Meningitis

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Practice Essentials

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



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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:

Up to 95% of patients with bacterial meningitis have at least two of the four following symptoms: fever, headache, stiff neck, or altered mental status.

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:

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:

Infants may have the following:

The examination should evaluate the following:

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

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:

Blood studies that may be useful include the following:

In addition, the following tests may be ordered:

See Workup for more detail.

Management

Initial measures include the following:

Treatment of bacterial meningitis includes the following:

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

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:

See Treatment and Medication for more detail.

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).



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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:

Risk factors for meningitis include the following:

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:

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:

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).

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 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 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:

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.

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, cytomegalovirus, varicella zoster virus, and Listeria species. In addition, HIV itself may cause aseptic meningitis (see Meningitis in HIV).

Other viral causes of meningitis include the following:

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:

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:

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:

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 one of the leading cause of bacterial meningitis in children and young adults, but the incidence has decreased with use of the conjugate meningococcal vaccine.[6]

Risk factors for meningococcal meningitis include the following:

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:

Meningitis caused by gram-negative bacilli

Aerobic gram-negative bacilli include the following:

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:

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:

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. Unfortunately, up to 86% of cases of aseptic meningitis in adults have unknown causes, since molecular diagnostic techniques and arboviral serologies are underutilized.[7] 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



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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:

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, Powassan encephalitis, and Japanese encephalitis virus. Toscana virus is one of the most common causes of aseptic meningitis in the Mediterranean and is transmitted by a sandfly.[8]

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.[9]

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



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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.

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 was endemic in parts of Africa, with periodic epidemics occurring in the so-called sub-Saharan “meningitis belt,” as well as among religious pilgrims traveling to Saudi Arabia for the Hajj. The introduction of the MenAfriVac (Serum Institute of India Ltd, Hadapsur, Pune, India), a conjugate vaccine against serogroup A N meningitidis, in sub-Saharan Africa has now eliminated group A meningococcal meningitis outbreaks, but new epidemics are now occurring with serogroup W and C.[10]

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*



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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.[11]

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



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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. 

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.[12] 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.[13]

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.

Prognosis

Patients with bacterial meningitis who present with an impaired level of consciousness, hypotension, or seizures are at increased risk for neurologic sequelae or death.[14]

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[15] :

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:

Risk factors for hearing loss after pneumococcal meningitis are female gender, older age, severe meningitis, and infection with certain pneumococcal serotypes (eg, 12F).[16] Delayed complications include the following:

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:

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.

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.

History

Only about 44% of adults with bacterial meningitis exhibit the classic triad of fever, headache, and neck stiffness.[18] These symptoms can develop over several hours or over 1-2 days. In a large prospective study of 696 cases of adults with bacterial meningitis, van de Beek et al reported that 95% of the patients had 2 out of the following 4 symptoms: fever, headache, stiff neck, and altered mental status.[18]

Other symptoms can include the following:

Approximately 25% of patients with bacterial meningitis present acutely, well within 24 hours of the onset of symptoms. Occasionally, if a patient has been taking antibiotics for another infection, meningitis symptoms may take longer to develop or may be less intense.

Approximately 25% of patients have concomitant sinusitis or otitis that could predispose to S pneumoniae meningitis.[18] In contrast, patients with subacute bacterial meningitis and most patients with viral meningitis present with neurologic symptoms developing over 1-7 days. Chronic symptoms lasting longer than 1 week suggest the presence of meningitis caused by certain viruses or by tuberculosis, syphilis, fungi (especially cryptococci), or carcinomatosis.

Patients with viral meningitis may have a history of preceding systemic symptoms (eg, myalgias, fatigue, or anorexia). Patients with meningitis caused by the mumps virus usually present with the triad of fever, vomiting, and headache. This follows the onset of parotitis (salivary gland enlargement occurs in 50% of patients), which clinically resolves in 7-10 days.

As bacterial meningitis progresses, patients of any age may have seizures (30% of adults and children; 40% of newborns and infants). In patients who have previously been treated with oral antibiotics, seizures may be the sole presenting symptom; fever and changes in level of alertness or mental status are less common in partially treated meningitis than in untreated meningitis.

Atypical presentation may be observed in certain groups. Elderly individuals, especially those with underlying comorbidities (eg, diabetes, renal and liver disease), may present with lethargy and an absence of meningeal symptoms. Patients with neutropenia may present with subtle symptoms of meningeal irritation.

Other immunocompromised hosts, including organ and tissue transplant recipients and patients with HIV and AIDS, may also have an atypical presentation. Immunosuppressed patients may not show dramatic signs of fever or meningeal inflammation.

A less dramatic presentation―headache, nausea, minimal fever, and malaise―may be found in patients with low-grade ventriculitis associated with a ventriculoperitoneal shunt. Newborns and small infants also may not present with the classic symptoms, or the symptoms may be difficult to detect. An infant may appear only to be slow or inactive, or be irritable, vomiting, or feeding poorly. Other symptoms in this age group include temperature instability, high-pitched crying, respiratory distress, and bulging fontanelles (a late sign in one third of neonates).

Epidemiologic factors and predisposing risks should be assessed in detail. These may suggest the specific etiologic agent.

Exposures

A history of exposure to a patient with a similar illness is an important diagnostic clue. It may point to the presence of epidemic disease, such as viral or meningococcal meningitis.

Elicit any history of sexual contact or high-risk behavior from the patient. Herpes simplex virus (HSV) meningitis is associated with primary genital HSV infection and HIV infection. A history of recurrent bouts of benign aseptic meningitis suggests Mollaret syndrome, which is caused by HSV.

Animal contacts should be elicited. Patients with rabies could present atypically with aseptic meningitis; rabies should be suspected in a patient with a history of animal bite (eg, from a skunk, raccoon, dog, fox, or bat). Exposure to rodents suggests infection with lymphocytic choriomeningitis virus (LCM) virus and Leptospira infection. Laboratory workers dealing with these animals also are at increased risk of contracting LCM.

Brucellosis may be transmitted through contact with infected farm animals (eg, cows or pigs). The intake of unpasteurized milk and cheese also predisposes to brucellosis, as well as to L monocytogenes infection.

Previous medical treatment and existing conditions

A history of recent antibiotic use should be elicited. As many as 40% of patients who present with acute or subacute bacterial meningitis have previously been treated with oral antibiotics (presumably because of misdiagnosis at the time of initial presentation).

The presence of a ventriculoperitoneal shunt or a history of recent cranial surgery should be elicited. Patients with low-grade ventriculitis associated with a ventriculoperitoneal shunt may have a less dramatic presentation than those with acute bacterial meningitis, experiencing headache, nausea, minimal fever, and malaise. The presence of cochlear implants with a positioner has been associated with a higher risk of bacterial meningitis.

Alcoholism and cirrhosis are risk factors for meningitis. Unfortunately, the multiple etiologies of fever and seizures in patients with alcoholism or cirrhosis make meningitis challenging to diagnose.

Location and travel

Geographic location and travel history are important in the evaluation of patients. Infection with H capsulatum or B dermatitidis is considered in patients with exposure to endemic areas of the Mississippi and Ohio River valleys; C immitis is considered in regions of the southwestern United States, Mexico, and Central America. B burgdorferi is considered in regions of the northeastern and northern central United States, if tick exposure is a possibility.

Season and temperature

The time of year is an important variable because many infections are seasonal. With enteroviruses (which are found worldwide), infections occur during late summer and early fall in temperate climates and year-round in tropical regions. In contrast, mumps, measles, and varicella-zoster virus (VZV) are more common during winter and spring. Arthropod-borne viruses (eg, West Nile virus, St Louis encephalitis, and California encephalitis virus) are more common during the warmer months.

Physical Examination

The classic triad of meningitis consists of fever, nuchal rigidity, and altered mental status, but not all patients have all 3, and almost all patients have headache. Altered mental status can range from irritability to somnolence, delirium, and coma. The examination reveals no focal neurologic deficits in the majority of cases. Furthermore, the majority of patients with bacterial meningitis have a stiff neck, but the meningeal signs are insensitive for diagnosis of meningitis.[19]

Acute bacterial meningitis in otherwise healthy patients who are not at the extremes of age presents in a clinically obvious fashion. In contrast, most patients with subacute bacterial meningitis pose a diagnostic challenge. Systemic examination occasionally reveals a pulmonary or otitis media coinfection.

Systemic findings can also be present. Extracranial infection (eg, sinusitis, otitis media, mastoiditis, pneumonia, or urinary tract infection [UTI]) may be noted. Endotoxic shock with vascular collapse is characteristic of severe N meningitidis (meningococcal) infection.

General physical findings in viral meningitis are common to all causative agents, but some viruses produce unique clinical manifestations that help focus the diagnostic approach. Enteroviral infection is suggested by the presence of the following:

Increased blood pressure with bradycardia can also be present. Vomiting occurs in 35% of patients.

Nonblanching petechiae and cutaneous hemorrhages may be present in meningitis caused by N meningitidis (50%), H influenzae, S pneumoniae, or S aureus.[20] Arthritis is seen with meningococcal infection and with M pneumoniae infection but is less common with other bacterial species.

Infants

Infants may have the following:

In infants, the clinicians should examine the skin over the entire spine for dimples, sinuses, nevi, or tufts of hair. These may indicate a congenital anomaly communicating with the subarachnoid space.

Focal neurologic signs

Focal neurologic signs include isolated cranial nerve abnormalities (principally of cranial nerves III, IV, VI, and VII), which are present in 10-20% of patients. These result from increased intracranial pressure (ICP) or the presence of exudates encasing the nerve roots. Focal cerebral signs are present in 10-20% of patients and may develop as a result of ischemia from vascular inflammation and thrombosis.

Papilledema is a rare finding (< 1% of patients) that also indicates increased ICP, but it is neither sensitive nor specific: it occurs in only one third of meningitis patients with increased ICP and is present not only in meningitis but also in brain abscess and other disorders.

Signs of meningeal irritation

For more than 100 years, clinicians have relied on meningeal signs (nuchal rigidity, Kernig sign, and Brudzinski sign) to evaluate patients with suspected meningitis and help determine who should undergo a lumbar puncture (LP). However, a prospective study of 297 adults with suspected meningitis documented very low sensitivities for these signs: 5% for the Kernig sign, 5% for the Brudzinski sign, and 30% for nuchal rigidity.[19] Thus, the absence of the meningeal signs should not defer the performance of the LP.

Systemic and extracranial findings

Systemic findings on physical examination may provide clues to the etiology of a patient’s meningitis. Morbilliform rash with pharyngitis and adenopathy may suggest a viral etiology (eg, Epstein-Barr virus [EBV], cytomegalovirus [CMV], adenovirus, or HIV). Macules and petechiae that rapidly evolve into purpura suggest meningococcemia (with or without meningitis). Vesicular lesions in a dermatomal distribution suggest VZV. Genital vesicles suggest HSV-2 meningitis.

Sinusitis or otitis suggests direct extension into the meninges, usually with S pneumoniae or, less often, H influenzae. Rhinorrhea or otorrhea suggests a cerebrospinal fluid (CSF) leak from a basilar skull fracture, with meningitis most commonly caused by S pneumoniae.

Hepatosplenomegaly and lymphadenopathy suggest a systemic disease, including viral (eg, mononucleosislike syndrome in EBV, CMV, and HIV) and fungal (eg, disseminated histoplasmosis). The presence of a heart murmur suggests infective endocarditis with secondary bacterial seeding of the meninges.

Chronic meningitis

It is essential to perform careful general, systemic, and neurologic examinations, looking especially for the following:

Tuberculous meningitis

The presentation of chronic tuberculous meningitis may be acute, but the classic presentation is subacute and spans weeks. Patients generally have a prodrome consisting of fever of varying degrees, malaise, and intermittent headaches. Cranial nerve palsies (III, IV, V, VI, and VII) often develop, suggesting basilar meningeal involvement.

Clinical staging of tuberculous meningitis is based on neurologic status, as follows:

Syphilitic meningitis

The median incubation period before the appearance of symptoms in chronic syphilitic meningitis is 21 days (range, 3-90 days), during which time spirochetemia develops. Syphilitic meningitis usually occurs during the primary or secondary stage of syphilis, complicating 0.3-2.4% of primary infections during the first 2 years. Its presentation is similar to those of other types of aseptic meningitis, including headache, nausea, vomiting, and meningismus.

Meningovascular syphilis occurs later in the course of untreated syphilis, and the symptoms are dominated by focal syphilitic arteritis (ie, focal neurologic symptoms associated with signs of meningeal irritation) that spans weeks to months and results in stroke and irreversible damage if left untreated. Patients with concomitant HIV infection have an increased risk of accelerated progression.

Lyme meningitis

Although rare during stage 1 of Lyme disease, central nervous system (CNS) involvement with meningitis may occur in Lyme disease–associated chronic meningitis and is characterized by the concurrent appearance of erythema migrans at the site of the tick bite. More commonly, aseptic meningitis syndrome occurs 2-10 weeks after the erythema migrans rash. This represents stage 2 of Lyme disease, or the borrelial hematogenous dissemination stage.

Headache is the most common symptom of Lyme disease–associated chronic meningitis, with photophobia, nausea, and neck stiffness occurring less frequently. Somnolence, emotional lability, and impaired memory and concentration may occur. Facial nerve palsy is the most common cranial nerve deficit. These symptoms of meningitis usually fluctuate and may last for months if left untreated.

Fungal meningitis

Meningitis from C neoformans usually develops in patients with defective cell-mediated immunity (see CNS Cryptococcosis in HIV). It is characterized by the gradual onset of symptoms, the most common of which is headache.

Coccidioidal meningitis is the most serious form of disseminated coccidioidomycosis; it usually is fatal if left untreated. These patients may present with headache, vomiting, and altered mental function associated with pleocytosis, elevated protein levels, and decreased glucose levels. Eosinophils may be a prominent finding on CSF analysis.

Patients infected with B dermatitidis may present with an abscess or fulminant meningitis. Patients infected with H capsulatum may present with headache, cranial nerve deficits, or changes in mental status months before diagnosis.

Helminthic eosinophilic meningitis

After ingestion of A cantonensis larvae, which are found in raw or undercooked mollusks, most patients with symptomatic disease present with nonspecific and self-limited abdominal pain caused by larval migration into the bowel wall. On rare occasions, the larvae can migrate into the CNS and cause eosinophilic meningitis. Although A cantonensis is prevalent in Southeast Asia and tropical Pacific islands, infestations from this parasitic nematode have been reported in the United States and the Caribbean.[21]

Aseptic meningitis

In contrast to patients with bacterial meningitis, patients with aseptic meningitis syndrome usually appear clinically nontoxic, with no vascular instability. (See Aseptic Meningitis.) In many cases, a cause for meningitis is not apparent after initial evaluation, and the condition 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.

Complications

Immediate complications of meningitis include the following:

Delayed complications include the following:

Cerebral edema, cranial nerve palsy, and cerebral infarction

Some degree of cerebral edema is common with bacterial meningitis. This complication is an important cause of death.

Cranial nerve palsies and the effects of impaired cerebral blood flow, such as cerebral infarction, are caused by increased ICP. In certain cases, repeated LP or the insertion of a ventricular drain may be necessary to relieve the effects of this increase.

In cerebral infarction, endothelial cells swell, proliferate, and crowd into the lumen of the blood vessel, and inflammatory cells infiltrate the blood vessel wall. Foci of necrosis develop in the arterial and venous walls and induce arterial and venous thrombosis. Venous thrombosis is more frequent than arterial thrombosis, but arterial and venous cerebral infarctions can be seen in 30% of patients.

