Meningitis 

Infections of the central nervous system (CNS) can be divided into 2 broad categories: those primarily involving the meninges (meningitis) and those primarily confined to the parenchyma (encephalitis).

See the images of meningitis below.

Meningitis is a clinical syndrome characterized by inflammation of the meninges, 3 layers of membranes that enclose the brain and spinal cord. They consist of the following:

• Dura - A tough outer membrane
• Arachnoid - A lacy, weblike middle membrane
• Subarachnoid space - A delicate, fibrous inner layer that contains many of the blood vessels that feed the brain and spinal cord

Risk factors for meningitis include the following:

• Age of 60 years or greater
• Age of 5 years or less
• Diabetes mellitus, renal or adrenal insufficiency, hypoparathyroidism, or cystic fibrosis
• Immunosuppression, which increases the risk of opportunistic infections and acute bacterial meningitis
• Human immunodeficiency virus (HIV) infection, which predisposes to bacterial meningitis caused by encapsulated organisms, primarily S pneumoniae, and opportunistic pathogens
• Crowding (eg, military recruits and college dorm residents), which increases the risk of outbreaks of meningococcal meningitis
• Splenectomy and sickle cell disease, which increase the risk of meningitis secondary to encapsulated organisms
• Alcoholism and cirrhosis
• Recent exposure to others with meningitis, with or without prophylaxis
• Contiguous infection (eg, sinusitis)
• Dural defect (eg, traumatic, surgical, congenital)
• Thalassemia major
• Intravenous (IV) drug abuse
• Bacterial endocarditis
• Ventriculoperitoneal shunt
• Malignancy (increased risk of Listeria species infection)
• Some cranial congenital deformities

Clinically, meningitis manifests with meningeal symptoms (eg, headache, nuchal rigidity, photophobia), as well as pleocytosis (an increased number of white blood cells) in the cerebrospinal fluid (CSF). Depending on the duration of symptoms, meningitis may be classified as acute or chronic. (See Etiology and Clinical Presentation.)

Meningitis is anatomically divided into inflammation of the dura, sometimes referred to as pachymeningitis, which is less common, and leptomeningitis, which is more common and is defined as inflammation of the arachnoid tissue and subarachnoid space. (See Anatomy.)

Meningitis can also be divided into the following 3 general categories:

• Pyogenic (bacterial)
• Granulomatous
• Lymphocytic

The most common cause of meningeal inflammation is irritation caused by bacterial or viral infections. The organisms usually enter the meninges through the bloodstream from other parts of the body. Most cases of bacterial meningitis are localized over the dorsum of the brain; however, under certain conditions, meningitis may be concentrated at the base of the brain, such as with fungal diseases and tuberculosis. (See Etiology.)

Pyogenic (bacterial) meningitis consists of inflammation of the meninges and the underlying subarachnoid CSF. If not treated, bacterial meningitis may lead to lifelong debility or death.^{[1] [2]} The disease was uniformly fatal before the antimicrobial era, but with the advent of antimicrobial therapy, the overall mortality rate from bacterial meningitis has decreased. Nonetheless, it remains alarmingly high, being approximately 25%. (See Epidemiology.)

The emergence of resistant bacterial strains has prompted changes in antibiotic protocols in some countries, including the United States. Apart from dexamethasone, neuronal cell protectants still hold only future promise as adjunctive therapy. (See Treatment and Management and Medication.)

The specific infective agents that are involved in bacterial meningitis vary among different patient age groups, and the inflammation may evolve into the following conditions (see the images below):

• Ventriculitis
• Empyema
• Cerebritis
• Abscess formationChronic mastoiditis and epidural empyema in a patient with bacterial meningitis. This axial computed tomography scan shows sclerosis of the temporal bone (chronic mastoiditis), an adjacent epidural empyema with marked dural enhancement (arrow), and the absence of left mastoid air. Subdural empyema and arterial infarct in a patient with bacterial meningitis. This contrast-enhanced axial computed tomography scan shows left-sided parenchymal hypoattenuation in the middle cerebral artery territory, with marked herniation and a prominent subdural empyema.

Meningitis can also be also classified more specifically according to its etiology. Numerous infectious and noninfectious causes of meningitis have been identified. Examples of common noninfectious causes include medications (eg, nonsteroidal anti-inflammatory drugs [NSAIDs], antibiotics) and carcinomatosis. (See Etiology.)

