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Aseptic and Viral Meningitis


The term acute aseptic meningitis (AM) was introduced in 1925 to describe a self-limited central nervous system (CNS) syndrome characterized by acute onset of fever and meningeal irritation in which the cerebrospinal fluid (CSF) exhibited a mononuclear pleocytosis and was bacteriologically sterile. With advances in diagnostic methodologies it is now recognized that multiple infectious agents, drugs, and localized and systemic inflammatory conditions can cause AM syndrome ( Box 43.1 ). ,

BOX 43.1
Major Causes of Aseptic Meningitis Syndrome

Common

  • Enteroviruses A–D (echoviruses, coxsackieviruses, numbered enteroviruses)

  • Human parechoviruses

  • Arboviruses (Western equine encephalitis virus, St. Louis encephalitis virus, Colorado tick fever, La Crosse encephalitis virus, West Nile virus, tickborne encephalitis virus, Toscana virus)

  • Borrelia burgdorferi

  • Partially treated bacterial meningitis

Uncommon

  • Severe acute respiratory syndrome coronavirus 2

  • Herpes simplex virus type 2

  • Mumps virus

  • Human immunodeficiency virus

  • Mycobacterium tuberculosis

  • Parameningeal bacterial infection

  • Fungi ( Cryptococcus, Coccidioides, Histoplasma, Blastomyces )

Rare

  • Respiratory viruses (adenovirus, influenza, parainfluenza)

  • Lymphocytic choriomeningitis virus

  • Other herpesviruses (herpes simplex virus type 1, human herpesvirus 6, Epstein-Barr virus, varicella-zoster virus, cytomegalovirus)

  • Measles virus

  • Miscellaneous viruses (parvovirus B19, rotavirus)

  • Bartonella spp. (cat-scratch disease)

  • Spirochetes

  • Leptospira spp.

  • Brucella spp.

  • Parasites (e.g., Taenia solium [cysticercosis)], Toxoplasma gondii , Trichinella spiralis [trichinosis])

  • Mycoplasma pneumoniae

  • Rickettsia spp.

Noninfectious Causes

  • Drugs (e.g., nonsteroidal anti-inflammatory agents, agents instilled into cerebrospinal fluid, antiepileptic drugs)

  • Biologic products (e.g., immune globulin, OKT3, monoclonal antibodies)

  • Systemic immunologically mediated diseases (e.g., rheumatologic diseases, Behçet disease)

  • Neoplastic diseases

Viral meningitis can be described as a CNS infection that is associated with signs of meningeal irritation (i.e., neck stiffness, Kernig and Brudzinski signs) but not neurologic dysfunction as a result of brain parenchymal involvement. In contrast, viral encephalitis is a CNS disorder with evidence of brain parenchymal dysfunction manifested by an altered state of consciousness or other objective signs of neurologic dysfunction (e.g., seizures, cranial nerve palsies, abnormal reflexes, and paralysis). Although commonly discussed as separate syndromes, an overlap (meningoencephalitis) occurs frequently. This chapter focuses on viral agents more commonly associated with acute AM.

Etiologic Agents And Epidemiology

Due to the fact that AM is not a reportable disease in the US, the total annual cases and incidence are unknown. The estimated annual number of AM cases is believed to be at least 75,000. In Olmsted County and in Minnesota, the incidence of AM over 32 years was found to be 10.9 per 100,000 person years. The highest rates occurred in infants, toddlers, and children. The Centers for Disease Control and Prevention (CDC) reported that over a 10-year period the incidence of AM ranged from 1.5–4 per 100,000. The differences in incidences may be the result of underreporting owing to a passive reporting system used by the CDC. In Finland, a 14-year birth cohort study found the annual incidence of viral meningitis to be 27.8 per 100,000. The highest rates were observed in infants and children <4 years of age.

Before the advent of cell culture, a specific etiology of AM was identifiable in only 25% of cases. , Cell culture led to a substantial improvement in the identification of viral causes of AM, primarily owing to the identification of enterovirus (EV). Using cell culture in addition to animal inoculation and serology, the etiology of AM could be established in ∼55%–70% of cases. Cell culture clearly established EV as the dominant etiology of AM, accounting for ∼55%–90% of all identifiable causes. , Use of vaccines for prevention of mumps and polio led to nonpolio EVs becoming the overwhelming dominant cause of AM. , Nucleic acid amplification tests (NAATs) continue to support their significant etiologic role.

Enteroviruses and Parechoviruses

EVs are members of the Picornaviridae family of viruses. Four species (enteroviruses A–D), encompassing more than 110 confirmed or putative serotypes, are recognized within the genus.

EVs have a worldwide distribution. Although >100 serotypes comprise the genus, only a few cause disease each year. The dominant serotypes vary geographically and temporally. In regions with temperate climates, EV infections exhibit a strong seasonal epidemiology, occurring primarily in the summer and fall. In tropical and subtropical regions, infections occur year-round with increased incidence during the rainy season.

The use of NAAT has demonstrated that >70% of AM cases in children for which an etiology is identified are attributable to EV. , Given their significant contribution as causes of AM, it is not surprising that the seasonal occurrence of AM parallels activity of these viruses ( Fig. 43.1 ).

Figure 43.1, Seasonal incidence of aseptic meningitis in the US from 1986 to 1993, as reported to the Centers for Disease Control and Prevention. The summer predominance reflects the role of enteroviruses as the leading cause of the aseptic meningitis syndrome.

Parechoviruses, also found in the family Picornaviridae, are recognized to cause AM. Initially classified as EVs, but biologic, antigenic, and genomic differences led to their reclassification into a novel genus. , Most human parechovirus (HPeV) infections occur during the summer and fall. HPeV type 3 is the dominant type associated with AM and has been identified in an average of 5%–7% of EV-negative archival CSF specimens, , with higher rates in very young infants evaluated because of fever, sepsis-like, or neurologic symptoms. During a 13-month surveillance period, the incidence of HPeV in infants <90 days old was 0.04/1000 live births, while the incidence of EV was 0.79/1000 live births.

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