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Meningitis

  • Author: Rodrigo Hasbun, MD, MPH; Chief Editor: Michael Stuart Bronze, MD  more...
 
Updated: Feb 16, 2016
 

Practice Essentials

Meningitis is a clinical syndrome characterized by inflammation of the meninges. The image below depicts acute bacterial meningitis.

Acute bacterial meningitis. This axial nonenhanced Acute bacterial meningitis. This axial nonenhanced computed tomography scan shows mild ventriculomegaly and sulcal effacement.

Signs and symptoms

The classic triad of bacterial meningitis consists of the following:

  • Fever
  • Headache
  • Neck stiffness

Other symptoms can include nausea, vomiting, photalgia (photophobia), sleepiness, confusion, irritability, delirium, and coma. Patients with viral meningitis may have a history of preceding systemic symptoms (eg, myalgias, fatigue, or anorexia).

The history should also address the following:

  • Epidemiologic factors and predisposing risks
  • Exposure to a patients or animals with a similar illness
  • Previous medical treatment and existing conditions
  • Geographic location and travel history
  • Season and temperature

Acute bacterial meningitis in otherwise healthy patients who are not at the extremes of age presents in a clinically obvious fashion; however, subacute bacterial meningitis often poses a diagnostic challenge.

General physical findings in viral meningitis are common to all causative agents. Enteroviral infection is suggested by the following:

  • Exanthemas
  • Symptoms of pericarditis, myocarditis, or conjunctivitis
  • Syndromes of pleurodynia, herpangina, and hand-foot-and-mouth disease

Infants may have the following:

  • Bulging fontanelle (if euvolemic)
  • Paradoxic irritability (ie, remaining quiet when stationary and crying when held)
  • High-pitched cry
  • Hypotonia

The examination should evaluate the following:

  • Focal neurologic signs
  • Signs of meningeal irritation
  • Systemic and extracranial findings
  • Level of consciousness

In chronic meningitis, it is essential to perform careful general, systemic, and neurologic examinations, looking especially for the following:

  • Lymphadenopathy
  • Papilledema
  • Meningismus
  • Cranial nerve palsies
  • Other focal neurological signs

Patients with aseptic meningitis syndrome usually appear clinically nontoxic, with no vascular instability. They characteristically have an acute onset of meningeal symptoms, fever, and CSF pleocytosis that is usually prominently lymphocytic.

See Clinical Presentation for more detail.

Diagnosis

The diagnostic challenges in patients with clinical findings of meningitis are as follows:

  • Early identification and treatment of patients with acute bacterial meningitis
  • Assessing whether a treatable CNS infection is present in those with suspected subacute or chronic meningitis
  • Identifying the causative organism

Blood studies that may be useful include the following:

  • Complete blood count (CBC) with differential
  • Serum electrolytes
  • Serum glucose (which is compared with the CSF glucose)
  • Blood urea nitrogen (BUN) or creatinine and liver profile

In addition, the following tests may be ordered:

  • Blood, nasopharynx, respiratory secretion, urine or skin lesion cultures or antigen/polymerase chain reaction (PCR) detection assays
  • Syphilis testing
  • Serum procalcitonin testing
  • Lumbar puncture and CSF analysis
  • Neuroimaging (CT of the head or MRI of the brain)

See Workup for more detail.

Management

Initial measures include the following:

  • Shock or hypotension – Crystalloids
  • Altered mental status – Seizure precautions and treatment (if necessary), along with airway protection (if warranted)
  • Stable with normal vital signs – Oxygen, IV access, and rapid transport to the emergency department (ED)

Treatment of bacterial meningitis includes the following:

  • Prompt initiation of empiric antibacterial therapy as appropriate for patient age and condition
  • After identification of the pathogen and determination of susceptibilities, targeted antibiotic therapy as appropriate for patient age and condition
  • Steroid (typically, dexamethasone) therapy
  • In certain patients, consideration of intrathecal antibiotics

The following systemic complications of acute bacterial meningitis must be treated:

  • Hypotension or shock
  • Hypoxemia
  • Hyponatremia
  • Cardiac arrhythmias and ischemia
  • Stroke
  • Exacerbation of chronic diseases

Most cases of viral meningitis are benign and self-limited, but in certain instances, specific antiviral therapy may be indicated, if available.

Other types of meningitis are treated with specific therapy as appropriate for the causative pathogen, as follows:

  • Fungal meningitis - Cryptococcal (amphotericin B, flucytosine, fluconazole), Coccidioides immitis (fluconazole, amphotericin B, itraconazole), Histoplasma capsulatum (liposomal amphotericin B, itraconazole), or Candida (amphotericin plus 5-flucytosine)
  • Tuberculous meningitis (isoniazid, rifampin, pyrazinamide, ethambutol, streptomycin)
  • Parasitic meningitis (amebic [ Naegleria fowleri] or acanthamebic) - Variable regimens
  • Lyme meningitis (ceftriaxone; alternatively, penicillin G, doxycycline, chloramphenicol)

See Treatment and Medication for more detail.

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Background

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

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

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

  • Extremes of age (< 5 or >60 years)
  • Diabetes mellitus, chronic kidney failure, adrenal insufficiency, hypoparathyroidism, or cystic fibrosis
  • Immunosuppression, which increases the risk of opportunistic infections and acute bacterial meningitis
  • HIV infection, which predisposes to bacterial meningitis caused by encapsulated organisms, primarily Streptococcus pneumoniae, and opportunistic pathogens
  • Crowding (such as that experienced by 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, or congenital)
  • Thalassemia major
  • Intravenous (IV) drug abuse
  • Bacterial endocarditis
  • Ventriculoperitoneal shunt
  • Malignancy (increased risk of Listeria infection)
  • Some cranial congenital deformities

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

Anatomically, meningitis can be 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:

  • Bacterial (pyogenic)
  • Granulomatous
  • Aseptic

The most common cause of meningeal inflammation is bacterial or viral infection. 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, as with fungal diseases and tuberculosis. (See Etiology.)

Bacterial meningitis consists of pyogenic inflammation of the meninges and the underlying subarachnoid CSF. If not treated, it may lead to lifelong disability or death.[1, 2] Before the antimicrobial era, bacterial meningitis was uniformly fatal, but with the advent of antimicrobial therapy, the overall mortality from this disease has decreased. Nonetheless, it remains alarmingly high: 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 Medication.)

The specific infectious agents that are involved in bacterial meningitis vary among different patient age groups, and the inflammation may evolve into the following conditions:

  • Ventriculitis
  • Empyema
  • Cerebritis
  • Abscess formation

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] and antibiotics) and carcinomatosis. (See Etiology.)

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:

Chronic meningitis is a constellation of signs and symptoms of meningeal irritation associated with CSF pleocytosis that persists for longer than 4 weeks.

Unlike subacute (developing over 1-7 days) or chronic (>7 days) meningitis, which have myriad infectious and noninfectious etiologies, acute meningitis (< 1 day) 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’ (and usually >12 hours’) duration.

Patients with acute bacterial meningitis may decompensate very quickly. Consequently, they require emergency care, including the administration of appropriate antimicrobial therapy as soon as possible once bacterial meningitis is suspected or proven.

Nonbacterial meningitis

Fungal and parasitic forms of meningitis are also named according to their specific etiologic agent (eg, cryptococcal meningitis, Histoplasma meningitis, and amebic meningoencephalitis).

In many cases, a cause of meningitis is not apparent after initial evaluation, and the disease is therefore classified as aseptic meningitis. These patients characteristically have an acute onset of meningeal symptoms, fever, and CSF 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.