Brain parenchymal damage

Brain parenchymal damage is the most important and feared complication of bacterial meningitis. It can lead to the following disorders:

Cerebritis

Inflammation often extends along the perivascular (Virchow-Robin) spaces into the underlying brain parenchyma. Commonly, cerebritis results from direct spread of infection, either from otorhinologic infection or meningitis (including retrograde septic thrombophlebitis) or from hematogenous spread from an extracranial focus of infection. Parenchymal involvement, with edema and mass effect, may be localized or diffuse. Cerebritis can evolve to frank abscess formation in the gray matter–white matter junction.

Subdural effusion

In children with meningitis who are younger than 1 year, 20-50% of cases are complicated by sterile subdural effusions. Most of these effusions are transient and small to moderate in size. About 2% of them are infected secondarily and become subdural empyemas. In the empyema, infection and necrosis of the arachnoid membrane permit formation of a subdural collection.

In addition to young age, risk factors include rapid onset of illness, low peripheral white blood cell (WBC) count, and high CSF protein level. Seizures occur more commonly during the acute course of the disease, though long-term sequelae of promptly treated subdural effusions are similar to those of uncomplicated meningitis.

Ventriculitis

Ventriculitis may occur through the involvement of the ependymal lining of the ventricles. This complication occurs in 30% of patients overall but is especially common in neonates, with an incidence as high as 92%. The organisms enter the ventricles via the choroid plexuses. As a result of reduced CSF flow, and possibly of reduced secretion of CSF by the choroid plexus, the infective organisms remain in the ventricles and multiply.

Ventriculomegaly

Ventriculomegaly can occur early or late in the course of meningitis and is usually transient and mild to moderate in severity. As a result of the subarachnoid inflammatory exudate, CSF pathways may become obstructed, leading to hydrocephalus. Exudates in the foramina of Luschka and Magendie can cause noncommunicating hydrocephalus, whereas exudates that accumulate in the basilar cisterns or over the cerebral convexity can develop into communicating hydrocephalus.

Approach Considerations

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

Bacterial meningitis must be the first and foremost consideration in the differential diagnosis of patients with headache, neck stiffness, fever, and altered mental status. Acute bacterial meningitis is a medical emergency, and delays in instituting effective antimicrobial therapy result in increased morbidity and mortality.

In general, whenever the diagnosis of meningitis is strongly considered, a lumbar puncture should be promptly performed. Examination of the cerebrospinal fluid (CSF) is the cornerstone of the diagnosis. The diagnosis of bacterial meningitis is made by culture of the CSF sample. The opening pressure should be measured and the fluid sent for cell count (and differential count), chemistry (ie, CSF glucose and protein), and microbiology (ie, Gram stain and cultures).

A concern regarding LP is that the lowering of CSF pressure from withdrawal of CSF could precipitate herniation of the brain. Herniation can sometimes occur in acute bacterial meningitis and other CNS infections as the consequence of severe cerebral edema or acute hydrocephalus. Clinically, this is manifested by an altered state of consciousness, abnormalities in pupil reflexes, and decerebrate or decorticate posturing. The incidence of herniation after LP, even in patients with papilledema, is approximately 1%.

A screening computed tomography (CT) scan of the head may be performed before LP to determine the risk of herniation. A prospective study involving 301 adults with suspected meningitis found that the following baseline patient characteristics were associated with an abnormal finding on head CT[22] :

These factors have been included in the Infectious Diseases Society of America guidelines to decide who should undergo CT before LP.[23]

Obtaining a CT scan in a patient without any of the IDSA guidelines indications is of no clinical benefit and should be avoided.[24]

The decision to obtain a brain CT scan before LP should not delay the institution of antibiotic therapy; such delay can increase mortality. It should be also noted that herniation can occur in patients with bacterial meningitis who have a normal brain CT scan. The most reliable clinical signs that indicate the risk of herniation include deteriorating level of consciousness, brainstem signs, and a very recent seizure.

Other laboratory tests, which may include blood cultures, are needed to complement the CSF culture. These bacterial cultures are used for identification of the offending bacteria and occasionally its serogroup, as well as for determination of the organism’s susceptibility to antibiotics. Special studies, such as serology and nucleic acid amplification, may also be performed, depending on clinical suspicion of an offending organism.

As many as 50% of patients with pneumococcal meningitis also have evidence of pneumonia on initial chest radiography. This association occurs in fewer than 10% of patients with meningitis caused by H influenzae or N meningitidis and in approximately 20% of patients with meningitis caused by other organisms. (See Imaging in Bacterial Meningitis.)

Blood Studies

In patients with bacterial meningitis, a complete blood count (CBC) with differential will demonstrate polymorphonuclear leukocytosis with a left shift. Useful elements of the metabolic panel include the following:

The serum glucose level may be low if glycogen stores are depleted, or they may be high in infected patients with diabetes.

A coagulation profile and platelet count are indicated in cases of chronic alcohol use, chronic liver disease, or suspected disseminated intravascular coagulation (DIC). Patients with coagulopathies may require platelets or fresh frozen plasma (FFP) before LP.

Cultures and Bacterial Antigen Testing

Obtaining cultures before instituting antibiotics may be helpful if the diagnosis is uncertain. The utility of cultures is most evident when LP is delayed until head imaging can rule out the risk of brain herniation, in which cases adjunctive dexamethasone and antimicrobial therapy is rightfully initiated before CSF samples can be obtained. These cultures include the following:

Latex agglutination or counterimmunoelectrophoresis (CIE) of blood, urine, and CSF for specific bacterial antigens is occasionally recommended if diagnosis is challenging or in patients with partially treated meningitis. The Binax NOW S pneumoniae antigen test, if done on CSF, has a 99%-100% sensitivity and specificity and can even be positive despite prior antibiotic therapy.[25]

The use of nucleic acid amplification (eg, polymerase chain reaction [PCR] testing) has revolutionized the diagnosis of herpes simplex virus (HSV) meningitis. The availability of this technique has confirmed HSV as the cause of the recurrent Mollaret meningitis. This technique has also been applied to the diagnosis of enteroviral infections and the other herpesvirus infections. The PCR assay for enteroviruses has been demonstrated to be substantially more sensitive than culture and is 94-100% specific.

A multiplex PCR panel that identifies 14 pathogens (E coli K1, H influenzae, L monocytogenes, N meningitidis, S agalactiae, S pneumoniae, cytomegalovirus, enterovirus, herpes simplex virus 1, herpes simplex virus 2, human herpes virus 6, human parechovirus, varicella zoster, C neoformans/Cryptococcus gattii) in 1 hour with 0.2 mL of CSF is now widely available.

Syphilis Testing

Perform serologic tests to detect syphilis. Screening for syphilis is done with the nontreponemal tests: rapid plasma reagent (RPR) or Venereal Disease Research Laboratory (VDRL). Positive results are confirmed with one of the following specific treponemal tests:

In patients with syphilis, initial results on nontreponemal tests can serve as a baseline for gauging the success of therapy. Titers decrease and usually revert to negative or undetectable levels following effective treatment.

Serum Procalcitonin Testing

Increasing data suggest that serum procalcitonin (PCT) levels can be used as a guide to distinguish between bacterial and aseptic meningitis in children. Elevated serum PCT levels predict bacterial meningitis. The results of serum PCT testing, combined with other findings, could be helpful in making clinical decisions.[26]

In an analysis of retrospective, multicenter, hospital-based cohort studies, Dubos et al confirmed that measurement of the PCT level is the best biologic marker for differentiating bacterial meningitis from aseptic meningitis in children in the emergency department (ED). With a threshold of 0.5 ng/mL, the sensitivity and specificity of the PCT level in distinguishing between bacterial and aseptic meningitis were 99% and 83%, respectively.[26]

Lumbar Puncture and CSF Analysis

Elevated opening pressure correlates with increased risk of morbidity and mortality in bacterial and fungal meningitis. In bacterial meningitis, elevated opening pressure (reference range, 80-200 mm H2 O) suggests increased intracranial pressure (ICP) from cerebral edema. In viral meningitis, the opening pressure is usually within the reference range. The CSF opening pressure may be elevated at times in cryptococcal meningitis, suggesting increased ICP, and it is usually elevated in tuberculous meningitis.

The CSF cell count varies according to the offending pathogen (see Tables 5 and 6 below). It is usually in the few hundreds (100-1000/µL) with a predominance of lymphocytes in patients with viral meningitis. Some cases of echovirus, mumps, and HSV meningitis may produce a neutrophilic picture early in the course of disease. (See Lumbar Puncture.)

Table 5. CSF Findings in Meningitis by Etiologic Agent



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Table 6. Comparison of CSF Findings by Type of Organism



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CFS sample handling

After drawing the CSF sample, do the following with the tubes:

Microbiology and immunology studies for tube 3 include the following:

Tumor necrosis factor alpha (TNF-α), interleukin (IL)-1, and other cytokines have received increasing attention as mediators of the inflammatory response during bacterial meningitis. Leist et al reported detecting TNF-α in the CSF of 3 of 3 patients with bacterial meningitis, but in 0 of 7 patients with viral meningitis. Lopez-Cortez et al demonstrated that a TNF-α level higher than 150 pg/mL and an IL-1β level higher than 90 pg/mL showed sensitivities of 74% and 90%, respectively, in discriminating viral from aseptic meningitis.

Mustafa et al demonstrated that IL-1β can be detected in the CSF of 95% of infants and children with bacterial meningitis and that levels higher than 500 pg/mL were correlated with an increased risk of neurologic sequelae.[27]

These findings, though requiring both confirmation and amplification, suggest that analysis of TNF and other cytokines, in particular IL-1β, may prove valuable in differentiating acute bacterial meningitis from viral meningitis and possibly in detecting patients at particular risk for an adverse outcome. Their role in guiding adjunctive therapy, such as corticosteroids and nonsteroidal treatment of blood-brain barrier injury, is also under investigation.

CSF characteristics of acute bacterial meningitis

Examination of the CSF in patients with acute bacterial meningitis reveals the characteristic neutrophilic pleocytosis (cell count usually ranging from hundreds to a few thousand, with >80% PMNs). In some (25-30%) cases of L monocytogenes meningitis, a lymphocytic predominance may occur. A low CSF white blood cell (WBC) count (< 20/µL) in the presence of a high bacterial load suggests a poor prognosis.

According to Seupaul, the following 3 findings on CSF analysis have clinically useful likelihood ratios for the diagnosis of bacterial meningitis in adults[28] :

CSF characteristics of viral meningitis

In viral meningitis, the opening pressure is 90-200 mm H2 O, and the WBC count is 10-300/µL. Although the glucose concentration is typically normal, it can be below normal in meningitis from lymphocytic choriomeningitis virus (LCM), herpes simplex virus (HSV), mumps virus, and poliovirus. The protein concentration tends to be slightly elevated, but it can be within the reference range.

CSF characteristics of fungal meningitis

The diagnosis of cryptococcal meningitis relies on the identification of the pathogen in the CSF. The CSF is characterized by a lymphocytic pleocytosis (10-200/µL), a reduced glucose level, and an elevated protein level. The CSF picture of other fungal meningitides is similar to that of cryptococcal meningitis, usually with lymphocytic pleocytosis. Eosinophilic pleocytosis has rarely been associated with C immitis meningitis.

The definitive diagnosis usually relies on the demonstration of the specific fungal agent (eg, H capsulatum, C immitis, B dermatitidis, or Candida species) from clinical specimens, including the CSF. This could be in the form of fungal culture isolation (eg, C albicans growth from CSF).

More commonly, fungal serology (eg, presence of histoplasma antigen in the CSF) is used in the diagnosis of many cases of fungal meningitis because isolating these organisms from culture has proved difficult. It should be noted, however, that the serology for B dermatitidis is not accurate and a negative serology finding does not rule out the diagnosis.

A test used to detect fungal infection in the blood was successfully used in the diagnosis of fungal meningitis in an outbreak caused by contaminated steroids.[29] This outbreak involved 13,534 US patients who underwent epidural steroid injection and were exposed to methylprednisolone acetate from lots contaminated with environmental fungi; hundreds of these individuals developed serious CNS complications. The test (Fungitell, Beacon Diagnostics Laboratories), which measures levels of b-D-glucan (a glycoprotein found in the fungal cell wall), was used in CSF samples from patients exposed to the contaminated steroids who had negative fungal culture and polymerase chain reaction results. All patients with fungal meningitis had detectable b-D-glucan in their CSF.[29]

CSF characteristics of eosinophilic/parasitic meningitis

Primary amebic meningoencephalitis (PAM) caused by N fowleri is characterized by a neutrophilic pleocytosis, low glucose levels, elevated protein levels, and red blood cells (RBCs). Mononuclear pleocytosis may be observed in patients with subacute or chronic forms of PAM. Demonstration of the trophozoites, with the characteristic ameboid movement, on wet preparations of the CSF has been used for diagnosis. Alternatively, the ameba may be demonstrated in biopsy specimens.

In the presence of exposure, profound peripheral blood eosinophilia, and characteristic eosinophilic pleocytosis, suspicion of meningitis caused by A cantonensis, G spinigerum, or B procyonis should be entertained. Demonstrating the larvae ante mortem is usually difficult, and diagnosis relies on clinical presentation and a compatible epidemiologic history. Serologic tests may aid in the diagnosis. G spinigerum meningitis may mimic cerebrovascular disease in that it may cause cerebral hemorrhage.

CSF characteristics of Lyme meningitis

In patients with Lyme meningitis, the CSF is characterized by low-grade lymphocytic pleocytosis, low glucose levels, and elevated protein levels. Oligoclonal bands reactive to B burgdorferi antigens may be present. Demonstration of the specific antibody to B burgdorferi aids in the diagnosis.

Comparison between the antibody response in the CSF and that in the serum is a helpful diagnostic test. A CSF-to-serum ratio greater than 1 suggests intrathecal antibody production and neuroborreliosis.

CSF characteristics of tuberculous meningitis

In patients with tuberculous meningitis, the CSF is characterized by a predominantly lymphocytic pleocytosis; an elevated protein level, especially if a CSF block is present; and a low glucose level (< 40 mg/dL). PCR testing can provide a rapid diagnosis, though false-negative results may occur in samples containing very few organisms (< 2 colony-forming units [cfu]/mL). (See Tuberculous Meningitis.)

CSF glucose and protein

In bacterial meningitis, the CSF glucose level (reference range, 40-70 mg/dL) is less than 40 mg/dL in 60% of patients. A simultaneous blood glucose determination should be obtained for the purposes of comparison. In patients with elevated blood glucose levels as a result of diabetes mellitus, the CSF-to-blood glucose ratio may not be predictive. The CSF glucose level is usually within the reference range in viral meningitis, but it may be low in some cases of LCM, HSV, mumps virus, or poliovirus infection.

The CSF protein level (reference range, 20-50 mg/dL) is usually elevated in bacterial meningitis. In viral meningitis, these levels are also usually elevated, though they can be within the reference range. In syphilitic meningitis, abnormal CSF protein levels (elevated) and CSF glucose levels (decreased) may be observed in 10-70% of cases.

CSF Gram stain and acid-fast bacillus stain

Gram staining of the CSF permits rapid identification of the bacterial cause in 60-90% of patients with bacterial meningitis. The presence of bacteria is 100% specific, but the sensitivity of this test for detection is variable. The likelihood of detection is higher in the presence of a higher bacterial concentration and diminishes with prior antibiotic use.

