eMedicine Specialties > Infectious Diseases > CNS Infections

Meningitis

Author: Raymund R Razonable, MD, Consultant, Division of Infectious Diseases, Mayo Clinic of Rochester; Associate Professor of Medicine, Mayo Clinic College of Medicine
Coauthor(s): Michael R Keating, MD, Consultant, Assistant Professor of Medicine, Division of Infectious Diseases, Department of Medicine, Mayo Clinic College of Medicine
Contributor Information and Disclosures

Updated: Aug 26, 2009

Introduction

Background

Meningitis is a clinical syndrome characterized by inflammation of the meninges. Clinically, this medical condition manifests with meningeal symptoms (eg, headache, nuchal rigidity, photophobia) and an increased number of white blood cells in the cerebrospinal fluid (CSF; pleocytosis). Depending on the duration of symptoms, meningitis may be classified as acute or chronic. Acute meningitis denotes the evolution of symptoms within hours to several days, while chronic meningitis has an onset and duration of weeks to months. The duration of symptoms of chronic meningitis is characteristically at least 4 weeks.

There are numerous infectious and noninfectious causes of meningitis. Examples of common noninfectious causes include medications (eg, nonsteroidal anti-inflammatory drugs, antibiotics) and carcinomatosis. The focus of this article is the infectious causes of meningitis. Infectious agents that cause primarily encephalitis are not discussed in this article.

Meningitis can also be classified according to its etiology. Acute bacterial meningitis denotes a bacterial cause of this syndrome. This is usually characterized by an acute onset of meningeal symptoms and neutrophilic pleocytosis. Depending on the specific bacterial cause, the syndrome may be called, for example, Streptococcus pneumoniae meningitis, meningococcal meningitis, or Haemophilus influenzae meningitis. Fungal and parasitic causes of meningitis are also termed according to their specific etiologic agent, such as cryptococcal meningitis, Histoplasma meningitis, and amebic meningoencephalitis.

Pathophysiology

Three major pathways exist by which an infectious agent (ie, bacteria, virus, fungus, parasite) gains access to the central nervous system (CNS) and causes meningeal disease.

Initially, the infectious agent colonizes or establishes a localized infection in the host. This may be in the form of colonization or infection of the skin, nasopharynx, respiratory tract, gastrointestinal tract, or genitourinary tract. Most meningeal pathogens are transmitted through the respiratory route, as exemplified by the nasopharyngeal carriage of Neisseria meningitides (meningococcus) and nasopharyngeal colonization with S pneumoniae (pneumococcus).

From this site, the organism invades the submucosa by circumventing host defenses (eg, physical barriers, local immunity, phagocytes/macrophages) and gains access to the CNS by (1) invasion of the bloodstream (ie, bacteremia, viremia, fungemia, parasitemia) and subsequent hematogenous seeding of the CNS, which is the most common mode of spread for most agents (eg, meningococcal, cryptococcal, syphilitic, and pneumococcal meningitis); (2) a retrograde neuronal (ie, olfactory and peripheral nerves) pathway (eg, Naegleria fowleri, Gnathostoma spinigerum); or (3) direct contiguous spread (ie, sinusitis, otitis media, congenital malformations, trauma, direct inoculation during intracranial manipulation).

Certain respiratory viruses are thought to enhance the entry of bacterial agents into the intravascular compartment, presumably by damaging mucosal defenses. Once inside the bloodstream, the infectious agent must escape immune surveillance (eg, antibodies, complement-mediated bacterial killing, neutrophil phagocytosis). Subsequently, hematogenous seeding into distant sites occurs, including the CNS. The specific pathophysiologic mechanisms by which the infectious agents gain access into the subarachnoid space remain unclear.

Once inside the CNS, the infectious agents likely survive because host defenses (eg, immunoglobulins, neutrophils, complement components) appear to be limited in this body compartment. The presence and replication of infectious agents remain uncontrolled and incite a cascade of meningeal inflammation. This process of meningeal inflammation has been an area of extensive investigation in recent years that has led to a better understanding of meningitis pathophysiology.

Key advances in the pathophysiology of meningitis include the pivotal role of cytokines (eg, tumor necrosis factor-alpha [TNF-alpha], interleukin [IL]–1), chemokines (IL-8), and other proinflammatory molecules in the pathogenesis of pleocytosis and neuronal damage during bacterial meningitis. Increased CSF concentrations of TNF-alpha, IL-1, IL-6, and IL-8 are characteristic findings in patients with bacterial meningitis.