Acute bacterial meningitis

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, any of the following:

• Pneumococcal meningitis
• Haemophilus influenzae meningitis
• Staphylococcal meningitis
• Meningococcal meningitis
• Tuberculous meningitis

Unlike subacute (1-7 d) or chronic (>7 d) meningitis, which have myriad infectious and noninfectious etiologies, acute meningitis (< 1 d) is almost always a bacterial infection caused by 1 of several organisms. Depending on age and general condition, these gravely ill patients present acutely with signs and symptoms of meningeal inflammation and systemic infection of less than 24 hours' duration (and usually >12 hours’ duration). Patients with acute bacterial meningitis may decompensate very quickly, and so they require emergency care, including antimicrobial therapy, ideally within 30 minutes of emergency department (ED) presentation.

For more information, see the following:

• Meningococcal Meningitis
• Staphylococcal Meningitis
• Haemophilus Meningitis
• Tuberculous Meningitis

Subacute bacterial meningitis

Most bacterial meningitis is not acute. Approximately 75% of patients with bacterial meningitis present subacutely, with symptoms beginning several days prior. These ill patients still require urgent ED diagnosis and care to prevent further decompensation.

Meningitis caused by nonbacterial organisms

Fungal and parasitic causes of meningitis are also termed according to their specific etiologic agent, such as cryptococcal meningitis, Histoplasma meningitis, and amebic meningoencephalitis.

Viral meningitis

If, after an extensive workup, aseptic meningitis is found to have a viral etiology, it can be reclassified as a form of acute viral meningitis (eg, enterovirus meningitis, herpes simplex virus [HSV] meningitis).

Go to Viral Meningitis for complete information on this topic.

Aseptic meningitis

In many cases, a cause for meningitis is not apparent after initial evaluation and is therefore classified as aseptic meningitis. These patients characteristically have an acute onset of meningeal symptoms, fever, and cerebrospinal pleocytosis that is usually prominently lymphocytic.

When the cause of aseptic meningitis is discovered, the disease can be reclassified according to its etiology. If appropriate diagnostic methods are performed, a specific viral etiology is identified in 55-70% of cases of aseptic meningitis. However, the condition can also be caused by bacterial, fungal, mycobacterial, and parasitic agents.

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 brain is naturally protected from the body's immune system by a barrier the meninges create between the bloodstream and the brain. Normally, this protection is an advantage because the barrier prevents the body from attacking itself. However, in meningitis, the barrier can become a problem; once bacteria or other organisms have found their way to the brain, they are somewhat isolated from the immune system and can spread.

When the body tries to fight the infection, the problem can worsen; blood vessels become leaky and allow fluid, white blood cells, and other infection-fighting particles to enter the meninges and brain. This process, in turn, causes brain swelling and can eventually result in decreasing blood flow to parts of the brain, worsening the symptoms of infection.^[3]

Depending on the severity of bacterial meningitis, the inflammatory process may remain confined to the subarachnoid space. In less severe forms, the pial barrier is not penetrated, and the underlying parenchyma remains intact. However, in more severe forms of bacterial meningitis, the pial barrier is broken, and the underlying parenchyma is invaded by the inflammatory process. Thus, bacterial meningitis may lead to widespread cortical destruction, particularly when left untreated.

Replicating bacteria, increasing numbers of inflammatory cells, cytokine-induced disruptions in membrane transport, and increased vascular and membrane permeability perpetuate the infectious process in bacterial meningitis and account for the characteristic changes in CSF cell count, pH, lactate, protein, and glucose in patients with this disease.

Exudates extend throughout the CSF, particularly to the basal cisterns, damaging cranial nerves (eg, cranial nerve VIII, with resultant hearing loss), obliterating CSF pathways (causing obstructive hydrocephalus), and inducing vasculitis and thrombophlebitis (causing local brain ischemia).

Intracranial pressure and cerebral brain fluid

One 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 blood brain barrier permeability) are all thought to play a role in the development of increased ICP.

Without medical intervention, the cycle of decreasing cerebral brain fluid (CBF), worsening cerebral edema, and increasing ICP proceeds unchecked. Ongoing endothelial injury may result in vasospasm and thrombosis, further compromising CBF, and may lead to stenosis of large and small vessels. Systemic hypotension (septic shock) also may impair CBF, and the patient soon dies from systemic complications or from diffuse CNS ischemic injury.