The demonstration of AFB (eg, with auramine-rhodamine stain, Ziehl-Neelsen stain, or Kinyoun stain) in the CSF is difficult and usually requires a large volume of CSF. Meningeal biopsy, with the demonstration of caseating granulomas and AFB on the smear, offers a higher yield than the CSF AFB smear.

CSF culture and antigen testing

CSF bacterial cultures yield the bacterial cause in 70-85% of cases. The yield diminishes by 20% in patients who have received antimicrobial therapy. In these cases, some experts advocate the use of a CSF bacterial antigen assay. This is a latex agglutination technique that can detect the antigens of H influenzae type B (Hib), S pneumoniae, N meningitidis, E coli K1, and S agalactiae (group B streptococcus [GBS]). Its theoretical advantage is the detection of the bacterial antigens even after microbial killing, as is observed after antibacterial therapy.

Another attractive alternative is using the Binax NOW for S pneumoniae in the CSF. This assay has a 99-100% sensitivity and specificity for ruling out the most common cause of bacterial meningitis.[25]

Others studies, however, have shown that the CSF bacterial antigen assay may not be better than the Gram stain. Although it is specific (a positive result indicates a diagnosis of bacterial meningitis), a negative finding on the bacterial antigen test does not rule out meningitis (50-95% sensitivity).

Cryptococcal meningitis

C neoformans may be cultured from the CSF in cryptococcal meningitis. Other methods of identification include India ink preparation and the detection of CSF cryptococcal antigen. India ink has a sensitivity of only 50%, but it is highly diagnostic if positive.

Because of the low sensitivity of the India ink preparation, many centers have adapted the use of CSF cryptococcal antigen determination, a test with a sensitivity exceeding 90%. However, the CSF cryptococcal antigen determination is not universally available.

In instances when the India ink results are negative but the degree of clinical suspicion for cryptococcal meningitis is high, the CSF specimen may be sent to reference laboratories that can perform CSF cryptococcal antigen determination to confirm the diagnosis. In addition, the titer of the antigen could serve to monitor the response to treatment. Blood cultures and serum cryptococcal antigen should be obtained to determine whether cryptococcal fungemia is present.

Syphilitic meningitis

In syphilitic meningitis, isolating T pallidum from the CSF is extremely difficult and time-consuming. The spirochete could be demonstrated by using dark-field or phase-contrast microscopy on specimens collected from skin lesions (eg, chancres and other syphilitic lesions).

The diagnosis is usually supported by the CSF VDRL test, which has a sensitivity of 30-70% (a negative result on the CSF VDRL test does not rule out syphilitic meningitis) and a high specificity (a positive test result suggests the disease). Care must always be taken not to contaminate the CSF with blood during spinal fluid collection (eg, traumatic tap).

Lyme meningitis

CSF culture for B burgdorferi has a low yield. The CSF Lyme PCR assay, if available, offers a rapid, sensitive, and specific method of diagnosis. This assay is gaining popularity as the method of choice for diagnosing Lyme meningitis.

Cohn et al validated a clinical prediction rule for differentiating Lyme meningitis from aseptic meningitis. Their “rule of 7s” classifies children at low risk for Lyme meningitis when all of the following 3 criteria are met[30] :

Tuberculous meningitis

Culture for Mycobacterium usually takes several weeks and may delay definitive diagnosis. M tuberculosis detection assays involving nucleic acid amplification have become available and have the advantages of rapidity, high sensitivity, and high specificity. There remains a need for mycobacterial growth in cultures because this method offers the advantage of performing drug susceptibility assays.

Viral isolation from CSF

Isolation of viruses from the CSF has a sensitivity of 65-70% for enteroviruses. Alternatively, isolation of enteroviruses from throat and stool viral cultures may also indirectly implicate enterovirus as the cause of the meningitis. Culture of mumps virus from the CSF has a low sensitivity (30-50%). LCM virus may be cultured in blood early in the disease or in urine at a later stage.

Neuroimaging

Computed tomography (CT) of the head and magnetic resonance imaging (MRI) of the brain generally do not aid in the diagnosis of meningitis. Some patients may show meningeal enhancement, but its absence does not rule out the condition. Routinely obtaining CT scans of the head may lead to unnecessary delay in the performance of diagnostic lumbar puncture and the initiation of antibiotic therapy; the latter may be detrimental to the outcome in these patients.

Cerebral herniation following the lumbar tap procedure is rare in individuals with no focal neurologic deficits and no evidence of increased ICP. If it occurs, it usually does so within 24 hours after the LP; thus, herniation should always be considered in the differential diagnosis if the patient’s neurologic status deteriorates during that time frame.

According to the Infectious Diseases Society of America guidelines, the following are indications for screening head CT before LP in adult patients[23] :

In patients with suspected bacterial meningitis, blood cultures should be obtained and treatment initiated before imaging studies and LP. Neuroimaging may yield normal results or demonstrate small ventricles, effacement of sulci, and contrast enhancement over convexities (see the images below). Late findings include venous infarction and communicating hydrocephalus. Brain abscess, sinus or mastoid infection, skull fracture, and congenital anomalies must be ruled out. (See Imaging in Bacterial Meningitis.)



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



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Acute bacterial meningitis. This axial T2-weighted magnetic resonance image shows only mild ventriculomegaly.



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Acute bacterial meningitis. This contrast-enhanced, axial T1-weighted magnetic resonance image shows leptomeningeal enhancement (arrows).

Finally, neuroimaging studies are helpful in the detection of CNS complications of bacterial meningitis, such as the following (see the images below):

Approach Considerations

If the patient is in shock or hypotensive, crystalloid should be infused until euvolemia is achieved. If the patient’s mental status is altered, seizure precautions should be considered, seizures should be treated according to the usual protocol, and airway protection should be considered. If the patient is alert and in stable condition with normal vital signs, oxygen should be administered, intravenous (IV) access established, and rapid transport to the emergency department (ED) initiated. Institution of an ED triage protocol may help identify patients at risk.

In acute meningitis, regardless of presentation, a lumbar puncture (LP) and cerebrospinal fluid (CSF) examination are indicated to identify the causative organism and, in bacterial meningitis, the antibiotic sensitivities. Computed tomography (CT) of the head should be performed a before LP, if indicated. If no mass effect is present on head CT, LP is performed to obtain microbiology studies.

The performance of radiographic imaging should not delay the initiation of empiric antimicrobial therapy; such therapy should be initiated before head CT if indicated. It is vital to begin treatment as early as possible in the disease course; delay may contribute significantly to morbidity and mortality. In acutely ill patients, antibiotic therapy should be initiated promptly; in many of these cases, one should strongly consider giving adjunctive dexamethasone before the first antibiotic dose, or at least concomitantly with the dose.[23]

The patient’s condition and ED organization may warrant 8-12 hours of watchful waiting, followed by reexamination of the CSF (this should be done sooner if the patient’s condition deteriorates). If initial granulocytosis changes to mononuclear predominance, CSF glucose remains normal, and the patient continues to look well, the infection is most likely nonbacterial.

Treatment of complications

Systemic complications of acute bacterial meningitis must be treated, including the following:

Signs of hydrocephalus and increasing intracranial pressure (ICP) should be watched for. Fever and pain should be managed, straining and coughing controlled, seizures prevented, and systemic hypotension avoided. In otherwise stable patients, sufficient care includes elevating the head and monitoring neurologic status. When more aggressive maneuvers are indicated, some authorities favor early use of diuresis (ie, furosemide 20 mg IV or mannitol 1 g/kg IV), provided that circulatory volume is protected.

Hyperventilation in intubated patients, with an arterial carbon dioxide tension (PaCO2) of 25-30 mm Hg as the goal, may briefly lower ICP; hyperventilation to a PaCO2 lower than 25 mm Hg may decrease cerebral blood flow disproportionately and lead to CNS ischemia. Placement of an ICP monitor should be considered in comatose patients or those with signs of increased ICP. With elevated ICP, CSF should be removed until pressure decreases by 50%; ICP should then be maintained at less than 300 mm H2 O.

Because seizure activity increases ICP, seizures must be aggressively controlled if present. Control may be accomplished by giving lorazepam 0.1 mg/kg IV and IV load with phenytoin 15 mg/kg or phenobarbital 5-10 mg/kg.

Treatment of Subacute Meningitis

Patients with subacute meningitis (duration of symptoms >5 days prior to presentation) are more commonly immunosuppressed, have comorbidities, have fungal etiologies, have higher rates of hypoglycorrhachia, and have abnormal neurological findings than patients with acute meningitis.[31] Furthermore, patients with subacute meningitis are less likely to be treated empirically with intravenous antibiotics and have lower levels of CSF pleocytosis and serum WBC counts than patients with acute meningitis.

Treatment of Bacterial Meningitis

Bacterial meningitis (including meningococcal meningitis, Haemophilus influenzae meningitis, and staphylococcal meningitis) is a neurologic emergency that is associated with significant morbidity and mortality. Initiation of empiric antibacterial therapy is therefore essential for better outcome.[32, 33] (See tables 7 and 8 below.)

Table 7. Recommended Empiric Antibiotics for Suspected Bacterial Meningitis, According to Age or Predisposing Factors[33]



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Table 8. Specific Antibiotics and Duration of Therapy for Acute Bacterial Meningitis



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It is vital to institute empiric antimicrobial therapy (ie, antibacterial treatment or, in selected cases, antiviral or antifungal therapy) as soon as possible. The choice of agents is usually based on the known predisposing factors, initial CSF Gram stain results, or both. Once the pathogen has been identified and antimicrobial susceptibilities determined, the antibiotics may be modified for optimal targeted treatment.

Bacterial resistance, especially penicillin resistance among S pneumoniae strains, has been increasing worldwide. In March 2008, the US Food and Drug Administration (FDA) revised the susceptibility breakpoints for penicillin versus S pneumoniae. For nonmeningeal infections, the breakpoints are as follows:

For meningitis, the breakpoints are as follows:

With the new meningitis criteria (≥0.12 μg/mL), the prevalence of resistance was 34.8% in 2008, whereas with the old criteria (≥2 μg/mL), it was 12.3% for CSF.[34] The geographic distribution of this resistance is variable, and it is important to know the regional patterns when deciding on local empiric antibiotic therapy (see Medication). A large observational study of 548 pneumococcal meningitis cases from Brazil showed that penicillin resistance was associated with higher mortality even after adjustment for age and severity of illness.[35]

Appropriate antibiotic treatment for the most common types of bacterial meningitis reduces the risk of death. Mortality is higher with pneumococcal meningitis. In a nationwide observational cohort study from The Netherlands, adjunctive use of dexamethasone decreased pneumococcal meningitis mortality from 30% to 20%.[36]

The chosen antibiotic should attain adequate levels in the CSF, and its ability to do so usually depends on its lipid solubility, molecular size, and protein-binding capacity, as well as on the patient’s degree of meningeal inflammation. The penicillins, certain cephalosporins (ie, third- and fourth-generation agents), the carbapenems, fluoroquinolones, and rifampin provide high CSF levels.

Monitoring for possible drug toxicity during treatment (eg, with blood counts and renal and liver function monitoring) is warranted. The antimicrobial dose must be adjusted on the basis of the patient’s renal and hepatic function. At times, obtaining serum drug concentrations may be necessary to ensure adequate levels and to avoid toxicity in drugs with a narrow therapeutic index (eg, vancomycin and aminoglycosides). The patient must also be monitored for complications from the disease (eg, hydrocephalus, seizures, or hearing defects).

Antibiotic therapy: neonates to age 1 month

In the first month of life, the most common microorganisms are group B or D streptococci, Enterobacteriaceae (eg, E coli), and L monocytogenes. Primary treatment consists of a combination of ampicillin and cefotaxime. The recommended dosage for cefotaxime is 50 mg/kg IV every 6 hours, up to 12 g/day. Ampicillin dosages are as follows:

Alternative treatment consists of ampicillin plus gentamicin. Gentamicin dosages are as follows:

Most authorities recommend adding acyclovir 10 mg/kg IV every 8 hours for herpes simplex encephalitis.

Antibiotic therapy: age 1-3 months

In infants 1-3 months of age, the first-line agent is cefotaxime (50 mg/kg IV every 6 hours, up to 12 g/day) or ceftriaxone (75 mg/kg initially, then 50 mg/kg every 12 hours, up to 4 g/day) plus ampicillin (50-100 mg/kg IV every 6 hours). An alternative agent is chloramphenicol (25 mg/kg orally or IV every 12 hours) plus gentamicin (2.5 mg/kg IV or IM every 8 hours).

If the local prevalence of drug-resistant S pneumoniae (DRSP) is higher than 2%, vancomycin (15 mg/kg IV every 8 hours) should be added. Treatment with dexamethasone (0.4 mg/kg IV every 12 hours for 2 days or 0.15 mg/kg IV every 6 hours for 4 days) should be strongly considered, starting 15-20 minutes before the first dose of antibiotics.

Antibiotic therapy: age 3 months to 7 years

In older infants or young children (age 3 months to 7 years), the most common microorganisms are S pneumoniae, N meningitidis, and H influenzae. Primary treatment is with either cefotaxime (50 mg/kg IV every 6 hours, up to 12 g/day) or ceftriaxone (75 mg/kg initially, then 50 mg/kg every 12 hours, up to 4 g/day).

If the prevalence of DRSP is greater than 2%, vancomycin (15 mg/kg IV every 8 hours) should be added. In countries with a low prevalence of DRSP, penicillin G (250,000 units/kg/day IM or IV in 3-4 divided doses) may be considered. Because of the increasing prevalence of DRSP, penicillin G is no longer recommended in the United States.

An alternative (which may also be chosen if the patient is severely allergic to penicillin) is chloramphenicol (25 mg/kg orally or IV every 12 hours) plus vancomycin (15 mg/kg IV every 8 hours). Treatment with dexamethasone (0.4 mg/kg IV every 12 hours for 2 days or 0.15 mg/kg IV every 6 hours for 4 days) should be strongly considered, starting 15-20 minutes before the first dose of antibiotics.

Antibiotic therapy: age 7-50 years

In an older child or an otherwise healthy adult (age 7-50 years), the most common microorganisms in bacterial meningitis are S pneumoniae, N meningitidis, and L monocytogenes. In areas where the prevalence of DRSP is greater than 2%, primary treatment consists of with either cefotaxime or ceftriaxone plus vancomycin. Pediatric dosing is as follows:

Adult dosing is as follows:

Some experts add rifampin (pediatric dose, 20 mg/kg/day IV; adult dose, 600 mg/day orally). If Listeria is suspected, ampicillin (50 mg/kg IV every 6 hours) is added.

An alternative (which may also be chosen if the patient is severely penicillin-allergic) is chloramphenicol (12.5 mg/kg IV every 6 hours; not bactericidal) or clindamycin (pediatric dose, 40 mg/kg/day IV in 3-4 doses; adult dose, 900 mg IV every 8 hours; active in vitro but no clinical data) or meropenem (pediatric dose, 20-40 mg/kg IV every 8 hours; adult dose, 1 g IV every 8 hours; active in vitro but few clinical data). Imipenem is a proconvulsant and must be avoided.

In areas with a low prevalence of DRSP, cefotaxime or ceftriaxone plus ampicillin is recommended. Pediatric dosing is as follows:

Adult dosing is as follows:

An alternative (which may also be chosen if the patient is severely penicillin-allergic) is chloramphenicol (12.5 mg/kg IV every 6 hours) plus trimethoprim-sulfamethoxazole (TMP-SMX; TMP 5 mg/kg IV every 6 hours) or meropenem (pediatric dose, 20-40 mg/kg IV every 8 hours; adult dose, 1 g IV every 8 hours).

