Version October 2024
INTRODUCTION — Viral meningitis is defined as:
●A febrile illness with clinical signs and symptoms of meningeal irritation
●No associated neurologic dysfunction
●No evidence of bacterial pathogens in the cerebrospinal fluid (CSF) in a patient who has not received prior antibiotics
The epidemiology, pathogenesis, and etiology of viral meningitis will be reviewed here. Other related topics include:
●(See "Viral meningitis in children: Clinical features and diagnosis".)
●(See "Viral meningitis in children: Management, prognosis, and prevention".)
●(See "Bacterial meningitis in children older than one month: Clinical features and diagnosis".)
●(See "Bacterial meningitis in children older than one month: Treatment and prognosis".)
EPIDEMIOLOGY — Reported incidence rates of viral meningitis range from 10 to 20 cases per 100,000 children per year [1-3]. In the United States, viral meningitis accounts for approximately 26,000 to 42,000 hospitalizations each year [4]. The incidence is highest among infants <1 year old, with a second peak occurring in children >5 years old [3,4]. In temperate climates, most cases occur in the summer and autumn, reflecting the peak activity of enteroviral and arthropod-borne infections (table 1) [5,6].
PATHOGENESIS — Most viral pathogens affecting the central nervous system (CNS) initially infect mucosal surfaces of the respiratory and gastrointestinal tract, followed by viral replication in regional lymph nodes. This precedes a primary viremia that signals the onset of illness and subsequent seeding of other organs. Except for neonatal herpes simplex virus (HSV) infection, most viruses reach the CNS during a second viremia that follows viral replication in other organs, particularly the liver and spleen [7].
The mechanisms involved in viral transport from the circulation to the brain are not clearly understood. However, it is clear that transendothelial passage of the virus occurs in vessels of the choroid plexus, meninges, or cerebrum by one or more of the following mechanisms [7]:
●Bridging the endothelium within migrating leukocytes
●Pinocytosis or colloidal transport
●Breaking through damaged endothelium
●Direct infection of endothelial cells
The pathogenesis of viral meningitis associated with specific viruses is discussed below.
ETIOLOGY — Enteroviruses (EVs) are the most common cause of viral meningitis [1,6]. Other important causes of viral meningitis in children include human parechoviruses, herpesviruses, arboviruses, lymphocytic choriomeningitis virus (LCMV), rabies, and influenza.
Enteroviruses
●Epidemiology – EVs are responsible for approximately 85 percent of cases of viral meningitis [6]. Nonpolio-EV serotypes cycle from year to year; however, certain serotypes have remained prevalent. Coxsackieviruses A6 and B3 and echoviruses 30, 18, 9, and 11 were the most common serotypes detected in the United States from 2014 to 2016 [8]. EV-D68 was by far the most commonly detected EV during this time, but this was associated with a large outbreak in the United States during 2014 [9]. Viral meningitis in infants under three months of age has been associated mainly with group B coxsackieviruses and parechoviruses [10-12]. The epidemiology of EV infection is discussed in greater detail separately. (See "Enterovirus and parechovirus infections: Epidemiology and pathogenesis", section on 'Epidemiology'.)
EV-71, closely related to coxsackievirus A16 and the viral agent of hand-foot-mouth disease, has emerged as a significant cause of viral meningitis, encephalitis, and myelitis. It has been responsible for major outbreaks in Asia and sporadic cases in the United States and Europe [13-17]. (See "Enterovirus and parechovirus infections: Epidemiology and pathogenesis", section on 'Periodicity and variability of disease by serotype'.)
Approximately 1 percent of wild poliovirus infections are associated with paralytic illness. More common clinical presentations in susceptible individuals are asymptomatic infections, minor illness or abortive poliomyelitis, and aseptic meningitis or nonparalytic poliomyelitis. With successful vaccine eradication campaigns, polioviruses are no longer recovered from patients with aseptic meningitis in developed countries and only rarely in developing countries where poliomyelitis still occurs. Vaccine strains from the oral polio vaccine have rarely been recovered from the cerebrospinal fluid (CSF) of patients with aseptic meningitis [18-20]. (See "Poliomyelitis and post-polio syndrome", section on 'Poliomyelitis'.)