The proposed interplay among these mediators of inflammation is as follows:

• The exposure of cells (eg, endothelium, leukocytes, microglia, astrocytes, meningeal macrophages) to bacterial products released during replication and death incites the synthesis of cytokines and proinflammatory mediators. Recent data indicate that this process is likely initiated by the ligation of the bacterial components (eg, peptidoglycan, lipopolysaccharide) to pattern-recognition receptors such as the Toll-like receptors.
• TNF-alpha and IL-1 are the most prominent among the cytokines that mediate this inflammatory cascade. TNF-alpha is a glycoprotein derived from activated monocyte-macrophages, lymphocytes, astrocytes, and microglial cells. IL-1, previously known as endogenous pyrogen, is also produced primarily by activated mononuclear phagocytes and is responsible for the induction of fever during bacterial infections. Both molecules have been detected in the CSF of individuals with bacterial meningitis. In experimental models of meningitis, they appear early during the course of disease and have been detected within 30-45 minutes of intracisternal endotoxin inoculation.
• Many secondary mediators, such as IL-6, IL-8, nitric oxide, prostaglandins (PGE2), and platelet activation factor (PAF), are presumed to amplify this inflammatory event, either synergistically or independently. IL-6 induces acute-phase reactants in response to bacterial infection. The chemokine IL-8 mediates neutrophil chemoattractant responses induced by TNF-alpha and IL-1. Nitric oxide is a free radical molecule that can induce cytotoxicity when produced in high amounts. PGE2, a product of cyclooxygenase, appears to participate in the induction of increased blood-brain barrier (BBB) permeability. PAF, with its myriad of biologic activities, is believed to mediate the formation of thrombi and the activation of clotting factors within the vasculature. However, the precise roles of all these secondary mediators in meningeal inflammation remain unclear and should be investigated further.
• Overall, the net result is vascular endothelial injury and increased BBB permeability leading to the entry of many blood components into the subarachnoid space. In many patients, this contributes to vasogenic edema and elevated CSF protein levels. In response to the cytokines and chemotactic molecules, neutrophils migrate from the bloodstream and penetrate the damaged BBB, producing the profound neutrophilic pleocytosis characteristic of bacterial meningitis. The increased CSF viscosity resulting from the influx of plasma components into the subarachnoid space and diminished venous outflow lead to interstitial edema, and the products of bacterial degradation, neutrophils, and other cellular activation lead to cytotoxic edema.
• The ensuing cerebral edema (ie, vasogenic, cytotoxic, interstitial) significantly contributes to intracranial hypertension and a consequent decrease in cerebral blood flow. Anaerobic metabolism ensues, which contributes to increased lactate concentration and hypoglycorrhachia. In addition, hypoglycorrhachia results from decreased glucose transport into the spinal fluid compartment. Eventually, if this uncontrolled process is not modulated by effective treatment, transient neuronal dysfunction or permanent neuronal injury results.
• The level of cytokines, including IL-6, TNF-alpha, and interferon-gamma, has been found to be elevated in patients with aseptic meningitis.

Another important component or complication of meningitis is the development of increased intracranial pressure (ICP). The pathophysiology of this complication is complex and may involve many proinflammatory molecules as well as mechanical elements. Interstitial edema (secondary to obstruction of CSF flow, as in hydrocephalus), cytotoxic edema (swelling of cellular elements of the brain through the release of toxic factors from the bacteria and neutrophils), and vasogenic edema (increased BBB permeability) are all thought to play a role in the development of increased ICP.

Frequency

United States

The incidence of meningitis varies with the specific etiologic agent.

Bacterial meningitis remains a significant cause of morbidity and mortality throughout the world. The attack rate per year in the United States is reported at 0.6-4 cases per 100,000 population. Previously, the 3 most common pathogens that accounted for more than 80% of cases included H influenzae type B (HIB), N meningitidis, and S pneumoniae. Over the past two decades, the epidemiology has changed substantially because of several developments.

First, the widespread use of the HIB vaccination has decreased the incidence of HIB meningitis by more than 90% (see Table 1). As a result of this practice, HIB meningitis has been nearly eliminated in many developed countries where routine HIB vaccination is used. Consequently, bacterial meningitis is becoming more of a disease of adults, with the median age of patients shifting from younger than 2 years to 25 years. A total of 255 cases of invasive H influenzae disease among children younger than 5 years was reported to the US Centers for Disease Control and Prevention (CDC) in 1998 (in contrast to 20,000 cases of invasive disease among children in 1987). This shift has reportedly been less dramatic in the developing countries where the use of the HIB vaccine is not as widespread.

Table 1. Changing Epidemiology of Acute Bacterial Meningitis in the United States*

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International

The incidence of meningitis is presumed to be higher in developing countries because of less access to preventative services such as vaccination. An incidence rate that is 10-fold higher than that in developed countries has been reported.

Mortality/Morbidity

Mortality from meningitis varies with the specific etiologic agent.

• The mortality rate for viral meningitis (without encephalitis) is less than 1%. In patients with deficient humoral immunity (eg, agammaglobulinemia), enterovirus meningitis may have a fatal outcome.
• Bacterial meningitis was uniformly fatal before the antimicrobial era. With the advent of antimicrobial therapy, the overall mortality rate from bacterial meningitis has decreased but remains alarmingly high. It is reported to be approximately 25%. Among the common causes of acute bacterial meningitis, the highest mortality rate is observed with pneumococcus. The reported mortality rates for each specific organism are 19-26% for S pneumoniae meningitis, 3-6% for H influenzae meningitis, 3-13% for N meningitidis meningitis, and 15-29% for L monocytogenes meningitis.

