eMedicine Specialties > Infectious Diseases > CNS Infections

Meningitis

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

Updated: Aug 26, 2009

Introduction

Background

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

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

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

Pathophysiology

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

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

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

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

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

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

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

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

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

Frequency

United States

The incidence of meningitis varies with the specific etiologic agent.

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

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

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

International

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

Mortality/Morbidity

Mortality from meningitis varies with the specific etiologic agent.

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

Race

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

Sex

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

Age

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

Clinical

History

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

Physical

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

Causes

Acute bacterial meningitis

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

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

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

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

Aseptic meningitis syndrome

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

Table 3. Infectious Agents Causing Aseptic Meningitis Syndrome

Acute viral meningitis

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

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

Chronic meningitis

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

Table 4. Causes of Chronic Meningitis

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

Differential Diagnoses

Brain Abscess

Other Problems to Be Considered

Noninfectious meningitis, including medication-induced meningeal inflammation
Meningeal carcinomatosis
CNS vasculitis
Stroke
Encephalitis

Workup

Laboratory Studies

The cornerstone in the diagnosis of meningitis is examination of the CSF.

In general, whenever the diagnosis of meningitis is strongly considered, promptly perform a lumbar puncture.

Measure the opening pressure and send the fluid for cell count (and differential count), chemistry (ie, CSF glucose and protein), and microbiology (ie, Gram stain and cultures).

CT scan of the brain may be performed prior to lumbar puncture in some patient groups with a higher risk of herniation. These groups include those with newly onset seizures, an immunocompromised state, signs suspicious for space-occupying lesions (such as papilledema and focal neurologic signs), and moderate-to-severe impairment in consciousness.

Special studies, such as serology and nucleic acid amplification, may also be performed depending on clinical suspicion. There is increasing data to suggest that serum procalcitonin levels can be used as a guide to distinguish between bacterial and aseptic meningitis in children. The results yielded by a serum procalcitonin, combined with other findings, could be helpful in making clinical decisions.^{[1 ]}

Table 5. CSF Picture of Meningitis According to Etiologic Agent

Bacterial meningitis

• Examination of the CSF in patients with acute bacterial meningitis reveals the characteristic neutrophilic pleocytosis (usually hundreds to a few thousand, with >80% PMN cells). In some cases of L monocytogenes meningitis (25-30%), a lymphocytic predominance may occur. Low CSF WBC count (<20 cells/µL) in the presence of a high bacterial load suggests a poor prognosis.
• The opening pressure (reference range is 80-200 mm H2O) may be elevated, suggesting some form of increased ICP from cerebral edema.
• The CSF glucose (reference range is 40-70 mg/dL) is less than 40 mg/dL in 60% of patients. Obtain a simultaneous blood glucose determination for comparison purposes. Some patients may have elevated blood sugar levels as a result of underlying diabetes mellitus, and the predictive value of the CSF and blood sugar ratio may not be accurate in these circumstances.
• The CSF protein (reference range is 20-50 mg/dL) is usually elevated.
• CSF Gram stain 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 for detection is variable. The likelihood of detection is higher in the presence of a higher bacterial concentration and diminishes with prior antibiotic use.
• CSF bacterial cultures yield the bacterial cause in 70-85% of cases. The yield diminishes significantly 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 HIB, S pneumoniae, N meningitidis, E coli K1, and S agalactiae. Its theoretical advantage is the detection of the bacterial antigens even after microbial killing, as is observed following antibacterial therapy. Others, however, have shown that it may not be better than the Gram stain. It is specific (a positive result indicates a diagnosis of bacterial meningitis), but a negative finding on bacterial antigen test does not rule out meningitis (50-95% sensitivity).
• Obtain blood cultures and appropriate cultures from possible sites of infection. Obtain these promptly and prior to the administration of an antibacterial agent. The utility of these cultures is most evident in cases when the performance of a lumbar puncture is delayed by the need for head imaging (risk for herniation in a patient with focal neurologic deficit or coma) and when antimicrobial therapy is rightfully initiated before the lumbar puncture and neuroimaging tests.