Cerebral edema

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 role of cytokines and secondary mediators in bacterial meningitis

Key advances in understanding the pathophysiology of meningitis include insight into the pivotal roles 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 occurrences of bacterial meningitis.

Increased CSF concentrations of TNF-alpha, IL-1, IL-6, and IL-8 are characteristic findings in patients with bacterial meningitis. (Cytokine levels, including those of IL-6, TNF-alpha, and interferon-gamma, have been found to be elevated in patients with aseptic meningitis.)

The proposed events involving these inflammation mediators in bacterial meningitis begin with the exposure of cells (eg, endothelial cells, leukocytes, microglia, astrocytes, and meningeal macrophages) to bacterial products released during replication and death; this exposure incites the synthesis of cytokines and proinflammatory mediators. 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 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 cyclo-oxygenase (COX), appears to participate in the induction of increased blood-brain barrier permeability. PAF, with its myriad 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.

The net result of the above processes is vascular endothelial injury and increased blood-brain barrier 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 blood-brain barrier, producing the profound neutrophilic pleocytosis characteristic of bacterial meningitis.

Bacterial seeding

Bacterial seeding usually occurs by hematogenous spread. Organisms typically enter the meninges through the bloodstream, from other parts of the body. In patients without an identifiable source of infection, local tissue and bloodstream invasion by bacteria colonized in the nasopharynx may be a common source.

Many meningitis-causing bacteria are carried in the nose and throat, often without symptoms in the carrier. Most meningeal pathogens are transmitted through the respiratory route, as exemplified by the fact that Neisseria meningitidis (meningococcus) is carried nasopharyngeally and by the nasopharyngeal colonization with Streptococcus pneumoniae (pneumococcus).

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, and 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.

Bacterial seeding results in increased permeability of the blood-brain barrier, cerebral edema, and the presence of toxic mediators in the CSF. Inflammations are characterized by polymorphonuclear cell infiltration and extensive fibrinous exudation, which extends throughout the CSF, basal cisterns, and cranial nerves. Acute leptomeningitis results in congestion and hyperemia of the pia-arachnoid and distention of the subarachnoid space by the exudates.

Once in the CSF, the paucity of antibodies, complement components, and white blood cells allows the bacterial infection to flourish. Bacterial cell wall components initiate a cascade of complement- and cytokine-mediated events that result in increased permeability of the blood-brain barrier, cerebral edema, and the presence of toxic mediators in the CSF.

Initially, an 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, GI tract, or genitourinary tract. The organism invades the submucosa by circumventing host defenses (eg, physical barriers, local immunity, phagocytes/macrophages).

The following 3 major pathways exist by which an infectious agent (ie, bacterium, virus, fungus, and parasite) gains access to the CNS and causes meningeal disease:

• Invasion of the bloodstream (ie, bacteremia, viremia, fungemia, parasitemia) and subsequent hematogenous seeding of the CNS.
• A retrograde neuronal (ie, olfactory and peripheral nerves) pathway (eg, Naegleria fowleri, Gnathostoma spinigerum)

Direct contiguous spread (ie, sinusitis, otitis media, congenital malformations, trauma, direct inoculation during intracranial manipulation)

Invasion of the bloodstream, and subsequent seeding, is the most common mode of spread for most agents (eg, meningococcal, cryptococcal, syphilitic, and pneumococcal meningitis).

Rarely, infected contiguous structures invade via septic thrombi or osteomyelitic erosion; meningeal seeding may also occur with a direct bacterial inoculate during trauma, neurosurgery, or instrumentation. Meningitis in the newborn is transmitted vertically from colonized pathogens in the maternal intestinal or genital tract or horizontally from nursery personnel or caregivers at home.

Local extension from contiguous extracerebral infection (eg, otitis media, mastoiditis, or sinusitis) is a common cause. Possible pathways for the migration of pathogens from the middle ear to the meninges include the following:

• A systemic route in the bloodstream
• Along preformed tissue planes (eg, posterior fossa)
• Temporal bone fractures
• The oval or round window membranes of the labyrinths

In HIV-positive/AIDS patients, consider cryptococci, Mycobacterium tuberculosis, syphilis, HIV aseptic meningitis, and Listeria species. If the pathogen is unknown after an ED workup, draw a serum/CSF cryptococcal antigen and treat empirically as in adults older than 50 years (pending results of all blood and CSF tests) to cover the bacterial pathogens, particularly S pneumoniae and L monocytogenes, for which this patient population is most at risk .