Data on the need for dexamethasone treatment in adults are limited, though there is support for its use in developed countries when S pneumoniae is the suspected organism. The first dose of dexamethasone (0.4 mg/kg every 12 hours IV for 2 days or 0.15 mg/kg every 6 hours for 4 days) should be administered 15-20 minutes before the first dose of antibiotics.

Antibiotic therapy: age ≥50 years

In adults older than 50 years or adults with disabling disease or alcoholism, the most common microorganisms are S pneumoniae, coliforms, H influenzae, Listeria species, P aeruginosa, and N meningitidis.

Primary treatment, if the prevalence of DRSP is greater than 2%, is with either cefotaxime (2 g IV every 4 hours) or ceftriaxone (2 g IV every 12 hours) plus vancomycin (750-1000 mg IV every 12 hours or 10-15 mg/kg IV every 12 hours). If the CSF Gram stain shows gram-negative bacilli, ceftazidime (2 g IV every 8 hours) is given. In areas of low DRSP prevalence, treatment consists of cefotaxime (2 g IV every 4 hours) or ceftriaxone (2 g IV every 12 hours) plus ampicillin (50 mg/kg IV every 6 hours). Other options are meropenem, TMP-SMX, and doxycycline.

The Infectious Diseases Society of America guidelines recommend adjunctive dexamethasone in patients with suspected or proven community-acquired bacterial meningitis, but only in high-income countries.[23] The first dose of dexamethasone (0.4 mg/kg IV every 12 hours for 2 days or 0.15 mg/kg every 6 hours for 4 days) is given 15-20 minutes before the first dose of antibiotics.

Dexamethasone should be continued if the culture grows either S pneumoniae or H influenzae. However, some experts advise that adjunctive treatment should be continued irrespective of the causative bacterium because of the low incidence of adverse events.

Antibiotic therapy: HIV-infected patients

In HIV-infected patients, if an ED workup does not identify a pathogen, serum and CSF samples should be drawn for cryptococcal antigen testing. Empiric treatment should proceed 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. (See Meningitis in HIV.)

Steroid therapy

The use of corticosteroids (typically, dexamethasone, 0.15 mg/kg every 6 hours for 2-4 days) as adjunctive treatment for bacterial meningitis improves outcome by attenuating the detrimental effects of host defenses (eg, inflammatory response to the bacterial products and the products of neutrophil activation). Controversy surrounds this practice, however, in that dexamethasone may interrupt the cytokine-mediated neurotoxic effects of bacteriolysis, which are at maximum in the first days of antibiotic use.[37]

Theoretically, the anti-inflammatory effects of steroids decrease blood-brain barrier permeability and impede penetration of antibiotics into CSF. Decreased CSF levels of vancomycin have been confirmed in steroid-treated animals but not in comparably treated humans. Many authorities believe that all other antibiotics achieve minimal inhibitory concentrations (MICs) in CSF regardless of steroid use, and even vancomycin may not be affected to a clinically significant extent.

Nevertheless, the use of steroids has been shown to improve the overall outcome of patients with certain types of bacterial meningitis, including H influenzae, tuberculous, and pneumococcal meningitis.

In a meta-analysis by Brouwer et al, corticosteroids significantly reduced hearing loss and neurologic sequelae but did not reduce overall mortality. However, there was a trend toward lower mortality in adults receiving corticosteroids, and subgroup analyses showed that corticosteroids reduced severe hearing loss in H influenzae meningitis and reduced mortality in S pneumoniae meningitis. However, the investigators found no beneficial effect for patients in low-income countries.[38]

On the other hand, a meta-analysis of individual patient data by van de Beek et al was unable to identify which patients were most likely to benefit from dexamethasone treatment; indeed, no significant reduction in death or neurologic disability was found in any subgroups, including those determined by specific causative organisms, predexamethasone antibiotic treatment, HIV status, or age. The researchers concluded that the benefits of adjunctive dexamethasone in bacterial meningitis remain unproven.[39]

In developing countries, the use of oral glycerol (rather than dexamethasone) has been studied as adjunctive therapy in the treatment of bacterial meningitis in children. In limited studies, it appears to reduce the incidence of neurologic sequelae while causing few side effects.[40]

Intrathecal antibiotics

Intrathecal administration of antibiotics can be considered in patients with nosocomial meningitis (eg, meningitis developing after neurosurgery or placement of an external ventricular catheter) that does not respond to IV antibiotics. Although the FDA has not approved any antibiotics for intraventricular use, vancomycin and gentamicin are often used in this setting. Other agents used intrathecally include amikacin, polymyxin B, and colistin.[41]

Intrathecal antibiotic dosages have been determined empirically and are adjusted on the basis of the CSF concentrations of the agent. Typical daily doses are as follows[41] :

Treatment of Viral Meningitis

Most cases of viral meningitis are benign and self-limited. Often, patients need only supportive care and require no specific therapy. In certain instances, specific antiviral therapy may be indicated, if available. Instituting antiretroviral therapy may be necessary for patients with HIV meningitis that occurs during an acute seroconversion syndrome. In patients with immune deficiency (eg, agammaglobulinemia), immunoglobulin replacement has been used to treat chronic enteroviral infections.

Herpes simplex meningitis

The antiviral management of HSV meningitis is controversial. Acyclovir (10 mg/kg IV every 8 hours) has been administered for HSV-1 and HSV-2 meningitis. Some experts do not advocate antiviral therapy unless associated encephalitis is present, because the condition is usually benign and self-limited. This is exemplified by Mollaret syndrome, a recurrent but benign syndrome of lymphocytic pleocytosis that is now attributed to HSV.

Cytomegalovirus meningitis

Ganciclovir and foscarnet are used for cytomegalovirus (CMV) meningitis in immunocompromised hosts. Ganciclovir is given in an induction dosage of 5 mg/kg IV every 12 hours for 21 days and a maintenance dosage of 5 mg/kg every 24 hours. Oral valganciclovir (900 mg/day) can be used for maintenance if immunosuppression continues (as, for example, in AIDS patients or transplant recipients). Foscarnet is given in an induction dosage of 60 mg/kg IV every 8 hours for 21 days and a maintenance dosage of 90-120 mg/kg IV every 24 hours.

Treatment of Fungal Meningitis

Causes of fungal meningitis include the following:

Immune compromise is a predisposing factor in many of these cases and is often a consideration in the selection of treatment regimens.

Cryptococcal meningitis

Cryptococcal meningitis is a major opportunistic infection in AIDS patients. For initial therapy in these cases, administer amphotericin B (0.7-1 mg/kg/day IV) for at least 2 weeks, with or without flucytosine (100 mg/kg orally), in 4 divided doses. Liposomal preparations of amphotericin B may be used in patients who either have or are predisposed to develop renal dysfunction (amphotericin B liposome 3-4 mg/kg/day or amphotericin B lipid complex 5 mg/kg/day).

Fluconazole is given for consolidation therapy (400 mg/day for 8 weeks); itraconazole is an alternative if fluconazole is not tolerated. For maintenance therapy, long-term administration of fluconazole (200 mg/day) is most effective in preventing relapse (superior to itraconazole and amphotericin B at 1 mg/kg weekly). The risk of relapse is high in patients with AIDS.

In many cases, cryptococcal meningitis is complicated by increased ICP. Measuring the opening pressure during the LP is strongly advised. Efforts should be made to reduce such pressure through repetition of LP or insertion of a lumbar drain or a shunt. Medical maneuvers, such as administration of mannitol, have also been used.

The role of newer triazoles, such as voriconazole and posaconazole, has not been investigated. Echinocandins do not have activity against cryptococcus.

In resource-limited areas, amphotericin B and fluconazole are the optimal agents for treatment of HIV-related acute cryptococcal meningitis. Hence, treatment would consist of amphotericin and flucytosine, and policy makers and national departments of health in such countries should consider adding drugs that are typically unavailable in such settings (eg, flucytosine) for HIV treatment programs.[42] (See Meningitis in HIV.)

Induction and consolidation therapy for cryptococcal meningitis in patients who do not have AIDS and are not transplant recipients involves giving amphotericin B (0.7-1 mg/kg/day) plus flucytosine (100 mg/kg/day) for at least 4 weeks. Treatment may be extended to 6 weeks in patients with neurologic complications. After this initial period, fluconazole (400 mg/day) is given for at least 8 weeks. LP is recommended after 2 weeks to document sterilization of the CSF. If the infection persists, longer induction therapy is recommended (6 weeks).

Solid-organ transplant recipients with cryptococcal meningitis should be treated with liposomal amphotericin B (3-4 mg/kg/day IV) or amphotericin B lipid complex (5 mg/kg/day IV) plus flucytosine (100 mg/kg/day in 4 divided doses) for at least 2 weeks of induction therapy. This is followed by consolidation treatment with fluconazole (400-800 mg/day orally for 8 weeks) and then maintenance treatment with fluconazole (200 mg/day orally for 6-12 months).

Coccidioides immitis

The preferred treatment for meningitis caused by C immitis is oral fluconazole (400 mg/day). Some physicians initiate therapy with a larger dose of fluconazole (as high as 1000 mg/day) or with a combination of fluconazole and intrathecal amphotericin B. Itraconazole (400-600 mg/day) has been reported to be comparably effective. Lifelong treatment is usually required. (See Coccidioidomycosis.)

Histoplasma capsulatum

The recommended treatment for H capsulatum meningitis is liposomal amphotericin B (5 mg/kg/day IV for a total of 175 mg/kg given over 4-6 weeks), followed by oral itraconazole (200-300 mg 2 or 3 times daily for at least 1 year or until the resolution of CSF abnormalities and Histoplasma antigen levels). Blood levels of itraconazole should be measured to ensure good absorption of the oral drug.

This infection is associated with a poor outcome. Approximately 20-40% of patients with meningitis succumb to the infection despite amphotericin B therapy, and 50% of responders relapse after treatment is discontinued.

Candida species

The preferred initial therapy for candidal meningitis is amphotericin B (0.7 mg/kg/day). Flucytosine (25 mg/kg every 6 hours) is usually added and adjusted to maintain serum levels of 40-60 µg/mL. Azoles may be used for follow-up therapy or suppressive treatment.

The risk of relapse is high, and the duration of treatment is arbitrary. Some recommend continuing treatment for a minimum of 4 weeks after the complete resolution of symptoms. The removal of prosthetic materials (eg, ventriculoperitoneal shunts) is a significant component of therapy in candidal meningitis associated with neurosurgical procedures.

Sporothrix schenckii

The lipid formulation of amphotericin B is the recommended initial treatment; after the patient responds, itraconazole (200 mg twice daily) is recommended as step-down therapy and should be given to complete a total of at least 12 months of therapy.[43] Using itraconazole to achieve lifelong suppression may be attempted after initial therapy with amphotericin B. Fluconazole is less active against Sporothrix than itraconazole is.

Treatment of Tuberculous Meningitis

Treatment of tuberculous meningitis with a combination of first-line drugs is advocated. The selection depends on the resistance pattern in the community and the results of susceptibility testing (once available). Isoniazid and pyrazinamide attain good CSF levels (approximating blood levels). Rifampin penetrates the blood-brain barrier less efficiently but still attains adequate CSF levels. Ethambutol and streptomycin may also be part of combination therapy.

The dosages of drugs for tuberculous meningitis are similar to those used for pulmonary tuberculosis, as follows:

The recommended duration of treatment is 9-12 months.[44]

Corticosteroid therapy is indicated for patients with stage 2 or stage 3 disease (ie, those with evidence of neurologic deficits or deterioration in mental function). The rationale lies in the reduction of inflammatory effects associated with mycobacterial killing by the antimicrobial agents. The agent usually chosen is dexamethasone; the recommended dose is 60-80 mg/day, which may be tapered gradually during a span of 6 weeks.

Treatment of Syphilitic Meningitis

The treatment of choice for neurosyphilis is aqueous crystalline penicillin G (2-4 million U/day IV every 4 hours for 10-14 days), often followed with IM penicillin G benzathine (2.4 million U). An alternative is procaine penicillin G (2.4 million U/day IM) plus probenecid (500 mg orally every 6 hours for 14 days), followed by IM benzathine penicillin G (2.4 million U). These regimens are also used for neurosyphilis in patients with HIV infection. Because penicillin G is the treatment of choice, penicillin-allergic patients should undergo penicillin desensitization.

After treatment, CSF examination is repeated regularly (eg, every 6 months) to document the success of therapy. Failure of the cell count to normalize or the serologic titers to fall may warrant retreatment.

Treatment of Parasitic Meningitis

Primary amebic meningoencephalitis (PAM), caused by N fowleri, is usually fatal. The few survivors reported in the scientific literature benefited from early diagnosis and treatment with high-dose IV and intrathecal amphotericin B or miconazole and rifampin. More recently, miltefosine has been used to treat both N fowleri acute meningitis and Acanthamoeba chronic meningitis, resulting in cure in some instances, and should be used in suspected cases.[45]

Treatment of helminthic eosinophilic meningitis (such as that caused by A cantonensis or G spinigerum) is largely supportive. It includes adequate analgesia, therapeutic CSF aspiration, and the use of anti-inflammatory agents, such as corticosteroids. Anthelmintic therapy may be contraindicated, because clinical deterioration and death may occur as a consequence of severe inflammatory reactions to the dying worms.

Treatment of Lyme Meningitis

Ideally, neurologic complications of Lyme disease (other than Bell palsy) are treated with parenteral antibiotics. The drug of choice is ceftriaxone (2 g/day for 14-28 days). The alternative therapy is penicillin G (20 million U/day for 14-28 days). Doxycycline (100 mg orally or IV every 12 hours for 14-28 days) or chloramphenicol (1 g every 6 hours for 14-28 days) has also been used. Treatment for only 10 days has been associated with a high rate of residual symptoms.

Prevention

Vaccination and chemoprophylaxis are 2 means of preventing meningitis.

H influenzae vaccine

Vaccination against H influenzae type B (Hib) is strongly recommended in susceptible individuals (though there is no standard recommendation for H influenzae vaccination in adults). Vaccination against S pneumoniae is also strongly encouraged for susceptible individuals, including people older than 65 years and individuals with chronic cardiopulmonary illnesses. It is not known whether the adult use of conjugate pneumococcal vaccine decreases the incidence of S pneumoniae meningitis.

N meningitidis serogroups A, C, Y, and W-135 vaccine

Vaccinations against encapsulated bacterial organisms (eg, S pneumoniae and N meningitidis) are encouraged for people with functional or structural asplenia. Vaccinations should always be administered expeditiously to individuals who undergo splenectomy.

Vaccination with quadrivalent meningococcal polysaccharide vaccine should be offered to all high-risk populations, including those who have underlying immune deficiencies, those who travel to hyperendemic areas and epidemic areas, and those who do laboratory work that involves routine exposure to N meningitidis. College students who live in dormitories or residence halls are at modest risk; they should be informed about the risk and offered vaccination.