Race

• Meningitis affects people of all races.
• In the United States, black people have a higher reported rate of meningitis than white people and Hispanic people.

Sex

The attack rate for bacterial meningitis is reported to be 3.3 male cases per 100,000 population compared to 2.6 female cases per 100,000 population.

Age

• Meningitis occurs in people of all age groups, but very young individuals (infants and young children) and elderly individuals (>60 y) are more predisposed to the infection.
• Depending on their ages, individuals are also predisposed to certain etiologic agents. Escherichia coli K1 and S agalactiae meningitis are common among the neonatal group, and L monocytogenes meningitis is common among neonates and elderly individuals. See Table 2 for bacterial agents common among different age groups.
• The introduction of HIB immunization has shifted the median age of patients with bacterial meningitis from 15 months in 1986 to 25 years in 1995.

Clinical

History

• The classic presentation of meningitis includes fever, headache, neck stiffness, photophobia, nausea, vomiting, and signs of cerebral dysfunction (eg, lethargy, confusion, coma). These symptoms may develop later in the course of illness in some patients who may initially present with atypical symptoms such as leg pain and cold hands and feet.
• The triad of fever, nuchal rigidity, and change in mental status is found in only two thirds of patients. In a meta-analysis of 845 patients, the sensitivity and specificity of these classic symptoms were poor. Fever is the most common manifestation (95%), while stiff neck and headache are less common. However, the negative predictive value of these symptoms is high (ie, the absence of fever, neck stiffness, or altered mental status eliminates the diagnosis of meningitis in 99-100% of cases).
• The classic presentation of acute meningitis is the onset of symptoms within hours to a few days, compared to weeks for chronic meningitis.
• Atypical presentation may be observed in certain groups.
  • Elderly individuals, especially those with underlying comorbidities (eg, diabetes, renal and liver disease), may present with lethargy and an absence of meningeal symptoms.
  • Patients with neutropenia may present with subtle symptoms of meningeal irritation.
  • Other immunocompromised hosts, including organ and tissue transplant recipients and patients with HIV and AIDS, may also have an atypical presentation.
• Clues in the patient's clinical history may suggest the specific etiologic agent. Detailed epidemiologic and predisposing risks should be assessed.
  • The time of the year is an important variable because many infections are seasonal. Enteroviruses are observed worldwide, and infections occur during late summer and early fall in temperate climates and year-round in tropical regions. In contrast, mumps, measles, and varicella zoster viruses occur more commonly during winter and spring seasons. Arthropod-borne viruses occur during the warmer months (eg, St. Louis encephalitis, California encephalitis virus group).
  • History of exposure to a patient with a similar illness is an important epidemiological clue when determining etiology (eg, individuals who were in close contact with an index case of meningococcemia).
  • Elicit a history of sexual contact and high-risk behavior. HSV meningitis is associated with primary genital HSV infection and HIV infection.
  • The geographic location and a travel history are important in the evaluation of patients. Histoplasma capsulatum and Blastomyces dermatitidis are considered in patients with exposure to endemic areas of the Mississippi and Ohio River valleys. Coccidioides immitis is considered in regions of the southwestern United States, Mexico, and Central America. Borrelia burgdorferi is considered in regions of the northeastern and north central United States.
  • The intake of unpasteurized milk and cheese predisposes to brucellosis and L monocytogenes infection.
  • Animal contacts should be elicited. Patients with rabies could present atypically with aseptic meningitis, and rabies should be suspected in a patient with a history of animal bite (eg, skunk, raccoon, dog, fox, bat). Exposure to rodents suggests infection with lymphocytic choriomeningitis (LCM) virus and Leptospira infection. Laboratory workers dealing with these animals also are at increased risk of contracting LCM.
• Record evidence of systemic viral infection (ie, myalgias, fatigue, anorexia).
  • The presence of exanthemas; symptoms of pericarditis, myocarditis, or conjunctivitis; or syndromes of pleurodynia, herpangina, and hand-foot-and-mouth disease suggest enterovirus infection.
  • A history of recurrent bouts of benign aseptic meningitis suggests Mollaret syndrome, which is caused by HSV.
• The presence of a ventriculoperitoneal shunt and a history of recent cranial surgery should be elicited.
• The presence of cochlear implants with a positioner has been associated with a higher risk of bacterial meningitis.