Go to HIV-1 Associated CNS Conditions - Meningitis for complete information on this topic.

In patients who have had trauma or neurosurgery, the most common microorganisms are S pneumoniae (if CSF leak is present), Staphylococcus aureus, coliforms, and P aeruginosa. In patients with infected ventriculoperitoneal (atrial) shunt, the most common microorganisms are Staphylococcus epidermidis, S aureus, coliforms, Propionibacterium acnes, and diphtheroids (rare). Consult a neurosurgeon, since early shunt removal is usually necessary for cure.

In patients with aseptic meningitis (CSF pleocytosis and normal CSF glucose, negative bacteria on Gram stain), the most common microorganisms are enteroviruses, human herpesvirus-2 (HHV-2), lymphocytic choriomeningitis virus (LCM), HIV, and other viruses.

Other etiologies include drugs (NSAIDs, metronidazole, IV immunoglobulin) and, rarely, leptospirosis. Manage by repeating LP if necessary to rule out partially treated bacterial meningitis.

Pachymeningitis

On the basis of the finding of abundant pus, pachymeningitis most often results from a bacterial infection (usually due to staphylococcal or streptococcal organisms) that is localized to the dura. The source of the organisms is most often a skull defect (eg, skull fracture), an infection of the paranasal sinuses, or cranial osteomyelitis.

Meningitis caused by Haemophilus 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. 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 with H influenzae. The encapsulated type B strain of this bacterium is the form of H influenzae that most often causes meningitis.

The isolation of H influenzae in adults suggests the presence of an underlying medical disorder, such as the following:

• Paranasal sinusitis
• Otitis media
• Alcoholism
• CSF leak following head trauma
• Functional or anatomic asplenia
• Hypogammaglobulinemia

Go to Haemophilus Meningitis for complete information on this topic.

Meningitis caused by Streptococcus pneumoniae

S pneumoniae, a gram-positive coccus, is the most common bacterial cause of meningitis. In addition, 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).

S pneumoniae 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.

Patients with the following conditions are at increased risk for S pneumoniae meningitis:

• Hyposplenism
• Hypogammaglobulinemia
• Multiple myeloma
• Glucocorticoid treatment
• Defective complement (C1-C4)
• Diabetes mellitus
• Renal insufficiency
• Alcoholism
• Malnutrition
• Chronic liver disease

Meningitis caused by Streptococcus agalactiae

Streptococcus 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.

Predisposing risks in adults include the following:

• Diabetes mellitus
• Pregnancy
• Alcoholism
• Hepatic failure
• Renal failure
• Corticosteroid treatment

In 43% of adult cases, however, no underlying disease is present.

Meningitis caused by Neisseria meningitides

N meningitides 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). Currently, it is the leading cause of bacterial meningitis in children and young adults, accounting for 59% of cases.

Risk factors for Neisseria meningitis include the following:

• Deficiencies in terminal complement components (eg, membrane attack complex, C5-C9), which increases attack rates but is associated with surprisingly lower mortality rates
• Properdin defects that increase the risk of invasive disease
• Antecedent viral infection, household crowding, chronic medical illness, corticosteroid use, and active or passive smoking
• 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

Meningitis caused by Listeria monocytogenes

Listeria 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 to be 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.

At-risk groups include the following:

• Pregnant women
• Infants and children
• Elderly individuals (>60 y)
• Patients with alcoholism
• Adults who are immunosuppressed (eg, steroid use, transplant recipients, patients with acquired immunodeficiency syndrome [AIDS])
• Individuals with chronic liver and renal disease
• Individuals with diabetes
• Persons with iron-overload conditions (eg, hemochromatosis or transfusion-induced iron overload)

Meningitis caused by gram-negative bacilli

As a group, gram-negative bacilli can cause meningitis in certain groups of patients. Aerobic gram-negative bacilli include Escherichia coli, Klebsiella pneumoniae, Serratia marcescens, Pseudomonas aeruginosa, and Salmonella species.