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, enteroviral meningitis or herpes simplex virus [HSV] meningitis).

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Pathophysiology

Most cases of meningitis are caused by an infectious agent that has colonized or established a localized infection elsewhere in the host. Potential sites of colonization or infection include the skin, the nasopharynx, the respiratory tract, the gastrointestinal (GI) tract, and the genitourinary tract. The organism invades the submucosa at these sites by circumventing host defenses (eg, physical barriers, local immunity, and phagocytes or macrophages).

An infectious agent (ie, a bacterium, virus, fungus, or parasite) can gain access to the CNS and cause meningeal disease via any of the 3 following major pathways:

  • Invasion of the bloodstream (ie, bacteremia, viremia, fungemia, or parasitemia) and subsequent hematogenous seeding of the CNS
  • A retrograde neuronal (eg, olfactory and peripheral nerves) pathway (eg, Naegleria fowleri or Gnathostoma spinigerum)
  • Direct contiguous spread (eg, sinusitis, otitis media, congenital malformations, trauma, or direct inoculation during intracranial manipulation)

Invasion of the bloodstream and subsequent seeding is the most common mode of spread for most agents. This pathway is characteristic of meningococcal, cryptococcal, syphilitic, and pneumococcal meningitis.

Rarely, meningitis arises from invasion via septic thrombi or osteomyelitic erosion from infected contiguous structures. Meningeal seeding may also occur with a direct bacterial inoculate during trauma, neurosurgery, or instrumentation. Meningitis in the newborn may be transmitted vertically, involving pathogens that have colonized 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:

  • The bloodstream
  • Preformed tissue planes (eg, posterior fossa)
  • Temporal bone fractures
  • The oval or round window membranes of the labyrinths

The brain is naturally protected from the body’s immune system by the barrier that the meninges create between the bloodstream and the brain. Normally, this protection is an advantage because the barrier prevents the immune system from attacking the brain. However, in meningitis, the blood-brain barrier can become disrupted; 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, WBCs, 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 breached, 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. These processes 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, resulting in the following:

  • Damage to cranial nerves (eg, cranial nerve VIII, with resultant hearing loss)
  • Obliteration of CSF pathways (causing obstructive hydrocephalus)
  • Induction of vasculitis and thrombophlebitis (causing local brain ischemia)

Intracranial pressure and cerebral 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.

Without medical intervention, the cycle of decreasing CSF, worsening cerebral edema, and increasing ICP proceeds unchecked. Ongoing endothelial injury may result in vasospasm and thrombosis, further compromising CSF, and may lead to stenosis of large and small vessels. Systemic hypotension (septic shock) also may impair CSF, and the patient soon dies as a consequence of systemic complications or 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. The accumulation of the products of bacterial degradation, neutrophils, and other cellular activation leads to cytotoxic edema.

The ensuing cerebral edema (ie, vasogenic, cytotoxic, and 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.

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-α] and 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-α, IL-1, IL-6, and IL-8 are characteristic findings in patients with bacterial meningitis. Cytokine levels, including those of IL-6, TNF-α, 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. This process is likely initiated by the ligation of the bacterial components (eg, peptidoglycan and lipopolysaccharide) to pattern-recognition receptors, such as the Toll-like receptors (TLRs).

TNF-α and IL-1 are most prominent among the cytokines that mediate this inflammatory cascade. TNF-α 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 IL-1 and TNF-α 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 (eg, prostaglandin E2 [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-α and IL-1.

Nitric oxide is a free radical molecule that can induce cytotoxicity when produced in high amounts. PGE2, a product of cyclooxygenase (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 cases, 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.

Genetic predisposition to inflammatory response

The inflammatory response and the release of proinflammatory mediators are critical to the recruitment of excess neutrophils to the subarachnoid space. These activated neutrophils release cytotoxic agents, including oxidants and metalloproteins that cause collateral damage to brain tissue.

Pattern recognition receptors, of which TLR A4 (TLRA4) is the best studied, lead to increase in the myeloid differentiation 88 (MyD88)-dependent pathway and excess production of proinflammatory mediators. At present, dexamethasone is used to decrease the effects of cellular toxicity by neutrophils after they are present. Researchers are actively seeking ways of inhibiting TLRA4 and other proinflammatory recognition receptors through genetically engineered suppressors.[4]

Bacterial seeding

Bacterial seeding of the meninges usually occurs through hematogenous spread. In patients without an identifiable source of infection, local tissue and bloodstream invasion by bacteria that have colonized the nasopharynx may be a common source. Many meningitis-causing bacteria are carried in the nose and throat, often asymptomatically. Most meningeal pathogens are transmitted through the respiratory route, including Neisseria meningitidis (meningococcus) and S pneumoniae (pneumococcus).

Certain respiratory viruses are thought to enhance the entry of bacterial agents into the intravascular compartment, presumably by damaging mucosal defenses. Once in the bloodstream, the infectious agent must escape immune surveillance (eg, antibodies, complement-mediated bacterial killing, and neutrophil phagocytosis).

Subsequently, hematogenous seeding into distant sites, including the CNS, occurs. The specific pathophysiologic mechanisms by which the infectious agents gain access to the subarachnoid space remain unclear. Once inside the CNS, the infectious agents likely survive because host defenses (eg, immunoglobulins, neutrophils, and complement components) appear to be limited in this body compartment. The presence and replication of infectious agents remain uncontrolled and incite the cascade of meningeal inflammation described above.

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Etiology

Causes of meningitis include bacteria, viruses, fungi, parasites, and drugs (eg, NSAIDs, metronidazole, and IV immunoglobulin [IVIg]). Certain risk factors are associated with particular pathogens.

HIV infection increases susceptibility to meningitis from a variety of pathogens, including cryptococci, Mycobacterium tuberculosis, syphilis, and Listeria species. In addition, HIV itself may cause aseptic meningitis (see Meningitis in HIV).

Other viral causes of meningitis include the following:

  • Enteroviruses
  • West Nile virus
  • Human herpesvirus (HHV)-2
  • Lymphocytic choriomeningitis virus (LCM)

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

Pachymeningitis

As indicated by the presence of abundant pus, pachymeningitis most often results from a bacterial infection (usually staphylococcal or streptococcal) that is localized to the dura. The organisms most often gain access to the meninges via a skull defect (eg, a skull fracture) or spread from an infection of the paranasal sinuses or cranial osteomyelitis.

Haemophilus influenzae meningitis

H influenzae is a small, pleomorphic, gram-negative coccobacillus that is frequently found as part of the normal flora in the upper respiratory tract. The organism can spread from one individual to another in airborne droplets or by direct contact with secretions. Meningitis is the most serious acute manifestation of systemic infection with H influenzae. (See Haemophilus Meningitis.)

In the past, H influenzae was a major cause of meningitis, and the encapsulated type b strain of the organism (Hib) accounted for the majority of cases. Since the introduction of Hib vaccine in the United States in 1990, the overall incidence of H influenzae meningitis has decreased by 35%, with Hib accounting for fewer than 9.4% of H influenzae cases.[5]

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 after head trauma
  • Functional or anatomic asplenia
  • Hypogammaglobulinemia

Pneumococcal meningitis

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 focal infections, such as pneumonia, sinusitis, or endocarditis (as, for example, in Austrian syndrome, which is the triad of pneumococcal meningitis, endocarditis, and pneumonia).