Physical

• Signs of cerebral dysfunction are common, including confusion, irritability, delirium, and coma. These are usually accompanied by fever and photophobia.
• Signs of meningeal irritation are observed in only approximately 50% of patients with bacterial meningitis, and their absence certainly does not rule out meningitis.
  • Kernig sign: In a supine patient, flex the hip to 90° while the knee is flexed at 90°. An attempt to further extend the knee produces pain in the hamstrings and resistance to further extension.
  • Brudzinski sign: Passively flex the neck while the patient is in a supine position with extremities extended. This maneuver produces flexion of the hips in patients with meningeal irritation.
  • Nuchal rigidity: Resistance to passive flexion of the neck is also a sign.
  • Exacerbation of existing headache by repeated horizontal movement of the head, at a rate of 2-3 times per second, may also suggest meningeal irritation. 
• Cranial nerve palsies may be observed as a result of increased ICP or the presence of exudates encasing the nerve roots.
• Focal neurologic signs may develop as a result of ischemia from vascular inflammation and thrombosis.
• Seizures occur in approximately 30% of patients.
• Papilledema and other signs of increased ICP may be present.
  • Coma, increased blood pressure with bradycardia, and cranial nerve III palsy may be present.
  • The presence of papilledema also suggests a possible alternate diagnosis (eg, brain abscess).
• Systemic findings upon physical examination may provide clues to the etiology.
  • Morbilliform rash with pharyngitis and adenopathy may suggest a viral etiology (eg, Epstein-Barr virus [EBV], cytomegalovirus [CMV], adenovirus, HIV). Macules and petechiae that rapidly evolve into purpura suggest meningococcemia (with or without meningitis). Vesicular lesions in a dermatomal distribution suggest varicella-zoster virus. Genital vesicles suggest HSV-2 meningitis.
  • Sinusitis or otitis suggests direct extension into the meninges, usually with S pneumoniae and H influenzae. Rhinorrhea or otorrhea suggests a CSF leak from a basilar skull fracture, with meningitis most commonly caused by S pneumoniae.
  • Hepatosplenomegaly and lymphadenopathy suggest a systemic disease, including viral (eg, mononucleosislike syndrome in EBV, CMV, and HIV) and fungal (eg, disseminated histoplasmosis) disease.
  • The presence of a murmur suggests infective endocarditis with secondary bacterial seeding of the meninges.
  • Evidence of parotitis is observed in some cases of mumps meningitis.
  • The presence of a ventriculoperitoneal shunt or a cochlear implant may suggest a bacterial cause of meningitis.
• In contrast to bacterial meningitis, patients with aseptic meningitis syndrome usually appear clinically nontoxic with no vascular instability.

Causes

Acute bacterial meningitis

The widespread use of HIB vaccine has dramatically changed the epidemiology of bacterial meningitis during the past decade (see Table 1). Once the most common cause of bacterial meningitis in all age groups, the incidence of H influenzae meningitis has dramatically decreased from 48% to 7% of all cases. The rate of N meningitidis has remained constant at 14-25%, and this organism accounts for many cases among 2- to 18-year-old patients. S pneumoniae has become the most common cause in all age groups (see Table 2).

Table 2. The Most Common Bacterial Pathogens Based on Age and Predisposing Risks

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• S pneumoniae
  • S pneumoniae, a gram-positive coccus, remains an important bacterial pathogen in humans. It is a common colonizer of the human nasopharynx (5-10% of healthy adults and 20-40% of healthy children). It causes meningitis by escaping the local host defenses and phagocytic mechanisms, either through choroid plexus seeding from bacteremia or through direct extension from sinusitis or otitis media.
  • Presently, it is the most common bacterial cause of meningitis, accounting for 47% of cases. It is also associated with one of the highest mortality rates among the bacterial agents that cause meningitis (19-26%).
  • It is the most common bacterial agent in meningitis associated with basilar skull fracture and CSF leak.
  • It may be associated with other foci of infection, such as pneumonia, sinusitis, or endocarditis (ie, Austrian syndrome).
  • Patients with hyposplenism, hypogammaglobulinemia, multiple myeloma, glucocorticoid treatment, defective complement (C1-C4), diabetes mellitus, renal insufficiency, alcoholism, malnutrition, and chronic liver disease are at increased risk.
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    Pneumococcal meningitis in a patient with alcoholism. Courtesy of the CDC/Dr. Edwin P. Ewing, Jr.

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    Pneumococcal meningitis in a patient with alcoholism. Courtesy of the CDC/Dr. Edwin P. Ewing, Jr.