One vaccine protects against 4 strains of N meningitidis. As of February 2008, the CDC Advisory Committee on Immunization Practices (ACIP) no longer recommends routine immunization of children with this vaccine, but the ACIP continues to recommend routine immunization of teenagers and all children or adults at increased risk.[46]

In 2010, the ACIP issued updated recommendations for the use of meningococcal conjugate vaccines. Two recommendations focus on the routine vaccination of adolescents and on a primary series of vaccinations of persons aged 2-55 years with certain risk factors for meningococcal infection.[47]

Regarding the routine use of vaccines in adolescents, the 2010 CDC-ACIP guidelines specifically recommend 1 dose of meningococcal conjugate vaccine, preferably starting at 11 or 12 years. A booster dose should be given at age 16 years. If the primary dose was at age 13-15 years, the booster can be given at age 16-18 years. No booster is needed if the primary dose was given at age 16 years or later.[47]

Regarding specific recommendations for individuals with certain risk factors for meningococcal infection, the ACIP stated that HIV-infected individuals aged 11-18 years should be given a primary series of 2 doses, 2 months apart. This should be followed by a booster dose administered at age 16 years (if the primary dose was at age 11 or 12) or at age 16-18 years (if the primary dose was at age 13-15 years). No booster is needed if the primary dose was given at age 16 years or later.[47]

Persons aged 2-55 years who have persistent complement component deficiency or asplenia (functional or anatomic) should be given a primary series of 2 doses, 2 months apart, followed by a booster dose every 5 years. If a 1-dose primary series was given, the booster dose should be given as soon as possible, then every 5 years thereafter.[47]

In persons aged 2-55 years with a protracted increased risk for exposure to meningitis, the 2010 ACIP guidelines recommend a 1-dose primary series. The booster dose should be given after 3 years for children aged 2-6 years and after 5 years for persons aged 7 years or older, if the person remains at increased risk.[47]

N meningitidis serogroup B vaccine

According to the CDC, in 2012, approximately 500 cases of meningococcal disease were reported; of those, 160 resulted from serogroup B.

In October 2014, the FDA approved the first meningococcal vaccine for serogroup B (Trumenba) under the breakthrough therapy designation and accelerated approval regulatory pathways. Recent outbreaks of serogroup B meningococcal disease on a few college campuses have heightened concerns for this potentially deadly disease.

Approval was based on 3 randomized trials conducted in the United States and Europe in about 2800 adolescents. Among participants who were given 3 doses of the vaccine, 82% developed antibodies against 4 different N meningitidis serogroup B strains representative of those that cause serogroup B meningococcal disease in the United States compared with less than 1% before vaccination.[48]

In January 2015, a second meningococcal serogroup B vaccine was approved (Bexsero).[49]

Pneumococcal vaccine

The ACIP recommends administration of 13-valent pneumococcal polysaccharide-protein conjugate vaccine as part of routine childhood immunization.[50] The ACIP recommends targeted use of the 23-valent pneumococcal polysaccharide vaccine (PPSV23, formerly PPV23) in children aged 2-18 years with underlying medical conditions that increase the risk of pneumococcal disease or complications. Vaccination against measles and mumps effectively eliminates aseptic meningitis syndrome caused by these pathogens. In September 2014, the CDC recommended that all adults aged 65 years or older receive both PCV13 (13-valent pneumococcal conjugate vaccine) and PPSV23 (23-valent pneumococcal polysaccharide vaccine) as part of routine vaccination.[51]

Chemoprophylaxis

After exposure to an index case involving H influenzae, N meningitidis, or S pneumoniae, temporary nasopharyngeal carriage of the organism is typical. An association between carriage and the risk of disease has been described, especially for N meningitidis and H influenzae. This is the basis for the recommendations on chemoprophylaxis. However, such prophylaxis does not treat incubating invasive disease; accordingly close monitoring of individuals at highest risk is crucial.

To eliminate nasopharyngeal carriage of Hib and to decrease invasion of colonized susceptible individuals, rifampin (20 mg/kg/day for 4 days) is given. The index patient may need chemoprophylaxis if the administered treatment does not eliminate carriage.

Prophylaxis is suggested for contacts of persons with meningococcal meningitis (eg, household contacts, daycare center members who eat and sleep in the same dwelling, close contacts in military barracks or boarding schools, and medical personnel performing mouth-to-mouth resuscitation). Rifampin (600 mg PO every 12 hours for 2 days) can rapidly eradicate the carrier stage, and the prophylaxis persists for as long as 10 weeks after treatment.

Alternative agents for adults include ceftriaxone (250 mg IM in a single dose); this agent is also the safest choice in pregnant patients. Ceftriaxone has been shown to eradicate the carrier state for 14 days. Ciprofloxacin (500-750 mg in a single dose) is also effective.

Consultations

Consultation with an infectious diseases specialist is indicated. Consultation with a neurosurgeon is indicated in patients with any of the following:

Long-Term Monitoring

Vigilant surveillance for the development of complications is required in patients with meningitis. Seizure precautions are indicated, especially for patients with impaired mental function. Proper isolation precautions are indicated in cases of invasive meningococcal disease.

Patients must be monitored for potential adverse effects of medications, such as hypersensitivity reactions, cytopenia, or liver dysfunction. Drug-level monitoring may be needed for some antibiotics (eg, vancomycin and the aminoglycosides).

Infectious Diseases Society of America Guidelines on Healthcare-Associated Ventriculitis and Meningitis

Diagnosis

IDSA guidelines on the diagnosis of healthcare-associated ventriculitis and meningitis are as follows:[52]

Treatment

IDSA guidelines on the treatment of healthcare-associated ventriculitis and meningitis are as follows:[52]

Medication Summary

Begin empiric antibiotic coverage according to age and presence of overriding physical conditions. Empiric therapy also depends on prevalence of cephalosporin-resistant S pneumoniae (DRSP). In the United States, prevalence is considered high (>2-5%). Patients with severe penicillin (and presumed cephalosporin) allergies often require alternative therapy.

Trimethoprim-sulfamethoxazole (Bactrim, Bactrim DS, Septra DS, Sulfatrim)

Clinical Context:  Trimethoprim and sulfamethoxazole work together to inhibit bacterial synthesis of tetrahydrofolic acid. Trimethoprim prevents the formation of tetrahydrofolic acid by binding to bacterial dihydrofolate reductase. Sulfamethoxazole inhibits bacterial synthesis of dihydrofolic acid by competing with para-aminobenzoic acid, inhibiting folic acid synthesis. This results in inhibition of bacterial replication.

Class Summary

Empiric antimicrobial therapy should cover all likely pathogens in the context of this clinical setting. Trimethoprim-sulfamethoxazole (TMP-SMX) is effective against many aerobic gram-positive and gram-negative bacteria, but its use in bacterial meningitis is limited to patients with Listeria monocytogenes meningitis who have a penicillin allergy.

Doxycycline (Doryx, Adoxa, Doxy 100, Monodox, Oracea)

Clinical Context:  Doxycycline can be administered twice daily and is available in both intravenous (IV) and oral formulations. It is less likely to cause photosensitivity than other tetracyclines are. The maximum serum concentration of an IV dose of doxycycline occurs within 30 minutes of administration. The use of doxycycline in meningitis is limited to cases of Brucella or rickettsial meningitis.

Class Summary

Tetracyclines inhibit protein synthesis and, therefore, bacterial growth by binding with 30S and possibly 50S ribosomal subunits of susceptible bacteria. They are broad-spectrum bacteriostatic antibiotics that are used to treat infections caused by many gram-positive and gram-negative bacteria. They are contraindicated in children younger than 8 years of age, because they can cause tooth discoloration and bone growth retardation.

Meropenem (Merrem IV)

Clinical Context:  A broad-spectrum carbapenem antibiotic, meropenem inhibits cell wall synthesis and has bactericidal activity. It is effective against most gram-positive and gram-negative bacteria. Compared with imipenem, meropenem has slightly increased activity against gram-negative organisms and slightly decreased activity against staphylococci and streptococci. It also has limited activity against highly-penicillin-resistant S pneumoniae isolates.[43]

Class Summary

Carbapenems inhibit bacterial cell wall synthesis by binding to penicillin-binding proteins. Carbapenems, including meropenem, can be used for the treatment of meningitis.

Ciprofloxacin (Cipro, Cipro XR)

Clinical Context:  Quinolones have broad activity against gram-positive and gram-negative aerobic organisms. Ciprofloxacin has no activity against anaerobes. Ciprofloxacin has an off-label indication for prophylaxis against Neisseria meningitidis meningitis after close contact with an infected person.

Moxifloxacin (Avelox)

Clinical Context:  Quinolones have broad activity against gram-positive and gram-negative aerobic organisms. Infectious Diseases Society of America guidelines recommend moxifloxacin plus vancomycin as an alternative to third-generation cephalosporins in meningitis caused by penicillin- and ceftriaxone-resistant S pneumoniae strains.[17]

Class Summary

Fluoroquinolones inhibit bacterial DNA synthesis and, consequently, growth by inhibiting DNA gyrase and topoisomerases, which are required for replication, transcription, and translation of genetic material. The use of fluoroquinolones is not recommended in patients with myasthenia gravis.

Second-generation fluoroquinolones, such as gatifloxacin and moxifloxacin, have excellent cerebrospinal fluid (CSF) penetration, and animal models suggest that they are effective in penicillin- and ceftriaxone-resistant pneumococcal meningitis. (Clinical trial data are available only for trovafloxacin, which has been removed from the market.)

Chloramphenicol

Clinical Context:  Chloramphenicol is effective against gram-negative and gram-positive bacteria. It can be used as a substitute in the treatment of a meningococcal infection in penicillin-allergic patients. Worldwide, however, meningococcal strains have shown increasing resistance to chloramphenicol, and patients with pneumococcal meningitis have poor outcomes with chloramphenicol.

Class Summary

Chloramphenicol inhibits bacterial protein synthesis by binding to the 50S ribosomal subunit.

Vancomycin

Clinical Context:  Vancomycin is a glycopeptide antibiotic that is active against staphylococci, streptococci, and other gram-positive bacteria. It exerts antibacterial activity by inhibiting biosynthesis of peptidoglycan and is the drug of choice for highly penicillin-resistant and ceftriaxone-resistant S pneumoniae and methicillin-resistant Staphylococcus aureus (MRSA). It is a component of empiric first-line therapy for meningitis associated with central nervous system (CNS) shunts.

Because of poor CSF penetration, a higher dose of vancomycin is required for meningitis than for other infections. In patients with renal impairment, the dose is adjusted on the basis of the creatinine clearance.

Class Summary

Vancomycin inhibits bacterial cell wall synthesis by blocking glycopeptide polymerization. It is indicated for many infections caused by gram-positive bacteria.

Gentamicin

Clinical Context:  Although newer antibiotics are available, aminoglycosides such as gentamicin remain significant in treating severe infections. Aminoglycosides inhibit protein synthesis by irreversibly binding to the 30S ribosomal subunit. In meningitis or gram-negative meningitides, it must be administered intrathecally because of its poor CNS penetration. Dosing regimens are numerous; the dose is adjusted on the basis of the creatinine clearance and changes in the volume of distribution.

Streptomycin

Clinical Context:  Streptomycin has bactericidal action and inhibits bacterial protein synthesis. Susceptible organisms include Mycobacterium tuberculosis, Pasteurella pestis, Francisella tularensis, Haemophilus influenzae, Haemophilus ducreyi, donovanosis (granuloma inguinale), Brucella species, Klebsiella pneumoniae, Escherichia coli, Proteus species, Aerobacter species, Enterococcus faecalis, and Streptococcus viridans (in endocarditis, with penicillin). Streptomycin is always given as part of a total antituberculosis regimen.

Class Summary

Aminoglycosides primarily act by binding to 16S ribosomal RNA within the 30S ribosomal subunit. They have mainly bactericidal activity against susceptible aerobic gram-negative bacilli.

Ampicillin

Clinical Context:  A bactericidal beta-lactam antibiotic, ampicillin inhibits cell wall synthesis by interfering with peptidoglycan formation. The drug is indicated for L monocytogenes and Streptococcus agalactiae (group B streptococcus [GBS]) meningitis, usually in combination with gentamicin

Class Summary

Ampicillin is a second-generation penicillin that is active against many strains of E coli, Proteus mirabilis, Salmonella, Shigella, and H influenzae.

Penicillin G aqueous (Crystapen, Penicillin G potassium, Penicillin G sodium)

Clinical Context:  A beta-lactam antibiotic, penicillin G inhibits bacterial cell wall synthesis, resulting in bactericidal activity against susceptible microorganisms. It is active against many gram-positive organisms and is the drug of choice for syphilitic meningitis and susceptible organisms (eg, N meningitidis and penicillin-susceptible S pneumoniae).

Class Summary

Penicillins are highly active against gram-positive organisms.

Ceftriaxone (Rocephin)

Clinical Context:  Ceftriaxone is a third-generation cephalosporin with broad-spectrum gram-negative activity. It has lower efficacy against gram-positive organisms but excellent activity against susceptible pneumococcal organisms. It exerts an antimicrobial effect by interfering with the synthesis of peptidoglycan, a major structural component of the bacterial cell wall. It is an excellent antibiotic for the empiric treatment of bacterial meningitis.

Ceftazidime (Fortaz, Tazicef)

Clinical Context:  Ceftazidime is a third-generation cephalosporin with broad-spectrum activity against gram-negative organisms, lower efficacy against gram-positive organisms, and higher efficacy against resistant organisms. By binding to 1 or more of the penicillin-binding proteins, it arrests bacterial cell wall synthesis and inhibits bacterial replication.

Cefotaxime (Claforan)

Clinical Context:  Cefotaxime is a third-generation cephalosporin that is used to treat suspected or documented bacterial meningitis caused by susceptible organisms, such as H influenzae or N meningitidis. Like other beta-lactam antibiotics, cefotaxime inhibits bacterial growth by arresting bacterial cell wall synthesis.

Class Summary

Third-generation cephalosporins are less active against gram-positive organisms than first-generation cephalosporins are. They are highly active against Enterobacteriaceae, Neisseria, and H influenzae.

Ganciclovir (Cytovene)

Clinical Context:  Ganciclovir is a synthetic guanine derivative that is active against CMV. An acyclic nucleoside analog of 2′-deoxyguanosine, it inhibits the replication of herpesviruses in vitro and in vivo. Levels of ganciclovir-triphosphate are as much as 100-fold greater in CMV-infected cells than in uninfected cells, possibly because of preferential phosphorylation of ganciclovir in virus-infected cells.

Class Summary

Ganciclovir can be used to treat cytomegalovirus (CMV) meningitis in immunocompromised hosts.

Acyclovir (Zovirax)

Clinical Context:  A prodrug activated by cellular enzymes, acyclovir inhibits the activity of herpes simplex virus 1 (HSV-1), HSV-2, and varicella-zoster virus (VZV) by competing for viral DNA polymerase and incorporation into viral DNA. Acyclovir is used in HSV meningitis.

Foscarnet (Foscavir)

Clinical Context:  Foscarnet is an organic analogue of inorganic pyrophosphate that inhibits the replication of known herpesviruses, including CMV, HSV-1, and HSV-2. It inhibits viral replication at the pyrophosphate-binding site on virus-specific DNA polymerases. Foscarnet is used to treat CMV meningitis in immunocompromised hosts at induction dosages of 60 mg/kg IV every 8 hours and maintenance dosages of 90-120 mg/kg IV every 24 hours.

Class Summary

Antiviral agents interfere with viral replication; they weaken or abolish viral activity. They can be used in viral meningitis.