S pneumoniae is a common colonizer of the human nasopharynx; it is present in 5-10% of healthy adults and 20-40% of healthy children. It causes meningitis by escaping 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

Streptococcus agalactiae meningitis

Streptococcus agalactiae (group B streptococcus [GBS]) is a gram-positive coccus that inhabits the lower GI tract. It also colonizes the female genital tract at a rate of 5-40%, which explains why it is the most common agent of neonatal meningitis (associated with 70% of cases).

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.

Meningococcal meningitis

N meningitidis 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 of meningococcal meningitis (95-97%) are caused by serogroups B, C, and Y, whereas the A and C strains are observed in epidemics (< 3% of cases). Currently, N meningitidis is the leading cause of bacterial meningitis in children and young adults, accounting for 59% of cases.

Risk factors for meningococcal 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, chronic medical illness, corticosteroid use, and active or passive smoking
  • Crowded living conditions, as is observed in college dormitories (college freshmen living in dormitories are at highest risk) and military facilities, which has been reported in clustering of cases

Listeria monocytogenes meningitis

Listeria monocytogenes is a small gram-positive bacillus that causes 3% of bacterial meningitis cases and is associated with one of the highest mortalities (20%).[5] The organism is widespread in nature and has been isolated in the stool of 5% of healthy adults. Most human cases appear to be food-borne.

L monocytogenes 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.

Groups at risk include the following:

  • Pregnant women
  • Infants and children
  • Elderly individuals (>60 years)
  • Patients with alcoholism
  • Adults who are immunosuppressed (eg, steroid users, transplant recipients, or persons with 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

Aerobic gram-negative bacilli include the following:

  • Escherichia coli
  • Klebsiella pneumoniae
  • Serratia marcescens
  • P aeruginosa
  • Salmonella species

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 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 larvae during hyperinfection syndrome.

Staphylococcal meningitis

Staphylococci are gram-positive cocci that are part of the normal skin flora. Meningitis caused by staphylococci is associated with the following risk factors:

  • Neurosurgery
  • Head trauma
  • Presence of CSF shunts
  • Infective endocarditis and paraspinal infection

S epidermidis is the most common cause of meningitis in patients with CNS (ie, ventriculoperitoneal) shunts. (See Staphylococcal Meningitis.)

Aseptic meningitis

Aseptic meningitis is one of the most common infections of the meninges. If appropriate diagnostic methods are employed, a specific viral etiology is identified in 50-60% of cases of aseptic meningitis. However, aseptic meningitis can also be caused by bacteria, fungi, and parasites (see Table 1 below). It is noteworthy that partially treated bacterial meningitis accounts for a large number of meningitis cases with a negative microbiologic workup.

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

Category Agent
Bacteria Partially treated bacterial meningitis



Listeria monocytogenes



Brucella spp



Rickettsia rickettsii



Ehrlichia spp



Mycoplasma pneumoniae



Borrelia burgdorferi



Treponema pallidum



Leptospira spp



Mycobacterium tuberculosis



Nocardia spp



Parasites Naegleria fowleri



Acanthamoeba spp



Balamuthia spp



Angiostrongylus cantonensis



Gnathostoma spinigerum



Baylisascaris procyonis



Strongyloides stercoralis



Taenia solium (cysticercosis)



Fungi Cryptococcus neoformans



Coccidioides immitis



Blastomyces dermatitidis



Histoplasma capsulatum



Candida spp



Aspergillus spp



Viruses Enterovirus Poliovirus



Echovirus



Coxsackievirus A



Coxsackievirus B



Enterovirus 68-71



Herpesvirus (HSV) HSV-1 and HSV-2



Varicella-zoster virus



Epstein-Barr virus



Cytomegalovirus



HHV-6 and HHV-7



Paramyxovirus Mumps virus



Measles virus



Togavirus Rubella virus
Flavivirus West Nile virus



Japanese encephalitis virus



St Louis encephalitis virus



Bunyavirus California encephalitis virus



La Crosse encephalitis virus



Alphavirus Eastern equine encephalitis virus



Western equine encephalitis virus



Venezuelan encephalitis virus



Reovirus Colorado tick fever virus
Arenavirus LCM virus
Rhabdovirus Rabies virus
Retrovirus HIV
HHV = human herpesvirus; HSV = herpes simplex virus; LCM = lymphocytic choriomeningitis.
       

Enteroviruses account for of the majority of cases of aseptic meningitis in children, but West Nile virus and HSV-2 account for a substantial proportion of cases in adults. 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

Enteroviruses are 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 (NPEVs) 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. It was also reported 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) infection may manifest as meningitis in patients with the mononucleosis syndrome. Varicella-zoster virus (VZV, or HHV-3) and CMV cause 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.

The most common arthropod-borne viruses are West Nile virus, 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. Upon 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.

Patients with acute HIV infection may present with aseptic meningitis syndrome, usually as part of the mononucleosislike acute seroconversion phenomenon. HIV should always be suspected as a cause of aseptic meningitis in a patient with risk factors such as IV drug use or high-risk sexual behaviors. These patients will have negative results on HIV serologic tests (eg, enzyme-linked immunosorbent assay [ELISA] and Western blot); the diagnosis is made by the detection of serum HIV RNA on polymerase chain reaction (PCR) testing or of HIV p24 antigen.

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.

Toscana virus meningitis or encephalitis should be considered in travelers returning from the a Mediterranean country (eg, Italy, Spain, or Greece) during the summer. Toscana viruses are transmitted by the bite of a sandfly. Toscana virus infection can be diagnosed by performing paired serologies and CSF PCR, which in the United States is available only through the CDC.[6]

Chronic meningitis

Chronic meningitis can be caused by a wide range of infectious and noninfectious etiologies (see Table 2 below).

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

Category Agent
Bacteria Mycobacterium tuberculosis



Borrelia burgdorferi



Treponema pallidum



Brucella spp



Francisella tularensis



Nocardia spp



Actinomyces spp



Fungi Cryptococcus neoformans



Coccidioides immitis



Blastomyces dermatitidis



Histoplasma capsulatum



Candida albicans



Aspergillus spp



Sporothrix schenckii



Parasites Acanthamoeba spp



Naegleria fowleri



Angiostrongylus cantonensis



Gnathostoma spinigerum



Baylisascarisprocyonis



Schistosoma spp



Strongyloides stercoralis



Echinococcus granulosus



Brucellae are small gram-negative coccobacilli that cause zoonoses as a result of infection with Brucella abortus, Brucella melitensis, Brucella suis, or Brucella canis. Transmission to humans occurs after direct or indirect exposure to infected animals (eg, sheep, goats, or 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 for brucellosis include individuals who had contact with infected animals or their products (eg, through 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. Involvement of the CNS with tuberculous meningitis is usually caused by rupture of a tubercle into the subarachnoid space.

Tuberculous meningitis should always be considered in the differential diagnosis of patients with aseptic meningitis or chronic meningitis syndromes, especially those with basilar meningitis, symptoms of more than 5 days’ duration, or cranial nerve palsies. If tuberculous meningitis is suspected, antituberculosis therapy, with or without steroids, should be empirically started.

Treponema 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).

Borrelia burgdorferi, a tick-borne spirochete, is the agent of Lyme disease, the most common vector-borne disease in the United States. Meningitis may be part of a triad of neurologic manifestations of Lyme disease that also includes cranial neuritis and radiculoneuritis. Lyme disease meningitis is typically associated with a facial palsy that can sometimes be bilateral.

Cryptococcus neoformans is an encapsulated, yeastlike 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. Onset of cryptococcal meningitis may be acute, especially among patients with AIDS.