• N meningitidis
  • N meningitis is a gram-negative diplococcus that is carried in the nasopharynx of otherwise healthy individuals. It initiates invasion by penetrating the airway epithelial surface. The precise mechanism by which this occurs is unclear, but recent viral or mycoplasmal infection has been reported to disrupt the epithelial surface and facilitate invasion by meningococcus. Most sporadic cases (95-97%) are caused by serogroups B, C, and Y, while the A and C strains are observed in epidemics (<3% of cases).
  • Presently, it is the leading cause of bacterial meningitis in children and young adults, accounting for 59% of cases. The incidence of H influenzae meningitis has declined.
  • Risk factors include (1) deficiencies in terminal complement components (eg, membrane attack complex, C5-C9), which increases attack rates but is associated with surprisingly lower mortality rates; (2) properdin defects that increase the risk of invasive disease; (3) antecedent viral infection, household crowding, chronic medical illness, corticosteroid use, and active or passive smoking; and (4) overcrowding, as is observed in college dormitories (college freshmen living in dormitories are at highest risk) and military facilities, which has been reported for a clustering of cases.
• H influenzae
  • H influenzae is a small, pleomorphic, gram-negative coccobacilli that is frequently found as part of the normal flora in the upper respiratory tract of humans. Since the implementation of the HIB vaccine, the carriage rates for the B strain have decreased from 2-4% to less than 1%. It can spread from one individual to another by airborne droplets or direct contact with secretions.
  • Meningitis is the most serious acute manifestation of systemic infection. This is primarily caused by the encapsulated type B strain.
  • It primarily affects infants younger than 2 years. Its isolation in adults suggests the presence of an underlying medical disorder, including paranasal sinusitis, otitis media, alcoholism, CSF leak following head trauma, functional or anatomic asplenia, and hypogammaglobulinemia.
• L monocytogenes
  • L monocytogenes is a small gram-positive bacillus that causes 8% of bacterial meningitis cases and is associated with one of the highest mortality rates (22%).
  • It is widespread in nature and has been isolated in the human stool of 5% of healthy adults. Most human cases appear food-borne. It is a common food contaminant, with a recovery rate of up to 70% from raw meat, vegetables, and meats. Outbreaks have been associated with consumption of contaminated coleslaw, milk, cheese, and alfalfa tablets.
  • Persons at risk include pregnant women, infants and children, elderly individuals (>60 y), patients with alcoholism, adults who are immunosuppressed (eg, steroid use, transplant recipients, patients with AIDS), individuals with chronic liver and renal disease, individuals with diabetes, and those with conditions of iron overload (eg, hemochromatosis or transfusion-induced iron overload).
• S agalactiae
  • S agalactiae (group B streptococci) is a gram-positive coccus that is isolated from the lower gastrointestinal tract. It also colonizes the female genital tract at a rate of 5-40%, which explains why it is the most common (70%) agent of neonatal meningitis. It has also been reported in adults, primarily affecting individuals older than 60 years. The overall case-fatality rate in adults is 34%.
  • A recent increase has been noted in the incidence of invasive disease caused by this organism.
  • Predisposing risks in adults include diabetes mellitus, pregnancy, alcoholism, hepatic failure, renal failure, and corticosteroid treatment.
  • In 43% of adult cases, no underlying disease is present.
• Aerobic gram-negative bacilli (eg, E coli, Klebsiella pneumoniae, Serratia marcescens, P aeruginosa, Salmonella species)
  • As a group, the gram-negative bacilli can cause meningitis in certain groups of patients. E coli is a common agent of meningitis among neonates.
  • Other predisposing risk factors include (1) neurosurgical procedures or intracranial manipulation; (2) old age; (3) immunosuppression; (4) high-grade gram-negative bacillary bacteremia; and (5) disseminated strongyloidiasis, which has been reported as a classic cause of gram-negative bacillary bacteremia (as a result of the translocation of gut microflora with the Strongyloides stercoralis larva during hyperinfection syndrome).
• Staphylococcus species (S aureus and coagulase-negative staphylococci)
  • Staphylococci species are gram-positive cocci that are part of the normal skin flora.
  • Meningitis caused by staphylococci is associated with the following risk factors: (1) status postneurosurgery and posttrauma, (2) presence of CSF shunts, and (3) infective endocarditis and paraspinal infection.
  • Staphylococcus epidermidis is the most common cause of meningitis in patients with CNS (ie, ventriculoperitoneal) shunts.

Aseptic meningitis syndrome

Aseptic meningitis is the most common infectious syndrome affecting the CNS. Most episodes are caused by a viral pathogen, but they can also be caused by bacteria, fungi, or parasites (see Table 3). Importantly, partially treated bacterial meningitis accounts for a large number of meningitis cases with a negative microbiologic workup.

Table 3. Infectious Agents Causing Aseptic Meningitis Syndrome

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Acute viral meningitis

Viral meningitis comprises most aseptic meningitis syndromes. The viral agents for aseptic meningitis include the following:

• Enterovirus
  • Enterovirus belongs to the family Picornaviridae. It is classified further to include polioviruses (3 serotypes), coxsackievirus A (23 serotypes), coxsackievirus B (6 serotypes), echovirus (31 serotypes), and the newly recognized enterovirus serotypes 68-71.
  • They are distributed worldwide, and the infection rates vary depending on the season of the year and the age and socioeconomic status of the population.
  • The virus is usually spread by fecal-oral or respiratory routes and occurs during summer and fall in temperate climates and year-round in tropical regions.
  • Most of the infections occur in individuals who are younger than 15 years, with the highest attack rates in children who are younger than 1 year.
  • The nonpolio enteroviruses (NPEV) account for approximately 90% of cases of viral meningitis in which a specific pathogen can be identified.
  • Echovirus 30 was reported as the cause of an epidemic in Japan in 1991 and also as the cause of 20% of the cases of aseptic meningitis reported to the CDC in 1991.
  • In patients with deficient humoral immunity (eg, agammaglobulinemia), enterovirus meningitis may have a fatal outcome.
• Herpesvirus
  • The Herpesviridae family consists of large DNA-containing enveloped viruses. Eight members are known to cause human infections, and all have been implicated in meningitis syndromes, with the exception of HHV-8 or Kaposi sarcoma–associated virus.
  • HSV-1 is a cause of encephalitis, while HSV-2 more commonly causes meningitis. Although more commonly associated with HSV-2, both viruses have been implicated to cause Mollaret syndrome, a recurrent but benign aseptic meningitis syndrome.
  • EBV, or HHV-4, and CMV, or HHV-5, may manifest as meningitis during the mononucleosis syndrome.
  • Varicella zoster virus (VZV), or HHV-3, and CMV are causes of meningitis in immunocompromised hosts, especially patients with AIDS and transplant recipients.
  • HHV-6 and HHV-7 have been reported to cause meningitis in transplant recipients.
• Arthropod-borne viruses
  • The most common arthropod-borne viruses are St. Louis encephalitis virus (a flavivirus), Colorado tick fever, and California encephalitis virus (bunyavirus group, including La Crosse encephalitis virus).
  • St. Louis encephalitis virus is a mosquito-borne flavivirus that may cause a febrile syndrome, aseptic meningitis syndrome, and encephalitis. The infection usually occurs during the summer and early fall, with symptoms typical of acute aseptic meningitis. In the United States, the last epidemic of St. Louis encephalitis was in Florida in 1990. Twenty-four cases were reported to the CDC in 1998, with most cases originating from Louisiana.
  • Other members of the flavivirus group that may cause aseptic meningitis include tick-borne encephalitis virus and Japanese encephalitis virus.
  • California encephalitis is a common childhood disease of the CNS that is caused by a virus in the genus Bunyavirus. Most of the cases of California encephalitis are probably caused by mosquito-borne La Crosse virus. The infection usually occurs during the summer and early fall, with symptoms typical of acute aseptic meningitis.
• Lymphocytic choriomeningitis virus
  • LCM virus is a member of the arenaviruses, a family of single-stranded RNA-containing viruses with rodents as the animal reservoir.
  • The infection occurs worldwide, and most human cases occur among young adults during autumn.
  • The modes of transmission include aerosols and direct contact with rodents.
  • Outbreaks have also been traced to infected laboratory mice and hamsters.
  • Following exposure, an incubation period of approximately 5-10 days ensues, followed by a nonspecific febrile illness and an acute onset of aseptic meningitis. This may be associated with orchitis, arthritis, myocarditis, and alopecia.
• Human immunodeficiency virus
  • Aseptic meningitis syndrome may be the presenting symptom in a patient with acute HIV infection. This usually is part of the mononucleosislike acute seroconversion phenomenon.
  • Always suspect HIV as a cause of aseptic meningitis in a patient with risk factors such as intravenous drug use and in individuals who practice high-risk sexual behaviors.
• Other viruses causing meningitis
  • Patients with meningitis caused by the mumps virus usually present with the triad of fever, vomiting, and headache. It follows the onset of parotitis (salivary gland enlargement occurs in 50% of patients), which clinically resolves in 7-10 days.
  • Adenovirus (serotypes 1, 6, 7, and 12) has been associated with cases of meningoencephalitis. Chronic meningoencephalitis has been reported with serotypes 7, 12, and 32. The infection is usually acquired through a respiratory route.

Chronic meningitis

Chronic meningitis is a constellation of signs and symptoms of meningeal irritation associated with CSF pleocytosis that persists for longer than 4 weeks. The agents responsible for chronic meningitis are listed in Table 4.

