Background
Pediatric aseptic meningitis is an inflammation of the meninges caused mainly by nonbacterial organisms, specific agents, or other disease processes. Aseptic meningitis (including viral meningitis) is the most common infection of the central nervous system (CNS) in the pediatric population, occurring most frequently in children younger than 1 year. Despite advances in antimicrobial and general supportive therapies, CNS infections remain a significant cause of morbidity and mortality in children.
Because the classic signs and symptoms are often absent, especially in younger children, diagnosing pediatric CNS infections is a challenge to the emergency department (ED). Even when such infections are promptly diagnosed and treated, neurologic sequelae are not uncommon. Clinicians are faced with the daunting task of distinguishing the relatively few children who actually have CNS infections from the vastly more numerous children who come to the ED with less serious infections.
Pathophysiology
Organisms colonize and penetrate the nasopharyngeal or oropharyngeal mucosa, survive and multiply in the blood stream, evade host immunologic mechanisms, and spread through the blood-brain barrier. Infection cannot occur until colonization of the host has taken place (usually in the upper respiratory tract). The mechanisms by which circulating viruses penetrate the blood-brain barrier and seed the cerebrospinal fluid (CSF) to cause meningitis are unclear.
Viral infection causes an inflammatory response but to a lesser degree than bacterial infection does. Damage from viral meningitis may be due to an associated encephalitis and increased intracranial pressure (ICP).
The pathophysiology of aseptic meningitis caused by drugs is not well understood. This form of meningitis is infrequent in the pediatric population.
Etiology
Although many agents and conditions are known to be associated with pediatric aseptic meningitis, often a specific cause is not identified, because a complete diagnostic investigation is not always completed. Viruses are the most common cause, and enteroviruses (EVs) are the most frequently detected viruses. The use of molecular diagnostic techniques (eg, polymerase chain reaction [PCR] assay) has significantly increased diagnostic accuracy.
Viruses
EV infection is a frequent cause of febrile illnesses in children and is often asymptomatic. [1] Other viral pathogens include human parechovirus, paramyxovirus, herpesvirus, influenza virus, rubella virus, and adenovirus. Meningitis may occur in as many as 50% of children younger than 3 months with EV infection. EV infection can occur at any time during the year but is associated with epidemics in the summer and fall. [2] Viruses associated with aseptic meningitis include the following:
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Enteroviruses species A-D: this encompasses enterovirus, echoviruses, coxsackieviruses, and polioviruses [3] :
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Arbovirus (eastern, western, and Venezuelan equine encephalitis viruses; Powassan virus; California group viruses [primarily LaCrosse virus]; St. Louis encephalitis virus; West Nile virus; and Colorado tick fever)
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Mumps virus
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Herpes simplex virus (HSV) types 1 and 2
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Human herpesvirus type 6 (HHV6) and type 7 (HHV7)
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Varicella-zoster virus (VZV)
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Adenovirus types 3 and 7
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Lymphocytic choriomeningitis (associated with contact with guinea pigs, hamsters, and pet mice)
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Parainfluenza virus
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Rotavirus
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Coronavirus
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Variola virus
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Flavivirus [11]
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Toscana virus [12]
See the image below for an example of skin lesions due to echovirus type 9.
Skin lesions due to echovirus type 9 on neck and chest of young girl. Echoviruses belong to genus Enterovirus and are associated with illnesses including aseptic meningitis, nonspecific rashes, encephalitis, and myositis.