Numerous cases occur in healthy hosts (eg, persons 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, such as persons with AIDS, organ transplant recipients, and other patients who use steroids, cyclosporine, and other immunosuppressants. Cryptococcal meningitis has also been reported in patients with idiopathic CD-4 lymphopenia, Hodgkin disease, sarcoidosis, and cirrhosis.

Coccidioides 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 (eg, persons with AIDS and organ transplant recipients).

Blastomyces dermatitidis is a dimorphic fungus that has been reported to be endemic in North America (eg, in the Mississippi and Ohio River basins). It has also been isolated from parts of Central America, South America, the Middle East, and India. Its natural habitat is not well defined. Soil that is rich in decaying matter and environments around riverbanks and waterways have been demonstrated to harbor B dermatitidis 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 those 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 CNS. Involvement of the CNS occurs in fewer than 5% of cases.

Histoplasma capsulatum is one of the dimorphic fungi that exist in mycelial and yeast forms. It is usually found in soil and can occasionally cause a chronic meningitis. The preferred means of making the diagnosis is CSF histoplasma antigen detection.

Candida species are ubiquitous in nature. They are normal commensals in humans and are found in the skin, the GI tract, and the female genital tract. The most common species is Candida albicans, but the incidence of non-albicans candidal infections (eg, Candida tropicalis) is increasing, including species with antifungal resistance (eg, Candida krusei and Candida glabrata).

Involvement of the CNS usually follows hematogenous dissemination. The most important predisposing risks for acquiring disseminated candidal infection appear to be iatrogenic (eg, the administration of broad-spectrum antibiotics and the use of indwelling devices such as urinary and vascular catheters). Prematurity in neonates is considered a predisposing risk factor as well. Infection may also follow neurosurgical procedures, such as placement of ventricular shunts.

Sporothrix schenckii is an endemic dimorphic fungus that is often isolated from soil, plants, and plant products. Human infections are characteristically lymphocutaneous. Extracutaneous manifestations of sporotrichosis may occur, though meningeal sporotrichosis, which is the most severe form, is a rare complication. AIDS is a reported underlying risk factor in many described cases and 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 species of Naegleria recognized to be pathogenic in humans, 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 a person is swimming or playing in 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 is characterized by an acute onset of high fever, photophobia, headache, and altered mental status, similar to bacterial meningitis, occurring within 1 week after exposure. Because it is acquired via the nasal area, olfactory nerve involvement 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, consists of 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. These cases can be difficult to distinguish from culture-negative meningitis.

Angiostrongylus cantonensis, the rat lungworm, can cause eosinophilic meningitis (pleocytosis with more than 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.

Gnathostoma spinigerum, a GI parasite of wild and domestic dogs and cats, may cause eosinophilic meningoencephalitis. Humans acquire the infection after ingesting undercooked infected fish and poultry.

Baylisascaris 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 after accidental ingestion of food products contaminated with raccoon feces.

Additional causes of meningitis

Congenital malformation of the stapedial footplate has been implicated in the development of meningitis. Head and neck surgery, penetrating head injury, comminuted skull fracture, and osteomyelitic erosion may infrequently result in direct implantation of bacteria into the meninges. 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.

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Epidemiology

The incidence of meningitis varies according to 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. In these countries, the incidence has been reported to be 10 times higher than that in developed countries.

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 4100 cases and 500 deaths occurring annually in the United States, bacterial meningitis continues to be a significant source of morbidity and mortality. The annual incidence in the United States is 1.33 cases per 100,000 population.[5]

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.

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.

The overall incidence of bacterial meningitis in the US declined from 2.0 to 1.38 cases per 100,000 population between 1998 and 2007.[5] This was partially because of the widespread use of the Hib vaccination, which decreased the incidence of H influenzae meningitis by more than 90% (see Table 3 below). Routine Hib vaccination has nearly eliminating this pathogen as a cause of meningitis in many developed countries.

More recent prevention measures such as the pneumococcal conjugate vaccine and universal screening of pregnant women for GBS have further changed the epidemiology of bacterial meningitis.

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

Bacteria 1978-1981 1986 1995 1998-2007
Haemophilus influenzae 48% 45% 7% 6.7%  
Listeria monocytogenes 2% 3% 8% 3.4%  
Neisseria meningitidis 20% 14% 25% 13.9%  
Streptococcus agalactiae (group B streptococcus) 3% 6% 12% 18.1%  
Streptococcus pneumoniae 13% 18% 47% 58%  
*Nosocomial meningitis is not included; these data include only the 5 major meningeal pathogens.    

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

Because the frequency of bacterial meningitis in children has declined, the condition is becoming more of a disease of adults. Whereas the median age for persons with bacterial meningitis was 25 years in 1998, it was 15 months in 1986.[7]

The introduction of vaccines against S pneumoniae has substantially reduced the incidence of pneumococcal meningitis in children. Routine screening for GBS in pregnant women may have also reduced the incidence of meningitis from this pathogen. Routine vaccination against serogroup C meningococcus may also reduce the incidence of N meningitidis infections. During a 1998-2007 survey, the incidence of meningitis declined by 31%,[5] a decrease that can be credited to vaccination programs.

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, the incidence is increased in persons aged 60 years and older, independent of other factors. The annual incidence ranges from 1.7 to 7.2 cases per 100,000 adults; 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 meningitis from other etiologic agents (see Table 4 below). E coli K1 meningitis and S agalactiae meningitis are common among neonates, and L monocytogenes meningitis is common among neonates and the elderly. (The development of neonatal meningitis is related to labor and delivery; it results from colonized pathogens in the maternal intestinal or genital tract, immaturity, and environment.)

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

Risk or Predisposing Factor Bacterial Pathogen
Age 0-4 weeks Streptococcus agalactiae (GBS)



Escherichia coli K1



Listeria monocytogenes



Age 4-12 weeks S agalactiae



E coli



Haemophilus influenzae



Streptococcus pneumoniae



Neisseria meningitidis



Age 3 months to 18 years N meningitidis



S pneumoniae



H influenzae



Age 18-50 years S pneumoniae



N meningitidis



H influenzae



Age >50 years S pneumoniae



N meningitidis



L monocytogenes



Aerobic gram-negative bacilli



Immunocompromised state S pneumoniae



N meningitidis



L monocytogenes



Aerobic gram-negative bacilli



Intracranial manipulation, including neurosurgery Staphylococcus aureus



Coagulase-negative staphylococci



Aerobic gram-negative bacilli, including Pseudomonas aeruginosa



Basilar skull fracture S pneumoniae



H influenzae



Group A streptococci



CSF shunts Coagulase-negative staphylococci



S aureus



Aerobic gram-negative bacilli



Propionibacterium acnes



CSF = cerebrospinal fluid; GBS = group B streptococcus.

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

Epidemiology of specific bacterial pathogens of acute meningitis

H influenzae meningitis primarily affects infants younger than 2 years. S agalactiae meningitis occurs principally during the first 12 weeks of life but has also been reported in adults, primarily affecting individuals older than age 60 years. The overall case-fatality rate in adults is 34%. Among the bacterial agents that cause meningitis, S pneumoniae is associated with one of the highest mortalities (19-26%).

Epidemiology of aseptic meningitis

Aseptic meningitis has a reported incidence of 10.9 cases per 100,000 person-years. It occurs in individuals of all ages but 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.