●Transmission – Humans are the only known reservoir for EVs, and transmission of EV occurs most commonly by the fecal-oral route. A few members of the EV genus can be acquired by inhalation of infected droplets. Transplacental transmission resulting in stillbirth, abortion, or neonatal infection has been described with many different EVs, including polioviruses, coxsackieviruses, and EV-71 [21,22].
●Seasonality, risk factors, and incubation – In temperate climates, most EV infections occur in outbreaks during the warmest months; however, sporadic cases can develop throughout the year. In the United States, infections are seen more frequently from June to October [8]. In tropical and subtropical regions, the incidence of EV infections remains stable throughout the year. Individual host factors, such as immunodeficiency and age, can predispose to more severe nonpolio EV infections. Furthermore, children with a deficient humoral immunodeficiency, especially X-linked agammaglobulinemia, are at risk for developing chronic meningoencephalitis [23]. The incubation period for EV infection is approximately three to six days.
●Pathogenesis – The pathogenesis of EV infections has been extensively studied; however, many questions remain unsolved [24]. Following exposure, viral particles bind to specific receptors on enterocytes and traverse the intestinal lining cells to reach the Peyer's patches in the lamina propria, where they replicate [24]. Few viral particles may replicate in the nasopharynx, with subsequent spread to the respiratory tract lymphatics. An initial viremia spreads the virus to other organs such as the liver, spleen, and heart, where further replication occurs, generating a second major viremia that is associated with signs and symptoms of infection [24]. Seeding of the central nervous system (CNS) can occur during the first or second viremia; however, the mechanisms by which the virus enters the CNS remain unknown [24]. An alternative path involving neural spread has been proposed [24,25]. The molecular determinants of neurotropism and neurovirulence have been extensively studied for polioviruses and are now under investigation for nonpolio EVs. Genomic differences among EV serotypes might explain the tendency of some strains to cause aseptic meningitis and encephalitis [24].
Human parechoviruses — Parechovirus is a genus of the Picornaviridae virus family. Human parechoviruses include eight serotypes (HPeV types 1 through 8) and several provisional serotypes [26,27]. HPeV1 and HPeV2 were formerly classified as echovirus 22 and 23, respectively [28]. Symptoms of CNS involvement, including neonatal sepsis, meningitis, encephalitis, and paralysis, have been reported with HPeV types 1 and 3 [26,29-37].
HPeV have been identified in Asia [38-40], Australia [37], Europe [12,41-43], North America [28,35,44,45], and South America [46]. The rate of isolation from the CSF is usually highest between June and October but varies from region to region and year to year (eg, from 0.4 to 8.2 percent in the Netherlands and 0 to 17 percent in the United States) [12,35,36].
Herpesviruses — All members of the Herpesviridae family can cause viral meningitis; however, herpes simplex viruses (HSVs) are classically associated with neurologic infection [24]. Cytomegalovirus, varicella-zoster virus (VZV), human herpesvirus (HHV)-6 and HHV-7, and Epstein-Barr virus (EBV) infections are only infrequently associated with meningitis. (See "Human herpesvirus 6 infection in children: Clinical manifestations, diagnosis, and treatment", section on 'Less common manifestations'.)
Members of the Herpesviridae family share similar features: The virion, roughly spherical and encased by an envelope, measures 15 to 200 nm in diameter and contains a large double-stranded DNA molecule. Primary infection is followed by lifelong infection, with the potential risk for reactivation.
Herpesviridae have a worldwide distribution. Humans are the only reservoir for transmission to susceptible individuals. Infections occur worldwide without seasonal prevalence.
Herpes simplex virus — CNS infections caused by HSV can have devastating sequelae, particularly in neonates. In a retrospective cross-sectional study performed at 23 North American emergency departments, the prevalence of HSV infection among infants <60 days old undergoing meningitis evaluation was 0.42 percent [47].
The postulated mechanisms involved in the spread of HSV-1 to the brain include hematogenous dissemination, direct extension through the cribriform plate from infection of nasopharyngeal mucosa, or via neurogenic pathways [48,49]. Whether HSV-2 reaches the meninges by neuronal or hematogenous dissemination is under debate [50]. Humoral immunity does not prevent recurrent infections [51].