E coli are a common agent of meningitis among neonates.

Other predisposing risk factors for meningitis associated with gram-negative bacilli include the following:

• Neurosurgical procedures or intracranial manipulation
• Old age
• Immunosuppression
• High-grade gram-negative bacillary bacteremia
• Disseminated strongyloidiasis

Disseminated strongyloidiasis 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-associated meningitis

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:

• Status post neurosurgery and post trauma
• Presence of CSF shunts
• Infective endocarditis and paraspinal infection

Staphylococcus epidermidis is the most common cause of meningitis in patients with CNS (ie, ventriculoperitoneal) shunts.

Go to Staphylococcal Meningitis for complete information on this topic.

Aseptic meningitis

Aseptic meningitis is one of the most common infections of the meninges. As previously mentioned, if appropriate diagnostic methods are performed, a specific viral etiology is identified in 55-70% of cases of aseptic meningitis. However, aseptic meningitis can also be caused by bacteria, fungi, and parasites (see the Table 1 “Infectious Agents Causing Aseptic Meningitis Syndrome,” below). Importantly, partially treated bacterial meningitis accounts for a large number of meningitis cases with a negative microbiologic workup.

Go to Aseptic Meningitis for complete information on this topic.

Table 1. Infectious Agents Causing Aseptic Meningitis Syndrome (Open Table in a new window)

Enteroviruses account for 90% of cases of aseptic meningitis. The enteroviruses belong to the family Picornaviridae and are further classified as follows:

• Poliovirus (3 serotypes)
• Coxsackievirus A (23 serotypes)
• Coxsackievirus B (6 serotypes)
• Echovirus (31 serotypes)
• Newly recognized enterovirus serotypes 68-71

The virus is usually spread by fecal-oral or respiratory routes; infection occurs during summer and fall in temperate climates and year-round in tropical regions.

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 cases of aseptic meningitis reported to the Centers for Disease Control and Prevention (CDC) in 1991.

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 accounts for 0.5-3% of cases of aseptic meningitis; it is most commonly associated with primary genital infection and is less likely during recurrences. HSV-1 is a cause of encephalitis, while HSV-2 more commonly causes meningitis. Although Mollaret syndrome, a recurrent, but benign, aseptic meningitis syndrome, is more frequently associated with HSV-2; HSV-1 has also been implicated as a cause.

Epstein-Barr virus (EBV, or HHV-4) and cytomegalovirus (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 acquired immunodeficiency syndrome (AIDS) and transplant recipients. HHV-6 and HHV-7 have been reported to cause meningitis in transplant recipients.

The most common arthropod-borne viruses are St. Louis encephalitis virus (a flavivirus), Colorado tick fever virus, 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.

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 encephalitis virus.

LCM virus is a member of the arenaviruses, a family of single-stranded, RNA-containing viruses in which rodents are the animal reservoir. The modes of transmission include aerosols and direct contact with rodents.

Outbreaks have also been traced to infected laboratory mice and hamsters.

The mumps virus is the most common cause of aseptic meningitis in unimmunized populations, occurring in 30% of all patients with mumps.

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.

Aseptic meningitis syndrome may be the presenting symptom in a patient with acute HIV infection. This usually is part of the mononucleosis-like 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.

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.

Go to Aseptic Meningitis for complete information on this topic.

Chronic meningitis

The agents responsible for chronic meningitis are listed in Table 2 “Causes of Chronic Meningitis,” below.

Table 2. Causes of Chronic Meningitis (Open Table in a new window)

Brucella species are small gram-negative coccobacilli that cause zoonoses as a result of infection with B abortus, B melitensis, B suis, and B canis. Transmission to humans occurs following direct or indirect exposure to infected animals (eg, sheep, goat, cattle). 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.

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 spread through airborne droplet nuclei, and it infects one third of the world's 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.

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).

B burgdorferi, a tick-borne spirochete, is the agent of Lyme disease, the most common vector-borne disease in the United States.

C neoformans is an encapsulated, yeast like fungus that is ubiquitous. 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. 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 of C neoformans 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 is a soil-based, dimorphic fungus that exists in mycelial and yeast (spherule) forms. Persons at risk for coccidioidal meningitis include individuals exposed to the endemic regions (eg, tourists and local populations) and those with immune deficiency (ie, AIDS, organ transplantation).