Viruses are the major cause of aseptic meningitis. The enteroviruses are distributed worldwide, and the infection rates vary according to the season of the year and a population’s age and socioeconomic status. Most enteroviral infections occur in individuals who are younger than 15 years, with the highest attack rates in children who are younger than 1 year.

Arboviruses are an important cause of aseptic meningitis and encephalitis in the summer and fall months in the United States. West Nile virus was introduced to the United States in 1999 and has now spread throughout the continent. In 2012, the largest outbreak of West Nile virus infection to date occurred in the United States, with 5387 cases reported (about half of which were neuroinvasive disease, such as meningitis or encephalitis) and a 4.5% mortality.[8] West Nile virus can also cause acute flaccid paralysis, retinitis and nephropathy.

Other less common arboviruses include St Louis encephalitis virus, Jamestown canyon virus, La Crosse encephalitis virus, Powassan encephalitis virus, and Eastern equine encephalitis virus. In the United States, the last epidemic of St Louis encephalitis was in Monroe, Louisiana, in 2001; 63 cases were reported, with 3 deaths (4.7% mortality). 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.[9]

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

Of fungal causes, 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.

Of parasitic causes, 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.

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, after the control of bovine infections, the 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 to 411 cases per 100,000 population.

B burgdorferi is a tick-borne spirochete that is found in the temperate regions of much of the northern hemisphere. Endemic regions include North America (eg, the northeastern United States, Minnesota, Wisconsin, and parts of California and Oregon), Europe, and Asia.

C neoformans has a worldwide distribution. Serotypes B and C 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 southwestern United States, Mexico, and Central and South America). Persons who have migrated from or traveled to endemic areas may experience onset of disease in other parts of the world.

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

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Prognosis

Patients with meningitis who present with an impaired level of consciousness are at increased risk for neurologic sequelae or death. A seizure during an episode of meningitis also is a risk factor for mortality or neurologic sequelae, particularly if the seizure is prolonged or difficult to control.

In bacterial meningitis, several risk factors are associated with death and with neurologic disability. A risk score has been derived and validated in adults with bacterial meningitis. This score includes the following variables, which are associated with an adverse clinical outcome[10] :

  • Older age
  • Increased heart rate
  • Lower Glasgow Coma Scale score
  • Cranial nerve palsies
  • CSF leukocyte count lower than 1000/μL
  • Gram-positive cocci on CSF Gram stain

Advanced bacterial meningitis can lead to brain damage, coma, and death. In 50% of patients, several complications may develop in the days to weeks following infection. 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

Risk factors for hearing loss after pneumococcal meningitis are female gender, older age, severe meningitis, and infection with certain pneumococcal serotypes (eg, 12F).[11] Delayed complications include the following:

  • Decreased hearing or deafness
  • Other cranial nerve dysfunctions
  • Multiple seizures
  • Focal paralysis
  • Subdural effusions
  • Hydrocephalus
  • Intellectual deficits
  • Ataxia
  • Blindness
  • Waterhouse-Friderichsen syndrome
  • Peripheral gangrene

Seizures are a common and important complication, occurring in approximately one fifth of patients. The incidence is higher in patients younger than 1 year, reaching 40%. Approximately one half of patients with this complication have repeated seizures. Patients may die as a result of diffuse CNS ischemic injury or systemic complications.

Even with effective antimicrobial therapy, significant neurologic complications have been reported to occur in as many as 30% of survivors of bacterial meningitis. Close monitoring for the development of these complications is essential.

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

The prognosis in patients with 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).

Among bacterial pathogens, S pneumoniae causes the highest mortality (20-30% in adults, 10% in children) and morbidity (15%) in meningitis. If severe neurologic impairment is evident at the time of presentation (or if the onset of illness is extremely rapid), mortality is 50-90% and morbidity is even higher, even with immediate medical treatment. Meningitis caused by L monocytogenes or gram-negative bacilli also has a higher case-fatality rate than meningitis caused by other bacterial agents.

Reported overall mortality for meningitis from specific bacterial organisms is as follows:

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

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

The mortality for viral meningitis without encephalitis is less than 1%. In patients with deficient humoral immunity (eg, agammaglobulinemia), enteroviral 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 or >60 years) and those with significant comorbidities and underlying immunodeficiency.

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Patient Education

Patients and parents of young children should be educated about the benefits of vaccination in preventing meningitis. Vaccination against N meningitidis is recommended for all US college students.

Close contacts of patients with known or suspected N meningitidis or Hib meningitis may require education regarding the need for prophylaxis. All contacts should be instructed to come to the emergency department 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 patient education information, see the Brain and Nervous System Center and the Children’s Health Center, as well as Meningitis in Adults, Meningitis in Children, Brain Infection, and Spinal Tap.

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Contributor Information and Disclosures
Author

Rodrigo Hasbun, MD, MPH Associate Professor of Medicine, Section of Infectious Diseases, University of Texas Medical School at Houston

Disclosure: Received honoraria from Medicine''''''''s Company for speaking and teaching; Received honoraria from Cubicin for speaking and teaching; Received honoraria from Theravance for speaking and teaching; Received honoraria from Pfizer for speaking and teaching.

Chief Editor

Michael Stuart Bronze, MD David Ross Boyd Professor and Chairman, Department of Medicine, Stewart G Wolf Endowed Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center; Master of the American College of Physicians; Fellow, Infectious Diseases Society of America

Michael Stuart Bronze, MD is a member of the following medical societies: Alpha Omega Alpha, American Medical Association, Oklahoma State Medical Association, Southern Society for Clinical Investigation, Association of Professors of Medicine, American College of Physicians, Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Acknowledgements

Suur Biliciler, MD Neuromuscular Fellow, Department of Neurology, Baylor College of Medicine

Disclosure: Nothing to disclose.

Timothy S Brannan, MD Director, Department of Neurology, Jersey City Medical Center; Professor, Department of Neurology, Seton Hall School of Graduate Medical Education

Disclosure: Nothing to disclose.

Robert Cavaliere, MD Assistant Professor of Neurology, Neurosurgery and Medicine, Ohio State University College of Medicine

Disclosure: Nothing to disclose.

Sidney E Croul, MD Director of Neuropathology, Professor, Department of Pathology and Laboratory Medicine, Medical College of Pennsylvania Hahnemann University

Disclosure: Nothing to disclose.

Francisco de Assis Aquino Gondim, MD, MSc, PhD Associate Professor of Neurology, Department of Neurology and Psychiatry, St Louis University School of Medicine

Francisco de Assis Aquino Gondim, MD, MSc, PhD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and Movement Disorders Society

Disclosure: Nothing to disclose.

Alan Greenberg, MD Director, Associate Professor, Department of Internal Medicine, Jersey City Medical Center, Seton Hall University

Alan Greenberg, MD is a member of the following medical societies: Alpha Omega Alpha and American College of Physicians

Disclosure: Nothing to disclose.