●HSV-1 – HSV-1 is primarily transmitted by direct contact; therefore, the incidence of HSV-1 infection is influenced by socioeconomic status, age, and geographic location [51]. In developing countries, 70 to 80 percent of adolescents have serologic evidence of HSV-1 infection, while the age-specific prevalence of HSV-1 is decreasing in developed countries [50,51]. HSV-1 is the most common etiologic agent of sporadic necrotizing encephalitis, representing more than 85 percent of all cases, and is infrequently associated with aseptic meningitis [50,52,53]. Neonatal infections due to HSV-1 account for 25 percent of all cases of neonatal HSV infection, with an overall incidence of HSV infection in newborns ranging from 1 case in 2000 to 5000 deliveries per year [51]. (See "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Epidemiology and transmission'.)
Infections with HSV-2 are acquired mainly by sexual contact; however, increasing proportions of genital infections are due to HSV-1, acquired from orolabial lesions and herpetic whitlow [51]. Aseptic meningitis syndrome is usually caused by HSV-2 primary infection; it occurs mainly in adults but can occur in young children [54].
●HSV-2 – HSV-2 accounts for 75 percent of neonatal infections due to HSV. Infants become colonized with HSV mainly by vertical transmission through the vaginal canal and less frequently by ascending infection or during the postnatal period by horizontal transmission. The rate of perinatal transmission is 30 to 50 percent with maternal primary infection and 3 percent with recurrent infection [55]. (See "Genital herpes simplex virus infection and pregnancy".)
Clinical symptoms of meningitis have been reported in 36 percent of women and 11 percent of men with primary HSV-2 infection, but only 25 to 33 percent of patients with HSV meningitis ever report a history of genital lesions [50,52,56]. Furthermore, recurrent meningitis has been reported in 25 percent of adult patients with HSV-2 meningitis and can occur in young children (but rarely in neonates) [50,53,57-59]. Neonates, however, can develop recurrent episodes of encephalitis.
Mollaret meningitis is characterized by recurrent episodes of aseptic meningitis. Using polymerase chain reaction-based testing, HSV-2 has been strongly associated with Mollaret meningitis, a form of benign recurrent aseptic meningitis [6,60,61]. An additional few cases have been reported due to HSV-1 and EBV [6,62,63].
In the majority of patients, HSV mucosal lesions precede signs and symptoms of meningeal inflammation, with a mean interval of one week [50]. In general, neonates with disseminated and localized infections usually develop symptoms earlier than neonates with CNS infections: on average, 9 to 11 days and 16 to 17 days, respectively [64]. Beyond the neonatal period, the incubation period ranges from 2 days to 12 days, with a mean of four days [51].
Varicella-zoster virus — Since the introduction of the varicella vaccine, the incidence of VZV infection in children has declined substantially [65]. Furthermore, the overall incidence of neurologic complications of VZV infection in healthy children is less than 1 percent (most frequently, acute cerebellar ataxia and encephalitis). (See "Clinical features of varicella-zoster virus infection: Chickenpox" and "Epidemiology of varicella-zoster virus infection: Chickenpox".)
Aseptic meningitis is a rare complication of chickenpox and herpes zoster [24,66-68]. The syndrome known as zoster sine herpete is characterized by the presence of CSF pleocytosis, documented CNS infection with VZV by polymerase chain reaction, and absence of typical skin lesions [24].
Cytomegalovirus and Epstein-Barr virus — Meningitis due to cytomegalovirus and EBV is also rare; however, aseptic meningitis is the most common neurologic complication seen in patients with primary EBV infection [69,70]. The prevalence of EBV infection in pediatric patients has a direct correlation with socioeconomic status, with the highest incidence seen in developing countries. In the United States, approximately 50 percent of five-year-old children are seropositive for EBV [69]. (See "Clinical manifestations and treatment of Epstein-Barr virus infection".)
Human herpesvirus 6 and 7 — HHV-6, the etiologic agent of roseola, or exanthem subitum, is a common cause of febrile seizures in infancy and has been associated with meningitis in this age group [24,71] (see "Human herpesvirus 6 infection in children: Clinical manifestations, diagnosis, and treatment", section on 'Less common manifestations'). HHV-7, also associated with exanthem subitum and febrile seizures in infancy, can also cause meningitis in children [72,73]. (See "Human herpesvirus 7 infection".)