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 B dermatitidis, a dimorphic 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 individuals with underlying immune deficiency [eg, from HIV or pharmaceutical agents] and extremes of age) and may involve the skin, bones and joints, genitourinary tract, and the CNS. Involvement of the CNS occurs in fewer than 5% of cases.

H capsulatum is one of the dimorphic fungi that exist in mycelial and yeast forms. It is usually found in soil.

Candida 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, C tropicalis) is increasing, including species with antifungal resistance (eg, C krusei, C 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 is an endemic dimorphic fungus that is often isolated from soil, plants, and plant products. 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.

Infection with free-living amebas 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 amebas 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.

A cantonensis, the rat lungworm, can cause eosinophilic meningitis (pleocytosis with >10% eosinophils) in humans. 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. G spinigerum, a gastrointestinal parasite of wild and domestic dogs and cats, may cause eosinophilic meningoencephalitis. 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.

Go to Staphylococcal Meningitis for complete information on this topic.

Additional causes of meningitis

Congenital malformation of the stapedial footplate has also been implicated in the development of meningitis. Direct implantation of bacteria into the meninges occurs less frequently and is a complication of head and neck surgery, penetrating head injury, comminuted skull fracture, and osteomyelitic erosion. Skull fractures can tear the dura and cause a CSF fistula, especially in the region of the frontal ethmoid sinuses. Patients with any of these conditions are at risk for bacterial meningitis.

The incidence of meningitis varies with the specific etiologic agent, as well as in conjunction with a nation’s medical resources. The incidence is presumed to be higher in developing countries because of less access to preventive services, such as vaccination. An incidence rate that is 10-fold higher than that in developed countries has been reported.

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.

Epidemiology of bacterial meningitis

With almost 8000 cases and 2000 deaths occurring annually, bacterial meningitis continues to be a significant source of morbidity and mortality. The attack rate per year in the United States is reportedly 0.6-4 cases per 100,000 population.

Meningococcal meningitis is endemic in parts of Africa, India, and other developing areas. Periodic epidemics occur in the so-called sub-Saharan "meningitis belt," as well as among religious pilgrims traveling to Saudi Arabia for the Hajj. In parts of Africa, widespread epidemics of meningococcal meningitis occur regularly. In 1996, the biggest wave of meningococcal meningitis outbreaks ever recorded arose in West Africa. An estimated 250,000 cases and 25,000 deaths occurred in Niger, Nigeria, Burkina Faso, Chad, and Mali.

The incidence of neonatal bacterial meningitis is 0.25-1 case per 1000 live births. In addition, the incidence is 0.15 case per 1000 full-term births and 2.5 cases per 1000 premature births. Approximately 30% of newborns with clinical sepsis have associated bacterial meningitis.

The frequency of H influenzae type B (HIB) disease has been markedly reduced, but N meningitidis causes approximately 4 cases per 100,000 children aged 1-23 months. The risk of secondary meningitis is 1% for family contacts and 0.1% for daycare contacts. The rate of meningitis caused by S pneumoniae is 6.5 cases per 100,000 children aged 1-23 months.

Previously, HIB, N meningitidis, and S pneumoniae accounted for more than 80% of cases of bacterial meningitis. Since the late 20th century, however, the epidemiology of bacterial meningitis has been substantially changed by multiple developments.

An increased incidence of HIV infection worldwide resulted in a correspondingly increased frequency of meningitis caused by encapsulated organisms (primarily S pneumoniae).^[4]

Even so, the overall incidence of bacterial meningitis declined from 1.9 to 1.5 cases per 100,000 between 1998 and 2003.^[5] This was partially due to the widespread use of the HIB vaccination, which decreased the incidence of HIB meningitis by more than 90% (see Table 3 “Changing Epidemiology of Acute Bacterial Meningitis in the United States,” below), nearly eliminating it in many developed countries where routine HIB vaccination is used.

Because the frequency of bacterial meningitis in children has declined, the condition is becoming more of a disease of adults. The median age for persons with bacterial meningitis was 25 years in 1998, while in 1986, it was 15 months.^[6]

A total of 255 cases of invasive H influenzae disease among children younger than 5 years were reported to the CDC in 1998, in contrast to 20,000 cases among children in 1987. This shift has reportedly been less dramatic in developing countries, where the use of the HIB vaccine is not as widespread.