Acute viral meningitis

• The CSF picture of acute viral meningitis is different from the CSF picture of bacterial meningitis.
• The opening pressure is usually within the reference range.
• The CSF cell count is usually in the few hundreds (100-1000 cells/µL) with a predominance of lymphocytes. Some cases of echovirus, mumps, and HSV meningitis may produce a neutrophilic picture early in the course of disease.
• The CSF glucose level is usually within the reference range, but some cases of LCM, HSV, mumps, and polio may cause low CSF glucose levels.
• CSF protein levels may be within the reference range but are usually elevated.
• Virus isolation from the CSF can be performed. It has a sensitivity of 65-70% for enteroviruses. Alternatively, enterovirus isolation from throat and stool viral cultures may also be used to indirectly implicate it as the cause of the meningitis. Mumps viral culture from the CSF has a low sensitivity (30-50%). LCM virus may be cultured in blood early in the disease or later in the urine.
• The use of nucleic acid amplification (eg, PCR) has revolutionized the diagnosis of herpes simplex 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 enterovirus 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.
• In addition, the demonstration of a 4-fold rise between acute and convalescent sera traditionally has been used to document meningeal infection with these viral pathogens.

Cryptococcal 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 lymphocytes), a reduced glucose level, and an elevated protein level.
• The CSF opening pressure may be elevated at times, suggesting increased ICP.
• C neoformans may be cultured from the CSF. Other methods of identification have included 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 of greater than 90%. However, the CSF cryptococcal antigen determination is not universally available. In instances when the India ink results are negative but the 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.
• Obtain blood cultures and serum cryptococcal antigen to determine if cryptococcal fungemia is present.

Other fungal meningitis

• The CSF picture of other fungal meningitis is similar to the CSF picture 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, 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 is used in the diagnosis of many cases of fungal meningitis because isolating them from culture has been difficult (eg, presence of histoplasma antigen in the CSF). However, note that the serology for B dermatitidis is not accurate and a negative serology finding does not rule out the diagnosis.

Syphilitic meningitis

• The CSF in syphilitic meningitis is characterized by mild lymphocytic pleocytosis.
• Abnormal CSF protein levels (elevated) and CSF glucose levels (decreased) may be observed in 10-70% of cases.
• Isolating T pallidum from the CSF is extremely difficult and time consuming. The spirochete could be demonstrated 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 Venereal Disease Research Laboratory (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). Always take care to not contaminate the CSF with blood during spinal fluid collection (eg, traumatic tap).
• Perform serologic tests to detect syphilis, such as the nontreponemal (ie, rapid plasma reagent [RPR] or VDRL test) and specific treponemal (ie, fluorescent treponemal antibody absorption [FTA-Abs], Treponema pallidum hemoagglutination [TPHA], microhemagglutination-Treponema pallidum [MHA-TP]) tests to support the diagnosis. These also guide the success of therapy. The titer of the nonspecific treponemal tests decreases and usually reverts back to negative or undetectable levels following treatment.

Lyme neuroborreliosis

• The CSF in patients with Lyme meningitis 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 the serum is a helpful diagnostic test. A CSF-to-serum ratio of greater than 1 suggests intrathecal antibody production and neuroborreliosis.
• The culture for B burgdorferi has a low yield.
• The recent availability of the CSF Lyme PCR assay offers a rapid, sensitive, and specific method of diagnosis. This assay is gaining popularity as the method of choice for diagnosis of Lyme meningitis. Findings on blood Lyme PCR are usually negative.

Tuberculosis meningitis

• The CSF of patients with tuberculosis meningitis is characterized by a predominantly lymphocytic pleocytosis, usually in the hundreds.
• The opening CSF pressure is usually elevated.
• A characteristic hypoglycorrhagia (glucose <40 mg/dL) is present, and the protein level is usually elevated, especially if a CSF block is present.
• The demonstration of the acid-fast bacilli (eg, with auramine-rhodamine stain, Ziehl-Neelsen stain, Kinyoun stain) in the CSF is difficult and usually requires a large volume of CSF.
• Meningeal biopsy, with the demonstration of caseating granulomas and acid-fast bacilli on the smear, may prove useful because it has a higher yield than the CSF acid-fast bacilli smear.
• The 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 advantage of a rapid, sensitive, and specific method of tuberculosis detection.
• The need for mycobacterial growth in cultures remains because this offers the advantage of performing drug susceptibility assays.