Amphotericin B deoxycholate (Amphotericin B (conventional), Fungizone)

Clinical Context:  A polyene antibiotic produced by a strain of Streptomyces nodosus, amphotericin B can be fungistatic or fungicidal. It binds to sterols, such as ergosterol, in the fungal cell membrane, causing intracellular components to leak with subsequent fungal cell death. The drug is used to treat severe systemic infection and meningitis caused by susceptible fungi (ie, Candida albicans, Histoplasma capsulatum, and Cryptococcus neoformans).

Amphotericin B does not penetrate the CSF well. Intrathecal amphotericin may be needed in addition.

Amphotericin B lipid complex (Abelcet)

Clinical Context:  This agent is amphotericin B in phospholipid complexed form; it is a polyene antibiotic with poor oral availability. Amphotericin B is produced by a strain of S nodosus; it can be fungistatic or fungicidal. The drug binds to sterols (eg, ergosterol) in the fungal cell membrane, causing leakage of intracellular components and fungal cell death. Toxicity to human cells may occur via this same mechanism.

Fluconazole (Diflucan)

Clinical Context:  Fluconazole has fungistatic activity. It is a synthetic oral antifungal (broad-spectrum bistriazole) that selectively inhibits fungal cytochrome P450 and sterol C-14 alpha-demethylation, which prevents conversion of lanosterol to ergosterol, thereby disrupting cellular membranes.

Flucytosine (Ancobon)

Clinical Context:  Flucytosine is converted to fluorouracil after penetrating fungal cells and inhibits RNA and protein synthesis by competing with uracil. It is active against candidal and cryptococcal species and is used in combination with amphotericin B.

Itraconazole (Sporanox, Onmel)

Clinical Context:  Itraconazole has fungistatic activity. It is a synthetic triazole antifungal agent that slows fungal cell growth by inhibiting cytochrome P450-dependent synthesis of ergosterol, a vital component of fungal cell membranes.

Class Summary

Antifungal agents are used in the management of infectious diseases caused by fungi.

Rifampin (Rifadin)

Clinical Context:  Rifampin is used in combination with other antituberculous drugs. It inhibits DNA-dependent bacterial, but not mammalian, RNA polymerase. Cross-resistance may occur.

Isoniazid

Clinical Context:  Isoniazid is a first-line antituberculous drug that is used in combination with other antituberculous drugs to treat meningitis. It is usually administered for at least 12-24 months. Addition of pyridoxine (6-50 mg/day) is recommended if peripheral neuropathies secondary to isoniazid therapy develop.

Pyrazinamide

Clinical Context:  Pyrazinamide is a pyrazine analogue of nicotinamide; it may be bacteriostatic or bactericidal against Mycobacterium tuberculosis, depending on the drug concentration attained at the site of infection. Pyrazinamide's mechanism of action is unknown.

Ethambutol (Myambutol)

Clinical Context:  Ethambutol diffuses into actively growing mycobacterial cells (eg, tubercle bacilli). It impairs cell metabolism by inhibiting the synthesis of 1 or more metabolites, which in turn causes cell death. No cross-resistance has been demonstrated. Mycobacterial resistance is frequent with previous therapy.

Ethambutol is used in combination with second-line drugs that have not been administered previously. It is administered every 24 hours until permanent bacteriologic conversion and maximal clinical improvement are observed. Absorption is not significantly altered by food.

Class Summary

These agents are used in the management of mycobacterial disease in combination with other antituberculous agents.

Meningococcal (group A C Y and W-135) diphtheria conjugate vaccine (Menactra, Menveo)

Clinical Context:  This vaccine is composed of capsular polysaccharide antigens (groups A, C, Y, and W-135) of N meningitidis. Meningococcal vaccine may be used to prevent and control outbreaks of serogroup C meningococcal disease, according to Centers for Disease Control and Prevention (CDC) guidelines. It induces formation of bactericidal antibodies to meningococcal antigens.

The vaccine is used for active immunization against invasive meningococcal disease caused by inclusive serogroups. Although the vaccine induces antibody response for serogroup A in individuals as young as age 3 months, it is poorly immunogenic for serogroup C in recipients who are younger than age 18-24 months.

Meningococcal group B vaccine (Trumenba, Bexsero)

Clinical Context:  The vaccine is administered as a 3-dose series at months 0, 2, and 6 (Trumenba) or a 2-dose series given at least 1 month apart (Bexsero). It induces production of bactericidal antibodies directed against the capsular polysaccharides of serogroup B. It is indicated for active immunization to prevent invasive meningococcal disease caused by Neisseria meningitidis serogroup B in individuals aged 10 through 25 years.

Pneumococcal polysaccharide vaccine polyvalent (Pneumovax 23)

Clinical Context:  This vaccine contains capsular polysaccharides of 23 pneumococcal types, which constitute 98% of pneumococcal disease isolates.

Pneumococcal vaccine 13-valent (Prevnar 13)

Clinical Context:  Capsular polysaccharide vaccine against 13 strains of S pneumoniae conjugated to nontoxic diphtheria protein. Includes serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F.

Class Summary

Inactivated bacterial vaccines are used to induce active immunity against pathogens responsible for meningitis.

Dexamethasone (Baycadron)

Clinical Context:  Dexamethasone has many pharmacologic benefits, such as stabilizing cell and lysosomal membranes. It increases surfactant synthesis, increases serum vitamin A concentrations, and inhibits prostaglandin and proinflammatory cytokines (eg, tumor necrosis factor alpha [TNF-α], interleukin [IL]-6, IL-2, and interferon gamma).

The timing of dexamethasone administration is crucial. If this agent is used, it should be administered before or with the first dose of antibacterial therapy, so as to counteract the initial inflammatory burst consequent to antibiotic-mediated bacterial killing. A more intense inflammatory reaction has been documented after the massive bacterial killing induced by antibiotics.

Class Summary

The use of steroids has been shown to improve overall outcome for patients with certain types of bacterial meningitis, such as H influenzae, tuberculous, and pneumococcal meningitis. If steroids are given, they should be administered before or during the administration of antimicrobial therapy.

Mannitol (Osmitrol)

Clinical Context:  Mannitol may reduce subarachnoid-space pressure by creating an osmotic gradient between CSF in the arachnoid space and plasma. Doses of 1 g/kg IV have been used.

Class Summary

Mannitol produces osmotic diuresis and reduces intracranial pressure (ICP).

Furosemide (Lasix)

Clinical Context:  Furosemide is a loop diuretic that increases the excretion of water by interfering with the chloride-binding cotransport system, which, in turn, inhibits sodium and chloride reabsorption in the ascending loop of Henle and distal renal tubule. The proposed mechanisms for furosemide in lowering ICP include (1) lowering cerebral sodium uptake, (2) affecting water transport into astroglial cells by inhibiting the cellular membrane cation-chloride pump, and (3) decreasing CSF production by inhibiting carbonic anhydrase.

Class Summary

Loop diuretics are used to reduce ICP and treat cerebral edema.

Phenytoin (Dilantin, Phenytek)

Clinical Context:  Phenytoin works on the motor cortex, where it may inhibit the spread of seizure activity. The activity of brainstem centers responsible for the tonic phase of grand mal seizures may also be inhibited. Dosing should be individualized. Doses of 15 mg/kg have been used.

Class Summary

Anticonvulsants are used to help aggressively control seizures (if present) in acute meningitis, because seizure activity increases ICP.

Phenobarbital

Clinical Context:  Phenobarbital elevates the seizure threshold, limits the spread of seizure activity, and is a sedative. Doses of 5-10 mg/kg have been recommended.

Class Summary

Phenobarbital elevates the seizure threshold, limits the spread of seizure activity, and is a sedative. Doses of 5-10 mg/kg have been recommended.

Lorazepam (Ativan)

Clinical Context:  Lorazepam is a sedative hypnotic with a short onset of effect and a relatively long half-life. By increasing the action of gamma-aminobutyric acid (GABA), which is a major inhibitory neurotransmitter in the brain, it may depress all levels of the CNS, including the limbic system and the reticular formation. Doses of 0.1 mg/kg IV have been used to control seizures.

Class Summary

Anticonvulsants are used to help aggressively control seizures (if present) in acute meningitis, because seizure activity increases ICP.