Ronald A Greenfield, MD Professor, Department of Internal Medicine, University of Oklahoma College of Medicine

Ronald A Greenfield, MD is a member of the following medical societies: American College of Physicians, American Federation for Medical Research, American Society for Microbiology, Central Society for Clinical Research, Infectious Diseases Society of America, Medical Mycology Society of the Americas, Phi Beta Kappa, Southern Society for Clinical Investigation, and Southwestern Association of Clinical Microbiology

Disclosure: Pfizer Honoraria Speaking and teaching; Gilead Honoraria Speaking and teaching; Ortho McNeil Honoraria Speaking and teaching; Abbott Honoraria Speaking and teaching; Astellas Honoraria Speaking and teaching; Cubist Honoraria Speaking and teaching; Forest Pharmaceuticals Speaking and teaching

J Stephen Huff, MD Associate Professor of Emergency Medicine and Neurology, Department of Emergency Medicine, University of Virginia School of Medicine

J Stephen Huff, MD is a member of the following medical societies: American Academy of Emergency Medicine, American Academy of Neurology, American College of Emergency Physicians, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Lutfi Incesu, MD Professor, Department of Radiology, Ondokuz Mayis University School of Medicine; Chief, Neuroradiology and MR Unit, Department of Radiology, Ondokuz Mayis University Hospital, Turkey

Lutfi Incesu, MD is a member of the following medical societies: American Society of Neuroradiology and Radiological Society of North America

Disclosure: Nothing to disclose.

Uma Iyer, MD Resident Physician, Department of Neurology, State University of New York Upstate Medical Center

Disclosure: Nothing to disclose.

Pieter R Kark, MD, MA, FAAN, FACP Instructor in Palliative Care, The Lifetime Healthcare Companies

Disclosure: Nothing to disclose.

Michael R Keating, MD Associate Professor of Medicine, Chair, Division of Infectious Diseases, Department of Medicine, Mayo Clinic College of Medicine

Michael R Keating, MD is a member of the following medical societies: American College of Physicians, American Medical Association, American Society for Microbiology, American Society of Transplantation, Infectious Diseases Society of America, and International Immunocompromised Host Society

Disclosure: Nothing to disclose.

Anil Khosla, MBBS, MD Assistant Professor, Department of Radiology, St Louis University School of Medicine, Veterans Affairs Medical Center of St Louis

Anil Khosla, MBBS, MD is a member of the following medical societies: American College of Radiology, American Roentgen Ray Society, American Society of Neuroradiology, North American Spine Society, and Radiological Society of North America

Disclosure: Nothing to disclose.

John W King, MD Professor of Medicine, Chief, Section of Infectious Diseases, Director, Viral Therapeutics Clinics for Hepatitis, Louisiana State University Health Sciences Center; Consultant in Infectious Diseases, Overton Brooks Veterans Affairs Medical Center

John W King, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American Federation for Medical Research, American Society for Microbiology, Association of Subspecialty Professors, Infectious Diseases Society of America, and Sigma Xi

Disclosure: MERCK None Other

Marjorie Lazoff, MD Editor-in-Chief, Medical Computing Review

Marjorie Lazoff, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Emergency Physicians, American Medical Informatics Association, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Glenn Lopate, MD Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, Washington University School of Medicine; Director of Neurology Clinic, St Louis ConnectCare; Consulting Staff, Department of Neurology, Barnes-Jewish Hospital

Glenn Lopate, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and Phi Beta Kappa

Disclosure: Baxter Grant/research funds Other; Amgen Grant/research funds None

Joseph Richard Masci, MD Professor of Medicine, Professor of Preventive Medicine, Mount Sinai School of Medicine; Director of Medicine, Elmhurst Hospital Center

Joseph Richard Masci, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, Association of Professors of Medicine, and Royal Society of Medicine

Disclosure: Nothing to disclose.

C Douglas Phillips, MD Director of Head and Neck Imaging, Division of Neuroradiology, New York Presbyterian Hospital, Weill Cornell Medical College

C Douglas Phillips, MD is a member of the following medical societies: American College of Radiology, American Medical Association, American Society of Head and Neck Radiology, American Society of Neuroradiology, Association of University Radiologists, and Radiological Society of North America

Disclosure: Nothing to disclose.

Tarakad S Ramachandran, MBBS, FRCP(C), FACP Professor of Neurology, Clinical Professor of Medicine, Clinical Professor of Family Medicine, Clinical Professor of Neurosurgery, State University of New York Upstate Medical University; Chair, Department of Neurology, Crouse Irving Memorial Hospital

Tarakad S Ramachandran, MBBS, FRCP(C), FACP is a member of the following medical societies: American Academy of Neurology, American Academy of Pain Medicine, American College of Forensic Examiners, American College of International Physicians, American College of Managed Care Medicine, American College of Physicians, American Heart Association, American Stroke Association, Royal College of Physicians, RoyalCollegeofPhysicians and Surgeons of Canada, Royal College of Surgeons of England, and Royal Society of Medicine

Disclosure: Abbott Labs None None; Teva Marion None None; Boeringer-Ingelheim Honoraria Speaking and teaching

Raymund R Razonable, MD Consultant, Division of Infectious Diseases, Mayo Clinic of Rochester; Associate Professor of Medicine, Mayo Clinic College of Medicine

Raymund R Razonable, MD is a member of the following medical societies: American Medical Association, American Society for Microbiology, Infectious Diseases Society of America, and International Immunocompromised Host Society

Disclosure: Nothing to disclose.

Norman C Reynolds Jr, MD Neurologist, Veterans Affairs Medical Center of Milwaukee; Clinical Professor, Medical College of Wisconsin

Norman C Reynolds Jr, MD is a member of the following medical societies: American Academy of Neurology, Association of Military Surgeons of the US, Movement Disorders Society, Sigma Xi, and Society for Neuroscience

Disclosure: Nothing to disclose.

Robert Stanley Rust Jr, MD, MA Thomas E Worrell Jr Professor of Epileptology and Neurology, Co-Director of FE Dreifuss Child Neurology and Epilepsy Clinics, Director, Child Neurology, University of Virginia School of Medicine; Chair-Elect, Child Neurology Section, American Academy of Neurology

Robert Stanley Rust Jr, MD, MA is a member of the following medical societies: American Academy of Neurology, American Epilepsy Society, American Headache Society, American Neurological Association, Child Neurology Society, International Child Neurology Association, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Prem C Shukla, MD Associate Chairman, Associate Professor, Department of Emergency Medicine, University of Arkansas for Medical Sciences

Disclosure: Nothing to disclose.

Manish K Singh, MD Assistant Professor, Department of Neurology, Teaching Faculty for Pain Management and Neurology Residency Program, Hahnemann University Hospital, Drexel College of Medicine; Medical Director, Neurology and Pain Management, Jersey Institute of Neuroscience

Manish K Singh, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Pain Medicine, American Association of Physicians of Indian Origin, American Headache Society, American Medical Association, and American Society of Regional Anesthesia and Pain Medicine

Disclosure: Nothing to disclose.

Niranjan N Singh, MD, DNB Assistant Professor of Neurology, University of Missouri-Columbia School of Medicine

Niranjan N Singh, MD, DNB is a member of the following medical societies: American Academy of Neurology

Disclosure: Nothing to disclose.

Mark S Slabinski, MD, FACEP, FAAEM Vice President, EMP Medical Group

Mark S Slabinski, MD, FACEP, FAAEM is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American College of Emergency Physicians, American Medical Association, and Ohio State Medical Association

Disclosure: Nothing to disclose.

James G Smirniotopoulos, MD Professor of Radiology, Neurology, and Biomedical Informatics, Program Director, Diagnostic Imaging Program, Center for Neuroscience and Regenerative Medicine (CNRM), Uniformed Services University of the Health Sciences

James G Smirniotopoulos, MD is a member of the following medical societies: American College of Radiology, American Roentgen Ray Society, American Society of Head and Neck Radiology, American Society of Neuroradiology, American Society of Pediatric Neuroradiology, Association of University Radiologists, and Radiological Society of North America

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Florian P Thomas, MD, MA, PhD, Drmed Director, Spinal Cord Injury Unit, St Louis Veterans Affairs Medical Center; Director, National MS Society Multiple Sclerosis Center; Director, Neuropathy Association Center of Excellence, Professor, Department of Neurology and Psychiatry, Associate Professor, Institute for Molecular Virology, and Department of Molecular Microbiology and Immunology, St Louis University School of Medicine

Florian P Thomas, MD, MA, PhD, Drmed is a member of the following medical societies: American Academy of Neurology, American Neurological Association, American Paraplegia Society, Consortium of Multiple Sclerosis Centers, and National Multiple Sclerosis Society

Disclosure: Nothing to disclose.