Arboviruses — Arboviruses are a heterogeneous group of arthropod-borne RNA viruses responsible for important epidemics of CNS infections worldwide; these infections have been increasing in frequency [32]. Although encephalitis and meningoencephalitis are more commonly recognized as hallmarks of CNS infection by most of these viruses, aseptic meningitis is an important clinical manifestation of their disease spectrum [24].
Of the seven taxonomic families of arboviruses, three are more commonly involved in human disease: Flaviviridae, Togaviridae, and Bunyaviridae (table 2) [74]. Important arboviruses endemic in the United States include:
●West Nile virus (WNV) (see "Clinical manifestations and diagnosis of West Nile virus infection")
●Eastern equine encephalitis virus (see "Arthropod-borne encephalitides", section on 'Eastern equine encephalitis virus')
●Western equine encephalitis virus (see "Arthropod-borne encephalitides", section on 'Western equine encephalitis virus')
●La Cross virus (see "Arthropod-borne encephalitides", section on 'La Crosse encephalitis virus')
●St. Louis encephalitis virus (see "St. Louis encephalitis")
Other arboviruses are discussed separately. (See "Arthropod-borne encephalitides".)
The pathogenesis of arboviral CNS infection is relatively similar for all pathogens. Viruses are inoculated subcutaneously or intravenously during the bite of an infected vector (most commonly, mosquitoes) (table 2). Replication in the skin or muscle precedes a primary viremia that subsequently spreads the virus to the reticuloendothelial system or to the CNS. (See "Arthropod-borne encephalitides".)
Arboviruses have a worldwide distribution, with a highest incidence in tropical and developing regions. In the United States, arboviruses constitute most of the cases of viral meningitis that are not due to EV [75,76]. The incubation period for arboviral infections ranges from 1 to 18 days (table 2). (See "Arthropod-borne encephalitides".)
Most arboviruses are maintained in nature in a cycle involving a nonhuman primary vertebrate host and a primary arthropod vector that determine their geographic and seasonal distribution [77]. Human infections are seen most frequently at the peak of mosquito and tick activity during summer and fall or sporadically when the virus is brought into the peridomestic environment by a bridge vector [77]. The geographic distribution of arboviral infections in the United States is shown in the table (table 2).
The age distribution of infection varies according to the virus. Children are generally more susceptible than adults to CNS infections, particularly with infections due to St. Louis encephalitis, Eastern equine encephalitis, and Western equine encephalitis [74].
WNV has emerged as a major public health concern in the United States and Europe [78-82]. In a report from a national arboviral surveillance program in the United States from 2003 through 2012, the most common arboviral causes of meningitis in children were WNV and La Crosse virus [78-82]. La Cross virus tends to cause infection in younger children than does WNV [81]. WNV persists in nature as part of an enzootic cycle among wild birds, the primary reservoir, and Culex spp, the main mosquito vector. In the United States, as well as in other temperate climates, WNV infections coincide with maximal mosquito activity. In the United States, outbreaks occur from July to October, with the highest incidence seen in August [78,83]. (See "Epidemiology and pathogenesis of West Nile virus infection".)
Other viruses
Lymphocytic choriomeningitis virus — LCMV is an enveloped, single-stranded RNA virus member of the Arenaviridae family. It is a rare cause of human CNS infections in developed countries.
Rodents, including hamsters, rats, and mice, harbor and shed LCMV in nasal secretions, saliva, urine, semen, milk, and feces. Children living in impoverished conditions are at higher risk of acquiring the infection through ingestion of animal-urine-contaminated food, exposure of open wounds to contaminated dirt, or inhalation of aerosolized virus [84].
Transplacental infection with LCMV was first described in the United States in 1992, although initially reported in England in 1955 [84]. Transmission to the fetus occurs primarily during maternal viremia [84]. LCMV infections occur most commonly during the winter months, when rodents seek food and shelter in human dwellings.