What is meningitis?What are the signs and symptoms of bacterial and viral meningitis?What should be the medical history focus when meningitis is suspected?Which symptoms suggest enteroviral infection when meningitis is suspected?What are signs of meningitis in infants?What should a physical exam for meningitis include?Which exams should be performed in chronic meningitis?What are the signs of aseptic meningitis syndrome?What are the diagnostic challenges in suspected meningitis?Which blood studies are useful in the diagnosis of meningitis?Which lab tests should be ordered in suspected meningitis?What are the initial treatment measures that should be taken in suspected meningitis?What are the treatment options for bacterial meningitis?Which complications of acute bacterial meningitis must be treated initially?In which types of meningitis is therapy dictated by the etiologic pathogen (infectious agent)?What are the categories of infections of the central nervous system (CNS)?Which areas of the brain and spinal cord are affected by meningitis?What are risk factors for meningitis?What is the clinical presentation of meningitis?Which anatomical regions does meningitis affect?What causes meningitis?What is the mortality rate associated with bacterial meningitis?How has the emergence of antibiotic-resistant bacteria changed treatment approaches for meningitis?Which conditions may evolve from bacterial meningitis?What are the common noninfectious causes of meningitis?What are the subtypes of acute bacterial meningitis?What is chronic meningitis?How is acute meningitis differentiated from subacute or chronic meningitis?How are fungal and parasitic meningitis classified?What is aseptic meningitis?Is aseptic meningitis reclassified once a cause is identified?What is the most likely pathogenesis of meningitis?Which pathways allow an infectious agent (pathogen) access to the central nervous system (CNS) in meningitis?Meningitis infectious agents are spread most often through which pathway to the central nervous system (CNS)?What are the less common ways meningitis infectious agents are transmitted to the central nervous system (CNS)?How are meningitis infectious agents transmitted to a newborn?How do meningitis pathogens travel from the middle ear to the meninges?What is the role of the blood-brain barrier in the pathogenesis of meningitis?What is the disease course of untreated bacterial meningitis?What perpetuates the infectious process in bacterial meningitis?What is the pathophysiology of increased intracranial pressure (ICP) in meningitis?What is the disease course if increased intracranial pressure (ICP) due to meningitis is left untreated?What is the disease course if cerebral edema due to meningitis is left untreated?Which proinflammatory molecules (proteins) have a role in the pathogenesis of meningitis?What is the role of cytokines in the pathogenesis of meningitis?What is the role of secondary proinflammatory mediators in the pathogenesis of meningitis?What is the cause of profound neutrophilic pleocytosis in meningitis?What is the role of pattern recognition receptors in the pathogenesis of meningitis?What is the role of bacterial seeding in the pathogenesis of meningitis?How do infectious agents gain access to the subarachnoid space in meningitis?What causes aseptic meningitis?What are causes of meningitis?Does HIV infection increase the risk of meningitis?What are viral causes of meningitis?What are the common infectious agents (pathogens) of meningitis in patients with trauma or who are undergoing neurosurgery?What causes pachymeningitis (perimeningitis)?What is the role of Haemophilus influenza (H influenza) (type b) (Hib) in the development of meningitis?What does the presence of Haemophilus influenza (H influenza) in adults with meningitis suggest?What is the role of Streptococcus pneumoniae (S pneumoniae) in the development of meningitis?What are the risk factors for developing Streptococcus pneumoniae (S pneumoniae) (pneumococcal) meningitis?What is the role of Streptococcus agalactiae (group B Streptococcus) (GBS) in the transmission of neonatal meningitis?What are the risk factors for Streptococcus agalactiae (group B Streptococcus) (GBS) meningitis in adults?What is the role of Neisseria meningitidis (N meningitides) in the development of meningococcal meningitis?What are risk factors for developing meningococcal meningitis?What is the role of Listeria monocytogenes (L monocytogenes) in the development of meningitis?Which groups are at risk for Listeria monocytogenes (L monocytogenes) meningitis?Which aerobic gram-negative bacilli (Enterobacteriaceae) are etiologic agents of meningitis?What are risk factors for developing meningitis caused by gram-negative bacilli (Enterobacteriaceae)?What are risk factors for developing staphylococcal meningitis?What is the most common cause of aseptic meningitis in children and adults?How are enteroviruses classified?How are enteroviruses spread?How common are nonpolio enteroviruses (NPEVs) as a cause of viral meningitis?What is the incidence of aseptic meningitis due to echovirus 30 (EV30)?Which Herpesviridae (herpesviruses) cause meningitis?Which arthropod-borne viruses cause meningitis?Which virus causes California encephalitis?How is lymphocytic choriomeningitis virus (LCMV) transmitted?How common is aseptic meningitis caused by the mumps virus?When should HIV infection be suspected as the cause of aseptic meningitis?Which adenovirus serotypes are etiologic agents of meningoencephalitis?When should Toscana virus (TOSV) meningitis or encephalitis be suspected?What causes chronic meningitis?What is the role of Brucellae in the development of meningitis?What are the risk factors for developing brucellosis (Brucella meningitis)?What is the role of Mycobacterium tuberculosis (M tuberculosis) in the development of meningitis?When should tuberculous meningitis be suspected?How is Treponema pallidum (T pallidum) transmitted?What is the role of Borrelia burgdorferi (B burgdorferi) (Lyme disease) in the development of meningitis?What is the role of Cryptococcus neoformans (C neoformans) in the development of meningitis?What are the risk factors for developing coccidioidal meningitis?What are the risk factors for Blastomyces dermatitidis (B dermatitidis) infection and how likely is it to cause meningitis?What is the role of Histoplasma capsulatum (H capsulatum) in the development of meningitis?What are the risk factors for developing Candida meningitis?What are the risk factors for developing Sporothrix schenckii (S schenckii) meningitis?How is primary amebic meningoencephalitis (PAM) transmitted?What are the forms of primary amebic meningoencephalitis (PAM) and what are their presentations?What are Acanthamoeba and Balamuthia granulomatous amebic encephalitis?What is the role of Angiostrongylus cantonensis (A cantonensis) in the development of eosinophilic meningitis?What is the role of Gnathostoma spinigerum (G spinigerum) in the development of eosinophilic meningoencephalitis?What is the role of Baylisascaris procyonis (B procyonis) in the development of eosinophilic meningoencephalitis?What is the role of injuries, congenital malformations, and surgeries in the development of meningitis?Why is the incidence of meningitis higher in developing countries than in the US?What is the incidence of bacterial meningitis in the US?In what parts of the world is meningococcal meningitis endemic?What is the incidence of neonatal bacterial meningitis?Which preventive measures have decreased the incidence of bacterial meningitis in the US?Which preventive measures have decreased the incidence of pediatric bacterial meningitis in the US?What age groups are at highest risk for developing acute bacterial meningitis?How does age affect risk of meningitis from specific etiologic agents?Is bacterial meningitis more common in females or males?What is the mortality rate associated with pneumococcal meningitis?What is the incidence of aseptic meningitis?What factors influence the infection rates of aseptic meningitis?In addition to aseptic meningitis, what other disorders are caused by West Nile virus infection?Which less-common arboviruses have caused aseptic meningitis in the US?What is the epidemiology of lymphocytic choriomeningitis (LCM) virus infections?What is the global distribution of fungal pathogens that cause meningitis?What is the global distribution of parasites that cause meningitis?What is the global distribution of Brucella chronic meningitis?What is the global incidence of Mycobacterium tuberculosis (M tuberculosis) infection?What is the global distribution of Borrelia burgdorferi (B burgdorferi) (Lyme disease)?What is the global distribution of Cryptococcus neoformans (C neoformans)?What is the global distribution of Coccidioides immitis (C immitis)?What is the global distribution of Sporothrix schenckii (S schenckii)?Which presentations of meningitis increase the risk for neurologic sequelae or death?What are negative prognostic factors in adults with bacterial meningitis?What are the serious complications of bacterial meningitis?What are the delayed complications of pneumococcal meningitis?How common are seizures in meningitis?What is the incidence of neurologic complications of bacterial meningitis?What is mortality rate associated with bacterial meningitis?What is the prognosis of meningitis caused by opportunistic pathogens?Which pathogens cause the highest mortality and morbidity in bacterial meningitis?What is the prognosis for meningococcal meningitis versus pneumococcal meningitis?What is the prognosis for viral meningitis?What patient information (education) should be provided and to whom regarding meningitis preventive measures?Which atypical symptoms of meningitis may develop in infants?What are symptoms of meningitis?How soon do symptoms of bacterial meningitis develop?What symptoms may precede viral meningitis?How common are seizures in bacterial meningitis?Which patient groups are more likely to present with atypical symptoms of meningitis?Which factors should be assessed in cases of meningitis to help determine etiology?What should be the focus of the medical history in suspected meningitis?How common is bacterial meningitis following antibiotic use?Does the presence of a ventriculoperitoneal shunt or history of cranial surgery increase the risk of bacterial meningitis?Are alcoholism and cirrhosis risk factors for meningitis?What role does geographic location and travel history have in the identification of meningitis etiology?What roles do season and temperature have in the identification of meningitis etiology?What is the classic presentation of meningitis?How does the clinical presentation of acute bacterial meningitis differ from that of subacute bacterial meningitis?What are possible systemic findings of meningitis?What are expected physical findings in viral meningitis?Which etiologies of meningitis may present with nonblanching petechiae and cutaneous hemorrhages?What is the typical presentation of meningitis in infants?What are the focal neurologic signs of meningitis?When is lumbar puncture (LP) indicated in suspected meningitis?Which systemic findings on physical exam provide clues to the etiology of meningitis?Which physical exam findings suggest chronic meningitis?What are the presentation and clinical stages of chronic tuberculous meningitis?What is the presentation of syphilitic meningitis?What is the presentation of Lyme meningitis?What is the presentation of Cryptococcus neoformans (C neoformans) meningitis?What is the presentation of coccidioidal meningitis?What is the presentation of meningitis caused by Blastomyces dermatitidis (B dermatitidis) or Histoplasma capsulatum (H capsulatum)?What is the presentation of helminthic eosinophilic meningitis?What is the presentation of aseptic meningitis?What are immediate complications of meningitis?What disorders are caused by brain parenchymal damage in bacterial meningitis?What are the delayed complications of meningitis?Is cerebral edema a common complication of meningitis?What causes cranial nerve palsy and cerebral infarction in meningitis?How does cerebritis develop in meningitis?What are the risk factors for development of subdural effusion in meningitis?How does ventriculitis develop in meningitis and how common is it?How does ventriculomegaly develop in meningitis?Which disorders should be considered in differential diagnoses of meningitis?What are the differential diagnoses for Meningitis?What are the diagnostic challenges of meningitis?Why should acute bacterial meningitis be the first diagnosis considered in patients with headache, neck stiffness, fever, and altered mental status?Why should lumbar puncture be performed whenever meningitis is suspected?When is a CT scan of the head indicated in suspected meningitis?What lab tests should be performed in suspected meningitis?What does evidence of pneumonia on initial chest X-ray indicate in suspected meningitis?Which blood tests are useful in suspected bacterial meningitis?When are cultures most useful for diagnosing meningitis?When is latex agglutination or counterimmunoelectrophoresis (CIE) indicated in the evaluation of suspected meningitis?What is the role of polymerase chain reaction (PCR) testing in the diagnosis of meningitis?Which syphilis screening tests should be performed in the evaluation of suspected meningitis?What is the role of serum procalcitonin (PCT) testing in the diagnosis of meningitis?What does elevated opening pressure in lumbar puncture (LP) and cerebrospinal fluid (CSF) indicate in meningitis?What does cerebrospinal fluid (CSF) cell count indicate in meningitis?Why are four tubes of cerebrospinal fluid (CSF) sample drawn in suspected meningitis and where is each sent?What is the importance of tumor necrosis factor alpha (TNF-?), interleukin (IL)-1, and other cytokines in suspected bacterial meningitis?What are the cerebrospinal fluid (CSF) characteristics in acute bacterial meningitis?What are cerebrospinal fluid (CSF) characteristics in viral meningitis?What are cerebrospinal fluid (CSF) characteristics in fungal meningitis?Is fungal serology or cerebrospinal fluid (CSF) culture more commonly used in the workup of fungal meningitis?Can fungal infection in the blood be used to diagnose fungal meningitis?What are the cerebrospinal fluid (CSF) characteristics of primary amebic meningoencephalitis (PAM)?What are the cerebrospinal fluid (CSF) characteristics of Lyme meningitis?What are the cerebrospinal fluid (CSF) characteristics of tuberculous meningitis?What is the cerebrospinal fluid (CSF) glucose level in bacterial meningitis?What is the cerebrospinal fluid (CSF) protein level in bacterial meningitis?What is the sensitivity and specificity of Gram staining of cerebrospinal fluid (CSF) for bacterial meningitis?What is the role of acid-fast bacillus (AFB) stain in the diagnosis of meningitis?How often do cerebrospinal fluid (CSF) bacterial cultures or antigen assays yield the bacterial cause of meningitis?How effective are cerebrospinal fluid (CSF) culture and antigen testing in the diagnosis of cryptococcal meningitis?What tests are used to isolate Treponema pallidum (T pallidum) from cerebrospinal fluid (CSF) in syphilitic meningitis?What is the role of cerebrospinal fluid (CSF) cultures or assays in the diagnosis of Lyme meningitis?What are the roles of cerebrospinal fluid (CSF) cultures and assays in the diagnosis of tuberculous meningitis?What is the role of culture from cerebrospinal fluid (CSF) in viral meningitis?Is neuroimaging (CT scanning, MRI) used in the diagnosis of meningitis?When is cerebral herniation most likely to occur following lumbar puncture (LP) for meningitis?What are the IDSA guidelines for screening head CT scanning before lumbar puncture (LP) in adults with suspected meningitis?What neuroimaging findings suggest bacterial meningitis?What central nervous system (CNS) complications of bacterial meningitis are detected on neuroimaging?How is meningitis managed after initial treatment?What initial steps should be taken to treat suspected meningitis prior to arrival in the emergency department (ED)?Which tests should be performed first for acute meningitis?When should antimicrobial therapy be initiated for meningitis?Which systemic complications of acute bacterial meningitis should be immediately treated?How are patients monitored for systemic complications of acute bacterial meningitis?How is hyperventilation managed in intubated patients with meningitis?When is an intracranial pressure (ICP) monitor indicated in meningitis?How are seizures managed in meningitis?How is subacute meningitis treated?How is bacterial meningitis treated?What is the prevalence of penicillin resistance among Streptococcus pneumoniae (pneumococcal) strains that cause meningitis?Does treatment reduce the risk of mortality in meningitis?How should patients with bacterial meningitis be monitored during antibiotic treatment?What is the treatment for bacterial meningitis in the first month of life?What is the treatment for bacterial meningitis in infants aged 1-3 months?What is the treatment for bacterial meningitis in children aged 3 months to 7 years?What is the treatment for bacterial meningitis in children and adults aged 7-50 years?What antibiotic alternative is available for bacterial meningitis in children and adults aged 7-50 years with severe penicillin allergy?What is antibiotic treatment for bacterial meningitis in areas with a low prevalence of drug-resistant Streptococcus pneumoniae (DRSP)?What is the role of dexamethasone in the treatment of bacterial meningitis?What is the antibiotic treatment of choice for patients aged 50 years or older with meningitis?What are the IDSA guidelines for adjunctive dexamethasone in meningitis?What is the treatment for bacterial meningitis in the setting of HIV infection?Is the use of steroid therapy (dexamethasone) effective in the treatment of bacterial meningitis?What are the benefits of steroid therapy for bacterial meningitis?Is intrathecal administration of antibiotics FDA approved for the treatment of bacterial meningitis?How are intrathecal antibiotic dosages determined for bacterial meningitis?How is viral meningitis treated?How is herpes simplex (HSV) meningitis treated?How is cytomegalovirus (CMV) meningitis treated?What are the causes of fungal meningitis?How is cryptococcal meningitis treated?How is intracranial pressure (ICP) reduced in cases of cryptococcal meningitis?How is HIV-related acute cryptococcal meningitis treated?What is induction and consolidation therapy for cryptococcal meningitis?What is the treatment for solid-organ transplant recipients with cryptococcal meningitis?What is the treatment for meningitis caused by Coccidioides immitis (C immitis)?What is the treatment for Histoplasma capsulatum (H capsulatum) meningitis?What is treatment for candidal meningitis?What is the treatment for Sporothrix schenckii (S schenckii) meningitis?What is the treatment for tuberculous meningitis?When is corticosteroid therapy indicated for treatment of tuberculous meningitis?What is the treatment for syphilitic meningitis?How is parasitic meningitis treated?How is Lyme meningitis treated?How is meningitis prevented?Which patients should receive the H influenzae type B (Hib) or S pneumoniae vaccines?What vaccinations are recommended for patients with functional or structural asplenia?Who should be offered the quadrivalent meningococcal polysaccharide vaccine?What are the CDC Advisory Committee on Immunization Practices (ACIP) guidelines for the use of meningococcal conjugate vaccines?What are the CDC Advisory Committee on Immunization Practices (ACIP) guidelines for routine use of meningococcal vaccines in adolescents?What are the CDC Advisory Committee on Immunization Practices (ACIP) guidelines for use of meningococcal vaccines in individuals with HIV?What are the CDC Advisory Committee on Immunization Practices (ACIP) guidelines for use of meningococcal vaccines in individuals with persistent complement component deficiency or asplenia?What are the CDC Advisory Committee on Immunization Practices (ACIP) guidelines for persons with increased risk for exposure to meningitis?Which meningococcal vaccines for serogroup B are approved by the FDA?What are the CDC Advisory Committee on Immunization Practices (ACIP) guidelines for routine pneumococcal vaccinations?When is chemoprophylaxis for meningitis recommended?When are consultations with specialists indicated in the treatment of meningitis?How should meningitis be monitored?What are the IDSA guidelines on the diagnosis of healthcare-associated ventriculitis and meningitis?What are the IDSA guidelines on the treatment of healthcare-associated ventriculitis and meningitis?When should empiric antibiotic medications be given to treat meningitis?Which medications in the drug class Sulfonamides are used in the treatment of Meningitis?Which medications in the drug class Tetracyclines are used in the treatment of Meningitis?Which medications in the drug class Carbapenems are used in the treatment of Meningitis?Which medications in the drug class Fluoroquinolones are used in the treatment of Meningitis?Which medications in the drug class Antibiotics, Miscellaneous are used in the treatment of Meningitis?Which medications in the drug class Glycopeptides are used in the treatment of Meningitis?Which medications in the drug class Aminoglycosides are used in the treatment of Meningitis?Which medications in the drug class Penicillins, Amino are used in the treatment of Meningitis?Which medications in the drug class Penicillins, Natural are used in the treatment of Meningitis?Which medications in the drug class Cephalosporins, 3rd Generation are used in the treatment of Meningitis?Which medications in the drug class Antivirals, CMV are used in the treatment of Meningitis?Which medications in the drug class Antivirals, Other are used in the treatment of Meningitis?Which medications in the drug class Antifungals, Systemic are used in the treatment of Meningitis?Which medications in the drug class Antituberculous Agents are used in the treatment of Meningitis?Which medications in the drug class Vaccines, Inactivated, Bacterial are used in the treatment of Meningitis?Which medications in the drug class Corticosteroids are used in the treatment of Meningitis?Which medications in the drug class Diuretics, Osmotic Agents are used in the treatment of Meningitis?Which medications in the drug class Diuretics, Loop are used in the treatment of Meningitis?Which medications in the drug class Anticonvulsants, Hydantoins are used in the treatment of Meningitis?Which medications in the drug class Anticonvulsants, Barbiturates are used in the treatment of Meningitis?Which medications in the drug class Anticonvulsants, Other are used in the treatment of Meningitis?

Author

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

Disclosure: Received research grant from: Biofire<br/> Speaker for Biofire.

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; Fellow of the Royal College of Physicians, London

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.