Frederick M Vincent Sr, MD Clinical Professor, Department of Neurology and Ophthalmology, Michigan State University Colleges of Human and Osteopathic Medicine

Frederick M Vincent Sr, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American College of Forensic Examiners, American College of Legal Medicine, American College of Physicians, and Michigan State Medical Society

Disclosure: Nothing to disclose.

Amir Vokshoor, MD Staff Neurosurgeon, Department of Neurosurgery, Spine Surgeon, Diagnostic and Interventional Spinal Care, St John's Health Center

Amir Vokshoor, MD is a member of the following medical societies: Alpha Omega Alpha, American Association of Neurological Surgeons, American Medical Association, and North American Spine Society

Disclosure: Nothing to disclose.

Cordia Wan, MD Adult Neurologist, Kaiser Permanente Hawaii, Kaiser Permanente Southern California

Cordia Wan, MD is a member of the following medical societies: American Academy of Neurology

Disclosure: Nothing to disclose.

Eric L Weiss, MD, DTM&H Medical Director, Office of Service Continuity and Disaster Planning, Fellowship Director, Stanford University Medical Center Disaster Medicine Fellowship, Chairman, SUMC and LPCH Bioterrorism and Emergency Preparedness Task Force, Clinical Associate Progressor, Department of Surgery (Emergency Medicine), Stanford University Medical Center

Eric L Weiss, MD, DTM&H is a member of the following medical societies: American College of Emergency Physicians, American College of Occupational and Environmental Medicine, American Medical Association, American Society of Tropical Medicine and Hygiene, Physicians for Social Responsibility, Southeastern Surgical Congress, Southern Association for Oncology, Southern Clinical Neurological Society, and Wilderness Medical Society

Disclosure: Nothing to disclose.

Lawrence A Zumo, MD Neurologist, Private Practice

Lawrence A Zumo, MD is a member of the following medical societies: American Academy of Neurology, American College of Physicians, American Medical Association, and Southern Medical Association

Disclosure: Nothing to disclose.

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Pneumococcal meningitis in a patient with alcoholism. Courtesy of the CDC/Dr. Edwin P. Ewing, Jr.
Acute bacterial meningitis. This axial nonenhanced computed tomography scan shows mild ventriculomegaly and sulcal effacement.
Acute bacterial meningitis. This axial T2-weighted magnetic resonance image shows only mild ventriculomegaly.
Acute bacterial meningitis. This contrast-enhanced, axial T1-weighted magnetic resonance image shows leptomeningeal enhancement (arrows).
Chronic 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.
Table 1. Infectious Agents Causing Aseptic Meningitis
Category Agent
Bacteria Partially treated bacterial meningitis



Listeria monocytogenes



Brucella spp



Rickettsia rickettsii



Ehrlichia spp



Mycoplasma pneumoniae



Borrelia burgdorferi



Treponema pallidum



Leptospira spp



Mycobacterium tuberculosis



Nocardia spp



Parasites Naegleria fowleri



Acanthamoeba spp



Balamuthia spp



Angiostrongylus cantonensis



Gnathostoma spinigerum



Baylisascaris procyonis



Strongyloides stercoralis



Taenia solium (cysticercosis)



Fungi Cryptococcus neoformans



Coccidioides immitis



Blastomyces dermatitidis



Histoplasma capsulatum



Candida spp



Aspergillus spp



Viruses Enterovirus Poliovirus



Echovirus



Coxsackievirus A



Coxsackievirus B



Enterovirus 68-71



Herpesvirus (HSV) HSV-1 and HSV-2



Varicella-zoster virus



Epstein-Barr virus



Cytomegalovirus



HHV-6 and HHV-7



Paramyxovirus Mumps virus



Measles virus



Togavirus Rubella virus
Flavivirus West Nile virus



Japanese encephalitis virus



St Louis encephalitis virus



Bunyavirus California encephalitis virus



La Crosse encephalitis virus



Alphavirus Eastern equine encephalitis virus



Western equine encephalitis virus



Venezuelan encephalitis virus



Reovirus Colorado tick fever virus
Arenavirus LCM virus
Rhabdovirus Rabies virus
Retrovirus HIV
HHV = human herpesvirus; HSV = herpes simplex virus; LCM = lymphocytic choriomeningitis.
       
Table 2. Causes of Chronic Meningitis
Category Agent
Bacteria Mycobacterium tuberculosis



Borrelia burgdorferi



Treponema pallidum



Brucella spp



Francisella tularensis



Nocardia spp



Actinomyces spp



Fungi Cryptococcus neoformans



Coccidioides immitis



Blastomyces dermatitidis



Histoplasma capsulatum



Candida albicans



Aspergillus spp



Sporothrix schenckii



Parasites Acanthamoeba spp



Naegleria fowleri



Angiostrongylus cantonensis



Gnathostoma spinigerum



Baylisascarisprocyonis



Schistosoma spp



Strongyloides stercoralis



Echinococcus granulosus



Table 3. Changing Epidemiology of Acute Bacterial Meningitis in United States*
Bacteria 1978-1981 1986 1995 1998-2007
Haemophilus influenzae 48% 45% 7% 6.7%  
Listeria monocytogenes 2% 3% 8% 3.4%  
Neisseria meningitidis 20% 14% 25% 13.9%  
Streptococcus agalactiae (group B streptococcus) 3% 6% 12% 18.1%  
Streptococcus pneumoniae 13% 18% 47% 58%  
*Nosocomial meningitis is not included; these data include only the 5 major meningeal pathogens.    
Table 4. Most Common Bacterial Pathogens on Basis of Age and Predisposing Risks
Risk or Predisposing Factor Bacterial Pathogen
Age 0-4 weeks Streptococcus agalactiae (GBS)