Viral vaccines
Viral vaccines related to aseptic meningitis include the following:
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Polio vaccine
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Yellow fever vaccine [17]
Nonpyogenic bacteria
Certain bacterial infections may give rise to aseptic meningitis (eg, partially treated bacterial meningitis or brain abscess). Nonpyogenic bacteria associated with aseptic meningitis include the following:
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Treponema pallidum
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Borrelia (relapsing fever, Lyme disease)
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Bartonella
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Atypical mycobacteria
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Brucella
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Other organisms
Atypical organisms associated with aseptic meningitis include the following:
Parasites associated with aseptic meningitis include the following:
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Roundworms
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Tapeworms
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Flukes
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Amoebae
Fungal meningitis is rare but may occur in immunocompromised patients; children with cancer, previous neurosurgery, or cranial trauma; or premature infants with low birth weights. Most cases occur in children who are inpatients receiving antibiotic therapy. Fungi associated with aseptic meningitis include the following:
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Cryptococcus
Additional organisms associated with aseptic meningitis include the following:
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Blastomyces dermatitidis
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Coccidioides immitis
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Alternaria species
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Aspergillus species
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Cephalosporium species
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Cladosporium trichoides
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Drechslera hawaiiensis
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Paracoccidioides brasiliensis
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Petriellidium boydii
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Sporotrichum schenckii
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Ustilago species
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Zygomycetes species
Diseases and other conditions or events
Diseases associated with aseptic meningitis include the following:
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Leukemia
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Behçet disease
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Sjögren syndrome [18]
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Dermoid and epidermoid cysts [19]
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CNS tumor
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Recurrent benign endothelioleukocytic aseptic meningitis (Mollaret meningitis) [21]
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Neonatal-onset multisystem inflammatory disorder (one of the cryopyrin-associated periodic syndromes [CAPS]) [22]
Other conditions or events associated with aseptic meningitis include the following:
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Immunoglobulin replacement therapy
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Heavy metal poisoning
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Intrathecal agents
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Foreign bodies (eg, shunt or reservoir)
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Drugs
Epidemiology
United States statistics
The annual incidence is unknown because of underreporting but has been estimated to be approximately 75,000 cases per year in the United States. Before the introduction of the MMR vaccine program, the mumps virus was the most common cause, accounting for 5-11 of 100,000 cases of meningitis; it now accounts for approximately 0.3 of 100,000 cases, and EV has become the most common cause. Most cases occur in the summer and autumn with cases predominantly between June and October. [23, 24]
International statistics
Studies in Europe have indicated an incidence rate of 70 per 100,000 among children aged younger than 1 year and 5.2 per 100,000 among children 1-14 years of age. [25] In the United Kingdom, the causes of meningitis have changed since the introduction of vaccines against Haemophilus influenzae B (1992), Neisseria meningitidis (1999), and Streptococcus pneumoniae (2006), [26] with viruses being the most common etiology. In the United Kingdom, the admission rates for viral meningitis fell by almost two thirds following the introduction of the MMR vaccine. [25] Prior to the vaccine, mumps meningitis was likely the leading cause of viral meningitis. Following its introduction, peaks in admissions were noted in association with known outbreaks of echovirus 13 and 30.
The overall decline in admissions was due to a fall in admissions in those aged 1-14 years. Admissions with viral meningitis in those younger than 3 months have risen in recent years; however, this may be due to differences in clinical practice. Furthermore, there were biannual peaks in admissions for infants younger than 3 months, which may reflect the biannual spring time peaks reported in HPeV infections. [27] The proportion of cases recognized as being caused by enterovirus also rose, which could be attributed partially but not wholly to improved detection.
The Austrian reference laboratory for poliomyelitis received 1388 stool specimens for EV typing from patients with acute flaccid paralysis or aseptic meningitis between 1999 and 2007; 201 samples from 181 cases were positive for nonpoliomyelitis EV. [28] The mean patient age was 5-6 years, with 90% of cases in children younger than 14 years. Aseptic meningitis was identified in 65.6% of the cases. Echovirus 30 (E-30) was the most frequent viral cause of aseptic meningitis, due to an epidemic in 2000, followed by coxsackievirus B types 1-6 and EV 71. A study in Denmark showed similar findings with nonpolio enteroviruses being the most common causative agent, [29] with E-30 the leading viral pathogen in a Spanish study of aseptic meningitis. [4]
An outbreak of E-30 occurred between April and September 2013 in Marseille, South-East France. A study concluded that almost all E-30 emerged from local circulation of one parental virus. The findings also showed that human enterovirus outbreaks cause an excess of emergency ward consultations but probably also an excess of consultations to general practitioners, who receive the majority of nonspecific viral illness cases. [30] Similar outbreaks have been reported in California, Germany, Finland, Italy, and China. [31, 32, 33, 34, 35]
In South Africa, during an aseptic meningitis outbreak caused by coxsackie virus A9, 87.3% of those affected were aged younger than 10 years. [36] Outbreaks of meningitis caused by other types of enteroviruses also occur when new genetic variants develop. [37, 38]
Human parechoviruses are an increasingly recognized viral cause of aseptic meningitis. [8] They have similar seasonality and symptomatology to enteroviruses and along with enteroviruses are the main cause of aseptic meningitis in newborns and children under 1 year of age. [19, 39] Sixteen types have been identified with types 1-8 being the most studied. In the pediatric population, type 3 has been shown to cause meningitis and neonatal sepsis. [40] The other types are associated with gastroenteritis and respiratory illness. [7] Diagnostic assays for HPeV are not widely available, and thus its burden is thought to be underestimated. [6]
In an area of Southwestern Norway, where Lyme disease is endemic, it is the leading cause of meningitis. [41]
Age-related demographics
Aseptic meningitis is more common in children than in adults. [42, 43] This reflects increased frequency of enteroviral infections in children. [44] Rates of enterovirus and HPeV in young infants have risen, which may reflect reduced maternal seroprevalence and reduced transfer of maternal antibodies to the newborn. [45] In the UK, admission rates for children with viral meningitis have fallen since the introduction of the MMR vaccine; however, rates have risen in infants under 1 year of age.