Parasitic meningitis

• PAM caused by N fowleri is characterized by a neutrophilic pleocytosis, low glucose levels, elevated protein levels, and red blood cells. Mononuclear pleocytosis may be observed in patients with subacute or chronic forms of PAM. Demonstration of the trophozoites, with the characteristic amoeboid movement, using wet preparations of the CSF has been used for diagnosis. Alternatively, the amoeba could be demonstrated in biopsy specimens.
• Suspect meningitis caused by A cantonensis, G spinigerum, and B procyonis in the presence of exposure, profound peripheral blood eosinophilia, and characteristic eosinophilic pleocytosis. Demonstrating the larva antemortem is usually difficult, and diagnosis relies on clinical presentation and a compatible epidemiological history. Serologic tests may aid in the diagnosis. G spinigerum meningitis may mimic cerebrovascular disease because it may cause cerebral hemorrhage.

Imaging Studies

• Computed tomography scans of the head and magnetic resonance imaging of the brain do not aid in the diagnosis of meningitis. Some patients may show meningeal enhancement, but its absence does not rule out the condition.
• The practice of obtaining CT scans of the head may lead to the unnecessary delay in the performance of diagnostic lumbar puncture and the initiation of antibiotic therapy. The delay in the institution of antimicrobial therapy may be detrimental to the total 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 happens within 24 hours following the lumbar puncture and should always be considered in the differential diagnosis if the patient's neurologic status deteriorates.
• Neuroimaging is indicated in patients with prolonged fever, focal neurologic symptoms and signs, evidence of increased ICP, and suspected basilar fracture. It is also indicated for evaluation of the paranasal sinuses. These studies are helpful in the detection of CNS complications of bacterial meningitis, such as hydrocephalus, cerebral infarct, brain abscess, subdural empyema, and venous sinus thrombosis.

Procedures

• Perform lumbar puncture promptly in all patients whenever a strong clinical suspicion for meningitis exists.
• Neurosurgical procedures are performed in consultation with a neurosurgical service in the presence of severe intracranial hypertension, evidence of paranasal and mastoid infection that requires surgical drainage, skull fractures, foreign body–associated infections (eg, ventriculoperitoneal shunts), or an associated abscess formation.

Treatment

Medical Care

General guidelines

Lumbar puncture for CSF examination is urgently warranted in individuals in whom meningitis is clinically suspected.

In the absence of focal neurologic deficit, radiographic imaging of the head should not preclude performing a lumbar puncture. In addition, the performance of radiographic imaging should not defer the institution of empiric antimicrobial therapy.

Bacterial meningitis is a neurological emergency that is associated with significant morbidity and mortality. The initiation of empiric antibacterial therapy is therefore essential for better outcome.

Institute empiric antimicrobial therapy (ie, antibacterial treatment, or antivirals and antifungal therapy in selected cases) as soon as possible (see Table 6 and Table 7). This is usually based on the known predisposing factors and/or initial CSF Gram-stain results.

Significant delays in instituting antimicrobial treatment in individuals with bacterial meningitis could lead to significant morbidity and mortality.

The chosen antibiotic should attain adequate levels in the CSF. Achieving this usually depends on the drug's lipid solubility, its molecular size, its protein-binding capability, and the state of inflammation at the meninges. The penicillins, certain cephalosporins (ie, third- and fourth-generation cephalosporins), the carbapenems, fluoroquinolones, and rifampin provide high CSF levels.

Monitor for possible drug toxicity during treatment (eg, with blood counts and renal and liver function monitoring).

The dose of the chosen antimicrobial agent should always be adjusted based on the renal and hepatic function of the patient. 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, aminoglycosides).

Once the pathogen has been identified and antimicrobial susceptibilities determined, the antibiotics may be modified for optimal targetted treatment (see Table 8).

One of the major contributors to the morbidity associated with bacterial meningitis is the severity of inflammation. Therefore, pharmacologic interventions to reduce the degree of inflammation may improve outcome. Strongly consider the use of steroids as adjunctive treatment of bacterial meningitis. If steroids are given, they should be administered prior to or during the administration of antimicrobial therapy. The use of steroids has been shown to improve the overall outcome of patients with certain types of bacterial meninigitis, such as H influenzae, tuberculous, and pneumococcal meningitis.

Monitor for the occurrence of complications from the disease (eg, hydrocephalus, seizures, hearing defects) and its treatment (eg, drug toxicity, hypersensitivity).