Escherichia coli K1



Listeria monocytogenes



Age 4-12 weeks S agalactiae



E coli



Haemophilus influenzae



Streptococcus pneumoniae



Neisseria meningitidis



Age 3 months to 18 years N meningitidis



S pneumoniae



H influenzae



Age 18-50 years S pneumoniae



N meningitidis



H influenzae



Age >50 years S pneumoniae



N meningitidis



L monocytogenes



Aerobic gram-negative bacilli



Immunocompromised state S pneumoniae



N meningitidis



L monocytogenes



Aerobic gram-negative bacilli



Intracranial manipulation, including neurosurgery Staphylococcus aureus



Coagulase-negative staphylococci



Aerobic gram-negative bacilli, including Pseudomonas aeruginosa



Basilar skull fracture S pneumoniae



H influenzae



Group A streptococci



CSF shunts Coagulase-negative staphylococci



S aureus



Aerobic gram-negative bacilli



Propionibacterium acnes



CSF = cerebrospinal fluid; GBS = group B streptococcus.
Table 5. CSF Findings in Meningitis by Etiologic Agent
Agent Opening Pressure (mm H2 O) WBC count (cells/µL) Glucose (mg/dL) Protein (mg/dL) Microbiology
Bacterial meningitis 200-300 100-5000; >80% PMNs < 40 >100 Specific pathogen demonstrated in 60% of Gram stains and 80% of cultures
Viral meningitis 90-200 10-300; lymphocytes Normal, reduced in LCM and mumps Normal but may be slightly elevated Viral isolation, PCR assays
Tuberculous meningitis 180-300 100-500; lymphocytes Reduced, < 40 Elevated, >100 Acid-fast bacillus stain, culture, PCR
Cryptococcal meningitis 180-300 10-200; lymphocytes Reduced 50-200 India ink, cryptococcal antigen, culture
Aseptic meningitis 90-200 10-300; lymphocytes Normal Normal but may be slightly elevated Negative findings on workup
Normal values 80-200 0-5; lymphocytes 50-75 15-40 Negative findings on workup
LCM = lymphocytic choriomeningitis; PCR = polymerase chain reaction; PMN = polymorphonuclear leukocyte; WBC = white blood cell.
Table 6. Comparison of CSF Findings by Type of Organism
Normal Finding Bacterial Meningitis Viral Meningitis* Fungal Meningitis**
Pressure (mm H2 O)



50-150



Increased Normal or mildly increased Normal or mildly increased in tuberculous meningitis; may be increased in fungal; AIDS patients with cryptococcal meningitis have increased risk of blindness and death unless kept below 300 mm H2 O
Cell count (mononuclear cells/µL)



Preterm: 0-25



Term: 0-22



>6 months: 0-5



No cell count result can exclude bacterial meningitis; PMN count typically in 1000s but may be less dramatic or even normal (classically, in very early meningococcal meningitis and in extremely ill neonates); lymphocytosis with normal CSF chemistries seen in 15-25%, especially when cell counts < 1000 or with partial treatment; ~90% of patients with ventriculoperitoneal shunts who have CSF WBC count >100 are infected; CSF glucose is usually normal, and organisms are less pathogenic; cell count and chemistries normalize slowly (over days) with antibiotics Cell count usually < 500, nearly 100% mononuclear; up to 48 hours, significant PMN pleocytosis may be indistinguishable from early bacterial meningitis; this is particularly true with eastern equine encephalitis; presence of nontraumatic RBCs in 80% of HSV meningoencephalitis, though 10% have normal CSF results Hundreds of mononuclear cells
Microscopy



No organisms



Gram stain 80% sensitive; inadequate decolorization may mistake Haemophilus influenzae for gram-positive cocci; pretreatment with antibiotics may affect stain uptake, causing gram-positive organisms to appear gram-negative and decrease culture yield by average of 20% No organism India ink is 50% sensitive for fungi; cryptococcal antigen is 95% sensitive; AFB stain is 40% sensitive for tuberculosis (increase yield by staining supernatant from at least 5 mL CSF)
Glucose



Euglycemia: >50% serum



Hyperglycemia: >30% serum



Wait 4 hr after glucose load



Decreased Normal Sometimes decreased; aside from fulminant bacterial meningitis, lowest levels of CSF glucose are seen in tuberculous meningitis, primary amebic meningoencephalitis, and neurocysticercosis
Protein (mg/dL)



Preterm: 65-150



Term: 20-170



>6 months: 15-45



Usually >150, may be >1000 Mildly increased Increased; >1000 with relatively benign clinical presentation suggestive of fungal disease
AFB = acid-fast bacillus; CSF = cerebrospinal fluid; HSV = herpes simplex virus; RBC = red blood cell; PMN = polymorphonuclear leukocyte.



*Some bacteria (eg, Mycoplasma, Listeria, Leptospira spp, Borrelia burgdorferi [Lyme], and spirochetes) produce spinal fluid alterations that resemble the viral profile. An aseptic profile also is typical of partially treated bacterial infections (>33% of patients have received antimicrobial treatment, especially children) and the 2 most common causes of encephalitis—the potentially curable HSV and arboviruses.



**In contrast, tuberculous meningitis and parasites resemble the fungal profile more closely.



Table 7. Recommended Empiric Antibiotics for Suspected Bacterial Meningitis, According to Age or Predisposing Factors [25]
Age or Predisposing Feature Antibiotics
Age 0-4 wk Ampicillin plus either cefotaxime or an aminoglycoside
Age 1 mo-50 y Vancomycin plus cefotaxime or ceftriaxone*
Age >50 y Vancomycin plus ampicillin plus ceftriaxone or cefotaxime plus vancomycin*
Impaired cellular immunity Vancomycin plus ampicillin plus either cefepime or meropenem
Recurrent meningitis Vancomycin plus cefotaxime or ceftriaxone
Basilar skull fracture Vancomycin plus cefotaxime or ceftriaxone
Head trauma, neurosurgery, or CSF shunt Vancomycin plus ceftazidime, cefepime, or meropenem
CSF = cerebrospinal fluid.



*Add ampicillin if Listeria monocytogenes is a suspected pathogen.



Table 8. Specific Antibiotics and Duration of Therapy for Acute Bacterial Meningitis
Bacteria Susceptibility Antibiotic(s) Duration (days)
Streptococcus pneumoniae Penicillin MIC ≤0.06 μg/mL Recommended: Penicillin G or ampicillin



Alternatives: Cefotaxime, ceftriaxone, chloramphenicol



10-14
Penicillin MIC ≥0.12 μg/mL



Cefotaxime or ceftriaxone MIC ≥0.12 μg/mL



Recommended: Cefotaxime or ceftriaxone



Alternatives: Cefepime, meropenem



Cefotaxime or ceftriaxone MIC ≥1.0 μg/mL Recommended: Vancomycin plus cefotaxime or ceftriaxone



Alternatives: Vancomycin plus moxifloxacin



Haemophilus influenzae Beta-lactamase−negative Recommended: Ampicillin



Alternatives: Cefotaxime, ceftriaxone, cefepime, chloramphenicol, aztreonam, a fluoroquinolone



7
Beta-lactamase−positive Recommended: Cefotaxime or ceftriaxone



Alternatives: Cefepime, chloramphenicol, aztreonam, a fluoroquinolone



Beta-lactamase−negative, ampicillin-resistant Recommended: Meropenem



Alternatives: Cefepime, chloramphenicol, aztreonam, a fluoroquinolone



Neisseria meningitidis Penicillin MIC < 0.1 μg/mL Recommended: Penicillin G or ampicillin



Alternatives: Cefotaxime, ceftriaxone, chloramphenicol



7
Penicillin MIC ≥0.1 μg/mL Recommended: Cefotaxime or ceftriaxone



Alternatives: Cefepime, chloramphenicol, a fluoroquinolone, meropenem



Listeria monocytogenes ... Recommended: Ampicillin or penicillin G



Alternative: TMP-SMX



14-21
Streptococcus agalactiae ... Recommended: Ampicillin or penicillin G



Alternatives: Cefotaxime, ceftriaxone, vancomycin



14-21
Enterobacteriaceae ... Recommended: Cefotaxime or ceftriaxone



Alternatives: Aztreonam, a fluoroquinolone, TMP-SMX, meropenem, ampicillin



21
Pseudomonas aeruginosa ... Recommended: Ceftazidime or cefepime



Alternatives: Aztreonam, meropenem, ciprofloxacin



21
Staphylococcus epidermidis   Recommended: Vancomycin



Alternative: Linezolid



Consider addition of rifampin



 
MIC= minimal inhibitory concentration; TMP-SMX = trimethoprim-sulfamethoxazole.
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