Sex-related demographics
Studies have shown a male predilection in aseptic meningitis. [36, 43] In a Texan study, 59% of pediatric patients were male, whereas a Greek study showed a male:female ratio of 1.8:1. [42, 46] Further studies in South Korea and Japan have also demonstrated a higher proportion of males affected. [47, 48]
Race-related demographics
In the Texan study, adults with aseptic meningitis were more likely to be non-Hispanic White, and children were more likely to be Hispanic. [46] No background demographic data were provided; therefore, the significance of this finding is uncertain.
Prognosis
Full recovery is usual after uncomplicated viral aseptic meningitis, with most cases resolving within 7-10 days.
Recurrence is possible (known as Mollaret, or benign recurrent, meningitis). Associated viruses include Epstein-Barr virus (EBV), coxsackieviruses B5 and B2, echoviruses 9 and 7, herpes simplex virus (HSV)-1 and HSV-2, and human immunodeficiency virus (HIV).
Overall, it is felt there are no or minimal long-term effects. However, there is a lack of data regarding overall mortality, long-term morbidity, and psychological impact. HPeV has been implicated in neurologic sequelae and developmental delay in severe infections, with one meta-analysis showing 5% of children had neurologic sequelae during short-term follow up, increasing to 27% during long-term follow-up. [49]
In a Taiwanese study of EV 71 infections, 78 of 408 hospitalized children died, and among the children with rhombencephalitis due to EV infection, 14% died. [50] Subsequent studies suggested better outcomes. No deaths have been reported in Canadian, Korean, Greek, and American studies, [23, 42, 46, 47] and a Jordanian study of children with aseptic meningitis reported no neurologic sequelae. [51]
In a prospective national study in the UK looking at enterovirus and parechovirus meningitis in infants less than 90 days old between 2014 and 2015, two infants with EV meningitis died (2/668, 0.3%) and four survivors (4/666, 0.6%) had long-term complications at 12 months' follow-up. [52] Infants with HPeV meningitis survived without sequelae, and of 189 infants who had a formal hearing test, none had sensorineural hearing loss. [52] Another study has shown that hearing outcomes in children recovering from nonpolio enteroviral meningitis are good. [53]
The age of the child and the viral pathogen are the main determinants of prognosis. Preterm neonates and those who are immunocompromised are more likely to have a more severe systemic infection and thus a higher chance of neurologic sequelae. [52]
Complications
Serious complications are uncommon but can include unilateral deafness after mumps meningitis, chronic enteroviral meningitis (especially in patients with agammaglobulinemia), and hydrocephalus after lymphocytic choriomeningitis virus infection. Rhombencephalitis has been reported as a complication of EV 71 infection. [50] A case of fatal leukoencephalitis has been reported due to echovirus 18 infection. [54] HSV and arbovirus infections, as well as viral infections in AIDS patients, can result in severe neurologic disease.
Seizure disorders, behavioral problems, and speech delay (unrelated to hearing loss) have been reported. [49, 55] In a Korean study, 0.7% of children had neurologic problems such as seizures, amnesia, syndrome of inappropriate secretion of antidiuretic hormone (SIADH), and hydrocephalus, though none were permanent. [47]
Recurrence is possible (known as Mollaret, or benign recurrent meningitis). There is one case report with a familial association. [56]
Patient Education
For more information, visit the Meningitis Foundation of America website. The Meningitis Research Foundation offers useful material for nonexperts, parents, and healthcare professionals.
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Skin lesions due to echovirus type 9 on neck and chest of young girl. Echoviruses belong to genus Enterovirus and are associated with illnesses including aseptic meningitis, nonspecific rashes, encephalitis, and myositis.
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