Table 3. Changing Epidemiology of Acute Bacterial Meningitis in the United States* (Open Table in a new window)

The introduction of vaccines against S pneumoniae has substantially reduced the incidence of pneumococcal meningitis in children. The routine screening of group B streptococcus in pregnant women may have also reduced the incidence of meningitis due to S agalactiae. Routine vaccination against meningococcus with the use of serogroup C meningococcal conjugate vaccine may also reduce the incidence of N meningitidis infections. These efforts, together with the use of the HiB vaccine, has reduced the incidence of meningitis in recent years. During a 1998-2007 survey, the incidence of meningitis declined by 31%.^[7]

Excluding meningococcal meningitis, patients younger than 5 years or older than 60 years are at increased risk for bacterial meningitis, despite the above-mentioned shift in median age for persons with the disease.

Newborns are at highest risk for acute bacterial meningitis. After the first month of life, the peak incidence is in infants aged 3-8 months. In addition, statistics show an increased incidence in persons aged 60 years and older, independent of other factors. Annual incidences are 1.7-7.2 cases per 100,000 adults, and the mean annual incidence has been reported as 3.8 cases per 100,000 adults. Of patients with bacterial meningitis, 61% had no previous or present accompanying diseases that may have predisposed them to meningitis.

Depending on their age, individuals are also predisposed to other etiologic agents (see Table 4 “The Most Common Bacterial Pathogens Based on Age and Predisposing Risks,” below). E coli K1 and S agalactiae meningitis are common among the neonatal group, and L monocytogenes meningitis is common among neonates and elderly individuals. (The development of neonatal meningitis is related to labor delivery; it results from colonized pathogens in the maternal intestinal or genital tract, immaturity, and environment.)

The attack rate for bacterial meningitis is reportedly 3.3 male cases per 100,000 population, compared with 2.6 female cases per 100,000 population. (In meningitis caused by the mumps virus, males and females are affected equally.) In neonates, the male-to-female ratio is 3:1.

The epidemiology of bacterial meningitis continues to evolve as preventive strategies are implemented.

Table 4. The Most Common Bacterial Pathogens Based on Age and Predisposing Risks (Open Table in a new window)

Epidemiology of specific bacterial pathogens of acute meningitis

H influenzae meningitis primarily affects infants younger than 2 years.

S agalactiae has also been reported in adults, primarily affecting individuals older than age 60 years. The overall case-fatality rate in adults is 34%.

S pneumoniae is associated with one of the highest mortality rates among the bacterial agents that cause meningitis (19-26%).

Go to Haemophilus Meningitis for complete information on this topic.

Epidemiology of aseptic meningitis

Viruses are the major cause of aseptic meningitis syndrome, an illness that is reported to occur with an incidence rate of 10.9 cases per 100,000 person-years.

Aseptic meningitis occurs in individuals of all ages, although it is more common in children, especially during summer. No racial differences are reported.

Aseptic meningitis tends to occur 3 times more frequently in males than in females.

The enteroviruses are distributed worldwide, and the infection rates vary depending on the season of the year and a population’s age and socioeconomic status. Most enterovirus infections occur in individuals who are younger than age 15 years, with the highest attack rates in children who are younger than 1 year.

Infections with the St. Louis encephalitis virus usually occurs during the summer and early fall, with symptoms being 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.

Infection with the La Crosse encephalitis virus also usually occurs during the summer and early fall, with symptoms again being typical of acute aseptic meningitis.

Infections with the LCM virus occur worldwide; most human cases occur among young adults during autumn.

B dermatitidis is reportedly 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.

H capsulatum has been reported from many areas of the world, with the Mississippi and Ohio River valleys being the most endemic regions in North America.

A cantonensis 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.

G spinigerum is common in Southeast Asia, China, and Japan but has been reported sporadically worldwide.

Go to Aseptic Meningitis for complete information on this topic.

Epidemiology of chronic meningitis

Brucella -associated chronic meningitis 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 decreased to less than 0.5 cases per 100,000 population, and only 79 cases were reported to the CDC in 1998.