References

  1. Mann K, Jackson MA. Meningitis. Pediatr Rev. 2008 Dec. 29(12):417-29; quiz 430. [View Abstract]
  2. Ginsberg L, Kidd D. Chronic and recurrent meningitis. Pract Neurol. 2008 Dec. 8(6):348-61. [View Abstract]
  3. Berkhout B. Infectious diseases of the nervous system: pathogenesis and worldwide impact. IDrugs. 2008 Nov. 11(11):791-5. [View Abstract]
  4. Koedel U, Klein M, Pfister HW. New understandings on the pathophysiology of bacterial meningitis. Curr Opin Infect Dis. 2010 Jun. 23(3):217-23. [View Abstract]
  5. Thigpen MC, Whitney CG, Messonnier NE, Zell ER, Lynfield R, Hadler JL, et al. Bacterial meningitis in the United States, 1998-2007. N Engl J Med. 2011 May 26. 364(21):2016-25. [View Abstract]
  6. Castelblanco RL, Lee M, Hasbun R. Epidemiology of bacterial meningitis in the USA from 1997 to 2010: a population-based observational study. Lancet Infect Dis. 2014 Sep. 14 (9):813-9. [View Abstract]
  7. Shukla B, Aguilera EA, Salazar L, Wootton SH, Kaewpoowat Q, Hasbun R. Aseptic meningitis in adults and children: Diagnostic and management challenges. J Clin Virol. 2017 Sep. 94:110-114. [View Abstract]
  8. Jaijakul S, Arias CA, Hossain M, Arduino RC, Wootton SH, Hasbun R. Toscana meningoencephalitis: a comparison to other viral central nervous system infections. J Clin Virol. 2012 Nov. 55 (3):204-8. [View Abstract]
  9. Jaijakul S, Arias CA, Hossain M, Arduino RC, Wootton SH, Hasbun R. Toscana meningoencephalitis: a comparison to other viral central nervous system infections. J Clin Virol. 2012 Nov. 55(3):204-8. [View Abstract]
  10. Hasbun R. Update and advances in community acquired bacterial meningitis. Curr Opin Infect Dis. 2019 Jun. 32 (3):233-238. [View Abstract]
  11. Thigpen, M, Rosenstein, NE, Whitney, CG. Bacterial meningitis in the United States--1998-2003. Presented at the 43rd Annual Meeting of the Infectious Diseases Society of America, San Francisco, CA. October 2005;65.
  12. West Nile Virus. Centers for Disease Control and Prevention. Available at http://www.cdc.gov/ncidod/dvbid/westnile/index.htm. Accessed: March 29, 2013.
  13. La Crosse encephalitis. Centers for Disease Control and Prevention. Available at http://www.cdc.gov/lac/. Accessed: March 29, 2013.
  14. Aronin SI, Peduzzi P, Quagliarello VJ. Community-acquired bacterial meningitis: risk stratification for adverse clinical outcome and effect of antibiotic timing. Ann Intern Med. 1998 Dec 1. 129 (11):862-9. [View Abstract]
  15. Schut ES, Brouwer MC, Scarborough M, Mai NT, Thwaites GE, Farrar JJ, et al. Validation of a Dutch risk score predicting poor outcome in adults with bacterial meningitis in Vietnam and Malawi. PLoS One. 2012. 7(3):e34311. [View Abstract]
  16. Worsøe L, Cayé-Thomasen P, Brandt CT, Thomsen J, Østergaard C. Factors associated with the occurrence of hearing loss after pneumococcal meningitis. Clin Infect Dis. 2010 Oct 15. 51(8):917-24. [View Abstract]
  17. Gallegos C, Tobolowsky F, Nigo M, Hasbun R. Delayed Cerebral Injury in Adults With Bacterial Meningitis: A Novel Complication of Adjunctive Steroids?. Crit Care Med. 2018 Aug. 46 (8):e811-e814. [View Abstract]
  18. van de Beek D, de Gans J, Spanjaard L, Weisfelt M, Reitsma JB, Vermeulen M. Clinical features and prognostic factors in adults with bacterial meningitis. N Engl J Med. 2004 Oct 28. 351(18):1849-59. [View Abstract]
  19. Thomas KE, Hasbun R, Jekel J, Quagliarello VJ. The diagnostic accuracy of Kernig's sign, Brudzinski's sign, and nuchal rigidity in adults with suspected meningitis. Clin Infect Dis. 2002 Jul 1. 35(1):46-52. [View Abstract]
  20. Moses S. Meningitis: acute bacterial meningitis. Accessed February 8, 2011. Available at http://www.fpnotebook.com/neuro/ID/Mngts.htm
  21. Ramirez-Avila L, Slome S, Schuster FL, Gavali S, Schantz PM, Sejvar J, et al. Eosinophilic meningitis due to Angiostrongylus and Gnathostoma species. Clin Infect Dis. 2009 Feb 1. 48(3):322-7. [View Abstract]
  22. Hasbun R, Abrahams J, Jekel J, Quagliarello VJ. Computed tomography of the head before lumbar puncture in adults with suspected meningitis. N Engl J Med. 2001 Dec 13. 345(24):1727-33. [View Abstract]
  23. [Guideline] Tunkel AR, Hartman BJ, Kaplan SL, Kaufman BA, Roos KL, Scheld WM, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis. 2004 Nov 1. 39(9):1267-84. [View Abstract]
  24. Salazar L, Hasbun R. Cranial Imaging Before Lumbar Puncture in Adults With Community-Acquired Meningitis: Clinical Utility and Adherence to the Infectious Diseases Society of America Guidelines. Clin Infect Dis. 2017 Jun 15. 64 (12):1657-1662. [View Abstract]
  25. Moïsi JC, Saha SK, Falade AG, Njanpop-Lafourcade BM, Oundo J, Zaidi AK, et al. Enhanced diagnosis of pneumococcal meningitis with use of the Binax NOW immunochromatographic test of Streptococcus pneumoniae antigen: a multisite study. Clin Infect Dis. 2009 Mar 1. 48 Suppl 2:S49-56. [View Abstract]
  26. Dubos F, Korczowski B, Aygun DA, Martinot A, Prat C, Galetto-Lacour A, et al. Serum procalcitonin level and other biological markers to distinguish between bacterial and aseptic meningitis in children: a European multicenter case cohort study. Arch Pediatr Adolesc Med. 2008 Dec. 162(12):1157-63. [View Abstract]
  27. Mustafa MM, Lebel MH, Ramilo O, Olsen KD, Reisch JS, Beutler B, et al. Correlation of interleukin-1 beta and cachectin concentrations in cerebrospinal fluid and outcome from bacterial meningitis. J Pediatr. 1989 Aug. 115(2):208-13. [View Abstract]
  28. Seupaul RA. Evidence-based emergency medicine/rational clinical examination abstract. How do I perform a lumbar puncture and analyze the results to diagnose bacterial meningitis?. Ann Emerg Med. 2007 Jul. 50(1):85-7. [View Abstract]
  29. Hughes S. Blood assay used for CSF detection in fungal meningitis. Medscape Medical News. Available at http://at http://www.medscape.com/viewarticle/781179. Accessed: April 3, 2013.
  30. Cohn KA, Thompson AD, Shah SS, Hines EM, Lyons TW, Welsh EJ, et al. Validation of a clinical prediction rule to distinguish Lyme meningitis from aseptic meningitis. Pediatrics. 2012 Jan. 129(1):e46-53. [View Abstract]
  31. Sulaiman T, Salazar L, Hasbun R. Acute versus subacute community-acquired meningitis: Analysis of 611 patients. Medicine (Baltimore). 2017 Sep. 96 (36):e7984. [View Abstract]
  32. Gilbert DN, Moellering RC Jr, Sande MA. Antimicrobial Therapy. In: Sanford Guide to Antimicrobial Therapy. 33rd ed. March 15, 2003.
  33. van de Beek D, Brouwer MC, Thwaites GE, Tunkel AR. Advances in treatment of bacterial meningitis. Lancet. 2012 Nov 10. 380(9854):1693-702. [View Abstract]
  34. Mera RM, Miller LA, Amrine-Madsen H, Sahm DF. Impact of new Clinical Laboratory Standards Institute Streptococcus pneumoniae penicillin susceptibility testing breakpoints on reported resistance changes over time. Microb Drug Resist. 2011 Mar. 17(1):47-52. [View Abstract]
  35. Gouveia EL, Reis JN, Flannery B, Cordeiro SM, Lima JB, Pinheiro RM, et al. Clinical outcome of pneumococcal meningitis during the emergence of pencillin-resistant Streptococcus pneumoniae: an observational study. BMC Infect Dis. 2011 Nov 21. 11:323. [View Abstract]
  36. Brouwer MC, Heckenberg SG, de Gans J, Spanjaard L, Reitsma JB, van de Beek D. Nationwide implementation of adjunctive dexamethasone therapy for pneumococcal meningitis. Neurology. 2010 Oct 26. 75(17):1533-9. [View Abstract]
  37. van de Beek D, de Gans J, McIntyre P, Prasad K. Steroids in adults with acute bacterial meningitis: a systematic review. Lancet Infect Dis. 2004 Mar. 4(3):139-43. [View Abstract]
  38. Brouwer MC, McIntyre P, de Gans J, Prasad K, van de Beek D. Corticosteroids for acute bacterial meningitis. Cochrane Database Syst Rev. 2010 Sep 8. CD004405. [View Abstract]
  39. van de Beek D, Farrar JJ, de Gans J, Mai NT, Molyneux EM, Peltola H, et al. Adjunctive dexamethasone in bacterial meningitis: a meta-analysis of individual patient data. Lancet Neurol. 2010 Mar. 9(3):254-63. [View Abstract]
  40. Peltola H, Roine I. Improving the outcomes in children with bacterial meningitis. Curr Opin Infect Dis. 2009 Jun. 22(3):250-5. [View Abstract]
  41. van de Beek D, Drake JM, Tunkel AR. Nosocomial bacterial meningitis. N Engl J Med. 2010 Jan 14. 362(2):146-54. [View Abstract]
  42. Sloan D, Dlamini S, Paul N, Dedicoat M. Treatment of acute cryptococcal meningitis in HIV infected adults, with an emphasis on resource-limited settings. Cochrane Database Syst Rev. 2008 Oct 8. CD005647. [View Abstract]
  43. Kauffman CA, Bustamante B, Chapman SW, Pappas PG. Clinical practice guidelines for the management of sporotrichosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis. 2007 Nov 15. 45(10):1255-65. [View Abstract]
  44. Treatment of tuberculosis. MMWR Recomm Rep. 2003 Jun 20. 52:1-77. [View Abstract]
  45. El Sahly H, Udayamurthy M, Parkerson G, Hasbun R. Survival of an AIDS patient after infection with Acanthamoeba sp. of the central nervous system. Infection. 2017 Oct. 45 (5):715-718. [View Abstract]
  46. Report from the Advisory Committee on Immunization Practices (ACIP): decision not to recommend routine vaccination of all children aged 2-10 years with quadrivalent meningococcal conjugate vaccine (MCV4). MMWR Morb Mortal Wkly Rep. 2008 May 2. 57(17):462-5. [View Abstract]
  47. [Guideline] Updated recommendations for use of meningococcal conjugate vaccines --- Advisory Committee on Immunization Practices (ACIP), 2010. MMWR Morb Mortal Wkly Rep. 2011 Jan 28. 60(3):72-6. [View Abstract]
  48. FDA News Release: First vaccine approved by FDA to prevent serogroup B Meningococcal disease. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm420998.htm. Accessed: October 29, 2014.
  49. FDA News Release. FDA approves a second vaccine to prevent serogroup B meningococcal disease. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm431370.htm. Accessed: January 23, 2015.
  50. Nuorti JP, Whitney CG. Prevention of pneumococcal disease among infants and children - use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine - recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2010 Dec 10. 59:1-18. [View Abstract]
  51. Tomczyk S, Bennett NM, Stoecker C, Gierke R, Moore MR, Whitney CG, et al. Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine among adults aged =65 years: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 2014 Sep 19. 63(37):822-5. [View Abstract]
  52. [Guideline] Tunkel AR, Hasbun R, Bhimraj A, Byers K, Kaplan SL, Michael Scheld W, et al. 2017 Infectious Diseases Society of America's Clinical Practice Guidelines for Healthcare-Associated Ventriculitis and Meningitis. Clin Infect Dis. 2017 Feb 14. [View Abstract]
  53. Kim SW, Jin JH, Kang SJ, Jung SI, Kim YS, Kim CK, et al. Therapeutic efficacy of meropenem for treatment of experimental penicillin-resistant pneumococcal meningitis. J Korean Med Sci. 2004 Feb. 19(1):21-6. [View Abstract]
  54. Abdelnour A, Silas PE, Lamas MR, Aragón CF, Chiu NC, Chiu CH, et al. Safety of a quadrivalent meningococcal serogroups A, C, W and Y conjugate vaccine (MenACWY-CRM) administered with routine infant vaccinations: Results of an open-label, randomized, phase 3b controlled study in healthy infants. Vaccine. 2014 Jan 4. [View Abstract]
  55. Douglas D. Meningitis Vaccine Safe in Young Infants. Medscape [serial online]. Available at http://www.medscape.com/viewarticle/819521. Accessed: January 27, 2014.
  56. Jones SC, Morris J, Hill G, Alderman M, Ratard RC. St. Louis encephalitis outbreak in Louisiana in 2001. J La State Med Soc. 2002 Nov-Dec. 154(6):303-6. [View Abstract]
  57. Nkoumou MO, Clevenbergh P, Betha G, Kombila M. Bacterial meningitis in HIV positive compared to HIV negative patients in an internal medicine ward of Librevile, Gabon. Int Conf AIDS: International Conference on AIDS. Jul 7-12 2002;abstract no. ThPeB7368.
  58. Scheld WM, Koedel U, Nathan B, Pfister HW. Pathophysiology of bacterial meningitis: mechanism(s) of neuronal injury. J Infect Dis. 2002 Dec 1. 186 Suppl 2:S225-33. [View Abstract]
  59. van de Beek D, de Gans J, Tunkel AR, Wijdicks EF. Community-acquired bacterial meningitis in adults. N Engl J Med. 2006 Jan 5. 354(1):44-53. [View Abstract]

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

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.

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.

Category Agent
BacteriaPartially 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



VirusesEnterovirusPoliovirus



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



ParamyxovirusMumps virus



Measles virus



TogavirusRubella virus
FlavivirusWest Nile virus



Japanese encephalitis virus



St Louis encephalitis virus



BunyavirusCalifornia encephalitis virus



La Crosse encephalitis virus



AlphavirusEastern equine encephalitis virus



Western equine encephalitis virus



Venezuelan encephalitis virus



ReovirusColorado tick fever virus
ArenavirusLCM virus
RhabdovirusRabies virus
RetrovirusHIV
HHV = human herpesvirus; HSV = herpes simplex virus; LCM = lymphocytic choriomeningitis.
    
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



ParasitesAcanthamoeba spp



Naegleria fowleri



Angiostrongylus cantonensis



Gnathostoma spinigerum



Baylisascaris procyonis



Schistosoma spp



Strongyloides stercoralis



Echinococcus granulosus



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.  
Risk or Predisposing Factor Bacterial Pathogen
Age 0-4 weeksStreptococcus 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 shuntsCoagulase-negative staphylococci



S aureus



Aerobic gram-negative bacilli



Propionibacterium acnes



CSF = cerebrospinal fluid; GBS = group B streptococcus.
Agent Opening Pressure (mm H2 O) WBC count (cells/µL) Glucose (mg/dL) Protein (mg/dL) Microbiology
Bacterial meningitis200-300100-5000; >80% PMNs< 40>100Specific pathogen demonstrated in 60% of Gram stains and 80% of cultures
Viral meningitis90-20010-300; lymphocytesNormal, reduced in LCM and mumpsNormal but may be slightly elevatedViral isolation, PCR assays
Tuberculous meningitis180-300100-500; lymphocytesReduced, < 40Elevated, >100Acid-fast bacillus stain, culture, PCR
Cryptococcal meningitis180-30010-200; lymphocytesReduced50-200India ink, cryptococcal antigen, culture
Aseptic meningitis90-20010-300; lymphocytesNormalNormal but may be slightly elevatedNegative findings on workup
Normal values80-2000-5; lymphocytes50-7515-40Negative findings on workup
LCM = lymphocytic choriomeningitis; PCR = polymerase chain reaction; PMN = polymorphonuclear leukocyte; WBC = white blood cell.
Normal Finding Bacterial Meningitis Viral Meningitis* Fungal Meningitis**
Pressure (mm H2 O)



50-150



IncreasedNormal or mildly increasedNormal 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 antibioticsCell 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 resultsHundreds 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 organismIndia 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



DecreasedNormalSometimes 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 >1000Mildly increasedIncreased; >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.



Age or Predisposing Feature Antibiotics
Age 0-4 wkAmpicillin plus either cefotaxime or an aminoglycoside
Age 1 mo-50 yVancomycin plus cefotaxime or ceftriaxone*
Age >50 yVancomycin plus ampicillin plus ceftriaxone or cefotaxime plus vancomycin*
Impaired cellular immunityVancomycin plus ampicillin plus either cefepime or meropenem
Recurrent meningitisVancomycin plus cefotaxime or ceftriaxone
Basilar skull fractureVancomycin plus cefotaxime or ceftriaxone
Head trauma, neurosurgery, or CSF shuntVancomycin plus ceftazidime, cefepime, or meropenem
CSF = cerebrospinal fluid.



*Add ampicillin if Listeria monocytogenes is a suspected pathogen.



Bacteria Susceptibility Antibiotic(s) Duration (days)
Streptococcus pneumoniae Penicillin MIC ≤0.06 μg/mLRecommended: 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/mLRecommended: Vancomycin plus cefotaxime or ceftriaxone



Alternatives: Vancomycin plus moxifloxacin



Haemophilus influenzae Beta-lactamase−negativeRecommended: Ampicillin



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



7
Beta-lactamase−positiveRecommended: Cefotaxime or ceftriaxone



Alternatives: Cefepime, chloramphenicol, aztreonam, a fluoroquinolone



Beta-lactamase−negative, ampicillin-resistantRecommended: Meropenem



Alternatives: Cefepime, chloramphenicol, aztreonam, a fluoroquinolone



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



Alternatives: Cefotaxime, ceftriaxone, chloramphenicol



7
Penicillin MIC ≥0.1 μg/mLRecommended: 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.