*Vancomycin is added empirically to the initial regimen if the presence of penicillin-resistant S pneumoniae is suspected or if a high incidence of resistance is reported in the community.

*Use ceftriaxone if penicillin-resistant N meningitidis occurs in the community.

†Ceftriaxone is preferred. Ceftazidime is used when Pseudomonas infection is likely (eg, neurosurgical procedures).

• Antimicrobial therapy for bacterial meningitis
  • S pneumoniae
    • The increasing incidence of penicillin-resistant strains has changed the management of pneumococcal meningitis.
    • The third-generation cephalosporins (ceftriaxone 2-4 g/d or cefotaxime 8-12 g/d) with vancomycin (2-3 g/d, adjusted to therapeutic serum levels) are first-line empiric therapy, depending on the resistance patterns in the community.
    • The use of corticosteroids such as dexamethasone as adjunctive treatment for pneumococcal meningitis is now supported by recent studies demonstrating significant benefit with regards to reduction in case-fatality rate and neurologic sequelae.^{[2 ]}
    • Vancomycin has poor CSF penetration. The addition of dexamethasone could further decrease CSF penetration (see Use of steroids).
    • The efficacy of fluoroquinolones and newer agents, such as linezolid, has not been investigated in detail, and their use as first-line agents is not recommended.
    • Penicillin G (24 million U/d) remains the drug of choice for penicillin-susceptible strains.
  • N meningitidis
    • The antimicrobial therapy of choice is penicillin G (24 million U/d) or ampicillin (12 g/d).
    • Ceftriaxone (2-4 g/d) is used in the presence of resistant strains (MIC of 0.1-1 mcg/mL).
    • Data on the use of corticosteroids as adjunctive treatment of meningococcal meningitis are not as strong as those for pneumococcal meningitis. The systematic review on this topic indicates that the reduction in mortality and neurologic sequelae did not reach statistical significance.
  • H influenzae
    • Third-generation cephalosporins (ceftriaxone 4 g/d or cefotaxime 8-12 g/d) are first-line empiric therapy. Resistance to chloramphenicol and ampicillin is common.
    • The efficacy of dexamethasone (0.15 mg/kg q6h) in decreasing the incidence of hearing loss and neurologic sequelae has been clearly demonstrated in children.
  • L monocytogenes
    • Ampicillin (12 g/d) or penicillin G (24 million U/d) is the drug of choice.
    • The addition of gentamicin (3-5 mg/kg/d, divided tid) may add synergy.
    • The third-generation cephalosporins are inactive against L monocytogenes.
    • In patients who are allergic to penicillin, use trimethoprim-sulfamethoxazole (TMP-SMX) at 10 mg/kg/d of the TMP component.
  • Aerobic gram-negative bacilli
    • Third-generation cephalosporins are the drugs of choice. Cefepime is also commonly used. An aminoglycoside may be added for synergy.
    • In cases of P aeruginosa meningitis, the agent of choice among the third-generation cephalosporins is ceftazidime (2 g IV q8h). Ceftriaxone and cefotaxime are not effective against P aeruginosa.
    • The use of imipenem is limited because of seizure potential.
    • Quinolones are under investigation but are not currently recommended as first-line agents.
  • S agalactiae
    • Treat meningitis caused by S agalactiae with ampicillin (12 g/d) and an aminoglycoside.
    • Alternatives include third-generation cephalosporins and vancomycin.
  • Staphylococcus species
    • Treat meningitis caused by S aureus with nafcillin (9-12 g/d) or oxacillin (9-12 g/d).
    • Vancomycin (2-3 g/d, adjusted to serum levels) is the alternative in patients who are allergic to penicillin and is the first-line therapy for methicillin-resistant S aureus (MRSA) strains.
    • Vancomycin is the first-line therapy for coagulase-negative staphylococci. Adding rifampin (600 mg/d) may have a synergistic effect.
    • The use of newer agents such as linezolid and daptomycin for the treatment of staphylococcal meningitis remains investigational.
  • [#UseOfSteroids]Use of steroids
    • The present understanding of the pathogenesis of bacterial meningitis has led to multiple therapeutic trials that involve means to attenuate the detrimental effects of the host defenses (eg, inflammatory response to the bacterial products and the products of neutrophil activation) while eradicating bacteria with antibiotics.
    • Foremost among these measures is the use of steroids. However, in the experimental meningitis model, the use of steroids has been associated with decreased antimicrobial penetration into the CSF and decreased bactericidal activity of some antimicrobials, such as vancomycin. Recent clinical data, however, indicate that steroid use may offer benefit in certain cases of acute bacterial meningitis.