Rabies — Rabies is an enveloped, bullet-shaped RNA virus that causes fatal CNS infection [66]. Transmission of rabies from animal to human occurs mainly through direct contact with saliva from a rabid animal onto mucous membranes or into open wounds or by direct inoculation through a bite, followed by local replication and subsequent spread to the CNS [85]. Once the virus enters neuronal cells, it moves by passive neuronal transit, reaching the CNS by retrograde axonal transport. After reaching the CNS, there is a subsequent centrifugal spread back to peripheral sites, including the salivary and submaxillary glands. Following inhalation of viral particles, rabies virus reaches the CNS by direct neuronal transmission through the olfactory tract after initial replication in the olfactory epithelium [85]. (See "Clinical manifestations and diagnosis of rabies".)
Not all humans bitten by a rabid animal develop infection [85]. The incubation period is generally 20 to 60 days; however, it can be a short as five to six days and as long as six months to seven years [66]. Travelers to hyperendemic areas, especially children, are at increased risk.
Influenza — Influenza A and B viruses have been associated with different neurologic syndromes in children, including aseptic meningitis [24,86]. Influenza viruses are orthomyxoviruses of three antigenic types: A, B, and C. Influenza viruses are subclassified according to two surface antigens, neuraminidase and hemagglutinin, with shift and drifts accounting for pandemics and outbreaks [66,86]. (See "Influenza: Epidemiology and pathogenesis".)
In temperate climates, the circulation of influenza viruses has a seasonal variation, with a peak incidence in the United States during the months of January and February. Children younger than five years are at increased risk for influenza A virus infection of the CNS, mainly encephalitis. Although less frequent, influenza B virus can also be associated with CNS infections, mainly in children and adolescents [66,87,88]. (See "Seasonal influenza in children: Clinical features and diagnosis", section on 'Central nervous system'.)
Involvement of the CNS is a rare complication of influenza virus infection, mainly presenting as encephalitis rather than aseptic meningitis [86]. Children younger than five years are at higher risk for the development of neurologic complications independent of the strain involved [66]. Of the 121 children with fatal Fujian influenza A (a drift strain) in the United States in the 2003 to 2004 season, 60 percent were younger than five years (46 percent of these between 6 and 23 months of age) and a number of these patients had encephalitis [89]. The pathogenesis of influenza viral infection of the CNS remains unclear [66].
Severe acute respiratory syndrome coronavirus 2 — Although very rare, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can present with neurologic manifestations in the absence of respiratory symptoms, including meningitis [90,91]. SARS-CoV-2 infection in children is discussed separately. (See "COVID-19: Clinical manifestations and diagnosis in children".)
Less common viruses — Less common viral pathogens associated with aseptic meningitis and their geographic distribution are listed in the table (table 3).
Human metapneumovirus (hMPV) is a common cause of upper and lower respiratory tract infections in children. The ability of hMPV to invade the CNS was demonstrated in an infant with fatal encephalitis [92]. hMPV has been isolated from respiratory specimens in children with neurologic manifestations, but who lacked evidence of hMPV in the CSF [93,94].
Adenoviruses are responsible for a wide range of clinical manifestations affecting the respiratory tract, gastroenteritis, cystitis, and conjunctivitis. Life-threatening infections such as myocarditis and meningoencephalitis are rare but increasingly recognized [95]. (See "Pathogenesis, epidemiology, and clinical manifestations of adenovirus infection".)
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●Basics topics (see "Patient education: Viral meningitis (The Basics)")
SUMMARY
●Epidemiology – In children, viral meningitis occurs most frequently in infants <1 year old, with a second peak occurring in children >5 years old. In the United States, the peak incidence occurs from late spring to autumn, reflecting the peak activity of enteroviral and arthropod-borne infections (table 1). (See 'Epidemiology' above.)
●Pathogenesis – Most viral pathogens affecting the central nervous system (CNS) initially infect mucosal surfaces of the respiratory and gastrointestinal tract and reach the CNS through viremia following viral replication. (See 'Pathogenesis' above.)
●Etiology – Enteroviruses (EVs) are the most common cause of viral meningitis. Other important causes of viral meningitis in children include human parechoviruses, herpesviruses, arboviruses, lymphocytic choriomeningitis virus (LCMV), rabies, and influenza. (See 'Etiology' above.)
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