Table 4. Causes of Chronic Meningitis

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• Chronic bacterial meningitis
  • Brucella species are small gram-negative coccobacilli that cause zoonoses as a result of infection with Brucella abortus, Brucella melitensis, Brucella suis, and Brucella canis.
  • Transmission to humans occurs following direct or indirect exposure to infected animals (eg, sheep, goat, cattle).
  • It has a worldwide distribution and is common in the Middle East, India, Mexico, and Central and South America. In the United States following the control of bovine infections, incidence has decreased to less than 0.5 cases per 100,000 population, and only 79 cases were reported to the CDC in 1998.
  • Direct infection of the CNS occurs in fewer than 5% of cases, with most patients presenting with acute or chronic meningitis.
  • Persons at risk include individuals who had contact with infected animals (eg, sheep, goat, cattle) or their products (eg, intake of unpasteurized milk products). Veterinarians, abattoir workers, and laboratory workers dealing with these animals are also at risk.
• Tuberculous meningitis
  • M tuberculosis is an acid-fast bacillus that causes a broad range of clinical illnesses that can affect virtually any organ of the body. 
  • It is worldwide in distribution, and humans are its only reservoir. 
  • It is spread through airborne droplet nuclei, and it infects one third of the world's population. In 1997, the estimated case rates among endemic countries ranged from 62-411 cases per 100,000 population. 
  • Always consider tuberculous meningitis in the differential diagnoses of patients with aseptic meningitis or chronic meningitis syndromes. 
  • Involvement of the CNS with tuberculous meningitis is usually caused by rupture of a tubercle into the subarachnoid space. 
  • The presentation may be acute, but the classic presentation is subacute and spans weeks. Patients generally have a prodrome of fever of varying degrees, malaise, and intermittent headaches. Patients often develop central nerve palsies (III, IV, V, VI, and VII), suggesting basilar meningeal involvement. 
  • Clinical staging of meningeal tuberculosis is based on neurologic status. Stage 1 shows no change in mental function with no deficits and no hydrocephalus. Stage 2 refers to a patient with confusion and evidence of neurologic deficit. Stage 3 refers to an individual with stupor and lethargy.
• Spirochetal meningitis
  • T pallidum
    • T pallidum is a slender tightly coiled spirochete that is usually acquired by sexual contact. Other modes of transmission include direct contact with an active lesion, passage through the placenta, and blood transfusion (rare). The median incubation period before the appearance of symptoms is 21 days (range 3-90 d), during which time spirochetemia develops.
    • Three stages of disease are described, and involvement of the CNS can occur during any of these stages.
    • Syphilitic meningitis usually occurs during the primary or secondary stage, complicating 0.3-2.4% of primary infections during the first 2 years. Its presentation is similar to other agents of aseptic meningitis, with headache, nausea, vomiting, and meningismus
    • Other CNS syphilitic syndromes include meningovascular syphilis, parenchymatous neurosyphilis, and gummatous neurosyphilis, all of which are manifestations of late symptomatic neurosyphilis. Meningovascular syphilis occurs later in the course of untreated syphilis, and the symptoms are dominated by focal syphilitic arteritis (ie, focal neurologic symptoms associated with signs of meningeal irritation) that spans weeks to months and results in stroke and irreversible damage if left untreated. Patients with HIV have an increased risk of accelerated progression.
  • B burgdorferi
    • B burgdorferi is the agent of Lyme disease, the most common vector-borne disease in the United States. It is a tick-borne spirochete that occurs in the temperate regions of North America (eg, northeast United States, Minnesota, Wisconsin, parts of California and Oregon), Europe, and Asia. 
    • Lyme disease is characterized by 3 stages. Although rare during stage I, CNS involvement (with meningitis) may occur and is characterized by the concurrent appearance of erythema migrans at the site of tick bite. More commonly, aseptic meningitis syndrome occurs 2-10 weeks following the erythema migrans rash. This represents stage 2 of Lyme disease, or the borrelial hematogenous dissemination stage. Chronic neuroborreliosis is a hallmark of the third stage of Lyme disease and is characterized by subacute encephalopathy manifested by disturbance in mood, memory, language, or sleep. 
    • Headache is the most common symptom, with photophobia, nausea, and neck stiffness occurring less frequently. Symptoms of somnolence, emotional lability, and impaired memory and concentration may occur. Facial nerve palsy is the most common cranial nerve deficit. These symptoms of meningitis usually fluctuate and may last for months if left untreated.
• Fungal meningitis
  • C neoformans
    • C neoformans is an encapsulated yeastlike fungus that is ubiquitous and has a worldwide distribution. It has been found in high concentrations in aged pigeon droppings and pigeon nesting places. 
    • The 4 serotypes are designated A through D, with the A serotype causing most human infections. Serotypes B and C have been restricted mostly to tropical and subtropical regions, and serotype B has been isolated from eucalyptus trees. 
    • The infection is characterized by the gradual onset of symptoms, the most common of which is headache. 
    • The onset may be acute, especially among patients with AIDS. A large number of cases occur in healthy hosts (eg, with no known T-cell defect); however, approximately 50-80% of cases occur in immunocompromised hosts. At particular risk are individuals with defects of T-cell–mediated immunity (eg, those who use steroids, cyclosporine, and other immunosuppressants). 
    • Most cases have occurred among individuals with AIDS and among organ transplant recipients. It has also been reported in patients with idiopathic CD-4 lymphopenia, Hodgkin disease, and sarcoidosis.
  • C immitis
    • C immitis is a dimorphic fungus that exists in mycelial and yeast (spherule) forms. It is a soil-based fungus with a distribution limited to the endemic regions of the Western Hemisphere, within the north and south 40° latitudes (ie, parts of the southwest United States, Mexico, and Central and South America). 
