCMV. In the proper setting, lymphocytic pleocytosis with low CSF glucose may also raise concern about tuberculous or fungal meningitis.

Specific diagnosis of viral agents in CSF currently involves PCR amplification of viral RNA or DNA; at present, tissue culture isolation of virus is rarely performed for diagnostic purposes ( Table 42-1 ). PCR is rapid and has a high level of sensitivity in meningitis due to enteroviruses, HSV-2, and VZV during acute infection. PCR can identify all strains of enteroviruses but does not distinguish between individual strains. Enteroviral RNA can be identified in CSF in the first 1 or 2 days of meningitis, from throat for several days, and from stool for a few weeks. Because asymptomatic enterovirus infections are common in the summer months, enterovirus isolation from throat or stool does not make a definitive diagnosis of enterovirus meningitis. Use of an enterovirus PCR assay in the emergency department in children with aseptic meningitis has resulted in significantly less antibiotic use, shorter length of hospitalization, and lower hospital costs. Film-based multiplex assays, capable of detecting nucleic acids of multiple infectious agents provide rapid screening but should be followed up with conventional PCR. Although CSF PCR is the diagnostic study of choice in many viral meningitides, the assay may be negative early in the disease course, and diagnostic yield may be highest when CSF is obtained within 3 to 14 days of onset of meningitis. In certain instances, the detection of CSF immunoglobulins may have greater diagnostic sensitivity than PCR. This is the case in WNV neuroinvasive disease and other arbovirus infections, in which detection of virus-specific immunoglobulin M (IgM) is more sensitive than PCR. Similarly, detection of virus-specific immunoglobulin G (IgG) in CSF may prove diagnostic in infections due to protracted or reactivated VZV where PCR is negative. Identification of the causative agent in viral meningitis may be made retrospectively by detecting a rise in IgG antibody titers between acute and convalescent (obtained after 3 to 6 weeks) serum or, at times, by detecting an abnormal serum:CSF ratio of antiviral antibodies.

Other laboratory studies in viral meningitis are usually unhelpful. Peripheral white blood cell count may be normal or elevated. Computed tomography (CT) scans and magnetic resonance imaging (MRI) of the brain are typically normal. The electroencephalogram (EEG) is usually normal but may occasionally show mild background slowing. Marked asymmetries or seizure foci should not be seen unless encephalitis predominates.

Viral meningitis is sometimes referred to by the older term “aseptic meningitis.” This term, however, subsumes a broad range of clinical entities characterized by a meningeal reaction but distinct from purulent bacterial meningitis. It may include not only viral meningitis but also infections by bacteria that are not readily detected in routine cultures ( Leptospira icterohaemorrhagiae , Borrelia burgdorferi , Treponema pallidum , Mycoplasma pneumoniae ), meningeal involvement by Rickettsia , Ehrlichia , or Anaplasma , and infection by parasites such as Toxoplasma gondii . The possibility of infection by one of these agents should be kept in mind in a patient with suspected viral meningitis, since all are amenable to antibiotic treatment. In particular, B. burgdorferi can be a major cause of lymphocytic meningitis in endemic areas (see Chapter 39 ). Aseptic meningitis may also be associated with a variety of pharmacologic agents including nonsteroidal anti-inflammatory agents, trimethoprim-sulfamethoxazole, augmentin, carbamazepine, intravenous immunoglobulin G, and the murine monoclonal antibody OKT3. Treatment of viral meningitis is supportive in most cases. Analgesics may be required for individuals with severe headaches, and antiemetics for those with considerable nausea and vomiting. Hospitalization is seldom required except when vomiting is severe enough to cause dehydration or when bacterial meningitis cannot be excluded. Acyclovir and valacyclovir have been used to shorten the duration of illness in acute meningitis due to HSV-2 and VZV. However, controlled studies do not exist, and no standardized regimen has been developed. Patients with recurrent HSV meningitis may wish to keep oral acyclovir or valacyclovir at home and take the drug at the onset of meningeal symptoms. Ongoing twice daily treatment with valacyclovir at a dose of 0.5 mg has not been shown to prevent recurrence, but higher dosages have not been formally studied. The antiviral agent pleconaril, which prevents uncoating of viral RNA, has been used in enteroviral meningitis but is not routinely available in the United States.

As a group, patients with viral meningitis generally make a complete recovery within 1 to 2 weeks. Not all patients recover this quickly, however, and symptoms such as fatigue may last for weeks or even months. CSF abnormalities may also persist for well beyond the initial period of recovery. In addition, there have been occasional reports of permanent sequelae, usually but not always in small children, including cognitive impairment, deafness, and cranial nerve palsies. Aqueductal stenosis with hydrocephalus is a rare complication of HSV-2 and mumps meningitis.