M tuberculosis is worldwide in distribution, and humans are its only reservoir. In 1997, the estimated case rates among endemic countries ranged from 62-411 cases per 100,000 population.

B burgdorferi 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.

C neoformans has a worldwide distribution. Serotypes B and C of C neoformans have been restricted mostly to tropical and subtropical regions, and serotype B has been isolated from eucalyptus trees.

The distribution of C immitis is 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).

S schenckii has been reported worldwide, with most cases coming from the tropical regions of the Americas.

Patients with meningitis who present with an impaired level of consciousness are at increased risk for developing neurologic sequelae or dying. A seizure during an episode of meningitis also is a risk factor for mortality or neurologic sequelae.

Morbidity and mortality for bacterial and viral meningitis

Bacterial meningitis causes long-term sequelae and results in significant mortality beyond the neonatal period. Prolonged or difficult-to-control seizures are predictors of complications. Bacterial meningitis can be extremely serious. Morbidity, mortality, and prognosis depend on the pathogen, the patient's age and condition, and the severity of acute illness.^[8] Cerebral infarction and edema are predictors of poor outcome, as are the signs of disseminated intravascular coagulopathy and endotoxic shock. The presence of low-level pleocytosis (< 20 cells) in patients with bacterial meningitis suggests a poorer outcome.

Advanced bacterial meningitis can lead to brain damage, coma, and death. Long-term sequelae are seen in as many as 30% of survivors and vary with etiologic agent, patient age, presenting features, and hospital course. Patients usually have subtle CNS changes. Serious complications include the following:

• Hearing loss
• Cortical blindness
• Other cranial nerve dysfunction
• Paralysis
• Muscular hypertonia
• Ataxia
• Multiple seizures
• Mental motor retardation
• Focal paralysis
• Ataxia
• Subdural effusions
• Hydrocephalus
• Cerebral atrophy

Mortality rates for bacterial meningitis are highest in the first year of life, decrease in midlife, and increase again in old age. Bacterial meningitis is fatal in 1 in 10 cases, and 1 in 7 survivors is left with a severe handicap, such as deafness or brain injury.

Meningitis caused by S pneumoniae, L monocytogenes, and gram-negative bacilli has a higher case-fatality rate compared with meningitis caused by other bacterial agents.

The prognosis of meningitis caused by opportunistic pathogens depends on the underlying immune function of the host. Many patients who survive the disease require lifelong suppressive therapy (eg, long-term fluconazole for suppression in patients with HIV-associated cryptococcal meningitis).

Despite effective antimicrobial and supportive therapy, mortality rates among neonates remain high, with significant long-term sequelae in survivors.

In patients with deficient humoral immunity (eg, agammaglobulinemia), enterovirus meningitis may have a fatal outcome.

Among bacterial pathogens, pneumococcal bacteria cause the highest rates of mortality (20-30% in adults, 10% in children) and morbidity (15%) in meningitis. Mortality is 50-90% and morbidity is even higher if severe neurologic impairment is evident at the time of presentation (or with extremely rapid onset of illness), even with immediate medical treatment.

The reported mortality rates for specific bacterial organisms are as follows:

• S pneumoniae meningitis - 19-26%
• H influenzae meningitis - 3-6%
• N meningitidis meningitis - 3-13%
• L monocytogenes meningitis - 15-29%

Patients with meningococcal meningitis have a better prognosis than do those with pneumococcal meningitis, with a mortality rate of 4-5%; however, patients with meningococcemia have a poor prognosis, with a mortality rate of 20-30%.

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. Patients with viral meningitis usually have a good prognosis for recovery. The prognosis is worse for patients at the extremes of age (ie, < 2 y, >60 y) and those with significant comorbidities and underlying immunodeficiency.

Health professionals recommend vaccinating all US college students against N meningitidis.

See Treatment and Management for recommended prophylaxis for close contacts of patients with (suspected) N meningitidis or HIB meningitis. Instruct all contacts to return to the ED immediately at the first sign of fever, sore throat, rash, or symptoms of meningitis. Rifampin prophylaxis only eradicates the organism from the nasopharynx; it is ineffective against invasive disease.

For excellent patient education resources, visit eMedicine's Brain and Nervous System Center and Children's Health Center. In addition, see eMedicine's patient education articles Meningitis in Adults, Meningitis in Children, Brain Infection, and Spinal Tap.