    • The infection follows inhalation of the Arthroconidia. Extrapulmonary dissemination to the skin (most common), joints, and bones occurs in predisposed individuals. 
    • Coccidioidal meningitis is the most serious form of dissemination, and it usually is fatal if left untreated. These patients may present with headache, vomiting, and altered mental function associated with pleocytosis, elevated protein levels, and decreased glucose levels. Eosinophils may be a prominent finding in the CSF. 
    • Persons at risk include individuals exposed to the endemic regions (eg, tourists and local populations) and those with immune deficiency (ie, AIDS, organ transplantation).
  • B dermatitidis
    • B dermatitidis is a dimorphic fungus that has been reported to be endemic in North America (eg, Mississippi and Ohio River basins). It has also been isolated from parts of Central America, South America, the Middle East, and India.
    • The natural habitat of this fungus is not well defined. Soil that is rich in decaying matter and environments around riverbanks and waterways have been demonstrated to harbor the fungus during outbreaks and are thought to be risk factors for acquiring the infection. 
    • Inhalation of the conidia establishes a pulmonary infection. Dissemination may occur in certain individuals (including patients with AIDS) and may involve the skin, bones and joints, genitourinary tract, and the CNS. Involvement of the CNS occurs in fewer than 5% of cases, and patients may present with an abscess or fulminant meningitis.
  • H capsulatum
    • H capsulatum is one of the dimorphic fungi that exist in mycelial and yeast forms. It is usually found in soil.
    • It has been reported from many areas of the world, with the Mississippi and Ohio River valleys being the most endemic regions in North America. 
    • Primary infection follows inhalation exposure. Dissemination occurs in individuals with underlying immune deficiency (eg, from HIV or pharmaceutical agents) and extremes of age. 
    • Involvement of the CNS is rare but may occur as part of disseminated histoplasmosis and manifests most frequently as chronic meningitis. 
    • Patients may present with headache, cranial nerve deficits, or changes in mental status months prior to diagnosis.
  • Candida species
    • Candidal species are ubiquitous in nature. They are normal commensals in humans and are found in the skin, the gastrointestinal tract, and the female genital tract. 
    • The most common species is C albicans, but the incidence of non-albicans candidal infections (eg, Candida tropicalis) is increasing, including species with antifungal resistance (eg, Candida krusei, Candida glabrata). 
    • Involvement of the CNS usually follows hematogenous dissemination. The most important predisposing risk for acquiring disseminated candidal infection appears to be iatrogenic in nature (eg, use of broad-spectrum antibiotics and indwelling devices such as urinary and vascular catheters). AIDS is also considered a predisposing risk factor. Infection may also follow neurosurgical procedures, such as placement of ventricular shunts.
  • S schenckii
    • S schenckii is an endemic dimorphic fungus that is often isolated from soil, plants, and plant products. It has been reported worldwide, with most cases coming from the tropical regions of the Americas. 
    • Extracutaneous manifestations may occur, with meningeal sporotrichosis (a rare complication) being the worst complication of S schenckii infections. AIDS is a reported underlying risk factor in many described cases. It is associated with a poor outcome.
• Parasitic meningitis
  • Free-living amoebas (ie, Acanthamoeba, Balamuthia, Naegleria)
    • Infection with free-living amoebas is an infrequent but often life-threatening human illness, even in immunocompetent individuals. 
    • N fowleri is the only recognized human pathogenic species of Naegleria, and it is the agent of primary amebic meningoencephalitis (PAM). The parasite has been isolated in lakes, pools, ponds, rivers, tap water, and soil. Infection occurs when swimming or playing in the contaminated water sources (eg, inadequately chlorinated water and sources associated with poor decontamination techniques). The N fowleri amoebas invade the CNS through the nasal mucosa and cribriform plate. 
    • PAM occurs in 2 forms. The first form is an acute onset of high fever, photophobia, headache, and change in mental status, similar to bacterial meningitis, occurring within a week following exposure. Because it is acquired through the nasal area, involvement of the olfactory nerves may manifest as abnormal smell sensation. Death occurs in 3 days in patients who are not treated. The second form, the subacute or chronic form, is an insidious onset of low-grade fever, headache, and focal neurologic signs. Duration of illness is weeks to few months.
    • Acanthamoeba and Balamuthia cause granulomatous amebic encephalitis, which is a subacute opportunistic infection that spreads hematogenously from the primary site of infection (skin or lungs) to the CNS and causes an encephalitis syndrome.
  • Helminthic eosinophilic meningitis
    • A cantonensis, the rat lungworm, can cause eosinophilic meningitis (pleocytosis with >10% eosinophils) in humans. The parasite is common in Southeast Asia and the Pacific Islands. It has also been found in rats outside this region, particularly in regions of Africa, Puerto Rico, and Louisiana, presumably introduced by ship-borne rats from endemic areas. The adult parasite resides in the lungs of rats. Its eggs hatch and the larval stages are expelled in the feces. The larvae develop in the intermediate host, usually land snails, freshwater prawns, and crabs. Humans acquire the infection by ingesting raw mollusks. Following ingestion, most patients with symptomatic disease present with nonspecific and self-limited abdominal pain caused by larval migration into the bowel wall. On rare occasions, the larva can migrate into the CNS and cause eosinophilic meningitis.
    • G spinigerum, a gastrointestinal parasite of wild and domestic dogs and cats, may cause eosinophilic meningoencephalitis. This is common in Southeast Asia, China, and Japan but has been reported sporadically worldwide. Humans acquire the infection following ingestion of undercooked infected fish and poultry.
    • B procyonis is an ascarid parasite that is prevalent in the raccoon populations in the United States and rarely causes human eosinophilic meningoencephalitis. Human infections occur following accidental ingestion of food products contaminated with raccoon feces.

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