    • The use of adjunctive dexamethasone (0.15 mg/kg per dose q6h for 2-4 d) decreases hearing loss and neurologic sequelae in children and infants with meningitis caused by HIB. The studies that support this largely have been carried out during the era when HIB was the most common meningeal pathogen.
    • More recent studies indicate that adjunctive steroids are also beneficial in the treatment of meningitis caused by bacterial pathogens other than HIB. In a large cohort of patients with acute meningitis due to pneumococcus, meningococcus, and other bacteria, the administration of adjunctive dexamethasone was significantly associated with a reduction in mortality and other unfavorable outcomes. The benefit was most apparent in cases due to pneumococcus.
    • The recent accumulation of scientific evidence about the benefits of steroid use suggests that it should be considered as adjunctive treatment in most adult patients in whom acute bacterial meningitis is suspected.
    • The timing of dexamethasone administration is crucial. If used, it should be administered before or with the first dose of antibacterial therapy. This is to counteract the initial inflammatory burst consequent to antibiotic-mediated bacterial killing. A more intense inflammatory reaction has been documented following the massive bacterial killing induced by antibiotics.
• Viral meningitis
  • Most viral meningitides are benign and self-limited. Often, they require only supportive care and do not require specific therapy. In certain instances, specific antiviral therapy may be indicated, if available.
  • In patients with immune deficiency (eg, agammaglobulinemia), immunoglobulin replacement has been used to treat chronic enterovirus infections.
  • The antiviral management of herpes meningitis is controversial. Acyclovir (10 mg/kg IV q8h) 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.
  • Ganciclovir (induction dose of 5 mg/kg IV q12h, maintenance dose of 5 mg/kg q24h) and foscarnet (induction dose of 60 mg/kg IV q8h, maintenance dose of 90-120 mg/kg IV q24h) are used for CMV meningitis in immunocompromised hosts.
  • Instituting highly active antiretroviral therapy (HAART) may be necessary for patients with HIV meningitis that occurs during an acute seroconversion syndrome.
• Fungal meningitis
  • A number of different regimens have been demonstrated to be effective in the treatment of fungal meningitis. The following treatment options have been shown to be effective in many cases.
  • Treatment of AIDS-related cryptococcal meningitis (ie, C neoformans)
    • Induction therapy: Administer amphotericin B (0.7-1 mg/kg/d IV) for at least 2 weeks, with or without flucytosine (100 mg/kg PO) in 4 divided doses. Liposomal preparations of amphotericin B may be beneficial, but optimal doses have not been determined.
    • Consolidation therapy: Administer fluconazole (400 mg/d for 8 wk). Itraconazole is an alternative if fluconazole is not tolerated.
    • Maintenance therapy: Long-term antifungal therapy with fluconazole (200 mg/d) is most effective (superior to itraconazole and amphotericin B at 1 mg/kg/wk) to prevent relapse. 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 lumbar puncture is strongly advised. Make an effort to reduce such pressure by repeated lumbar puncture, a lumbar drain, or a shunt. Medical maneuvers, such as administration of mannitol, have also been used.
    • Role of newer agents such as voriconazole and posaconazole has not been investigated. Echinocandins do not have activity against cryptococcus.
    • For the optimal treatment for HIV-related acute cryptococcal meningitis in resource-limited areas, the agents that are used are amphotericin B and fluconazole. Hence, the treatment would consist of amphotericin and flucytosine and that policy makers and national departments of heath in such countries should consider adding drugs that are typically unavailable in such settings (eg, flucytosine) for HIV treatment programs.^{[3 ]}
  • Treatment of cryptococcal meningitis (ie, C neoformans) in patients without AIDS
    • Induction/consolidation: Administer amphotericin B (0.7-1 mg/kg/d) plus flucytosine (100 mg/kg/d) for 2 weeks. Then, administer fluconazole (400 mg/d) for a minimum of 10 weeks.
    • A lumbar puncture is recommended after 2 weeks to document sterilization of the CSF. If the infection persists, longer therapy is recommended. Solid organ transplant recipients require prolonged therapy.
  • C immitis
    • The preferred treatment for meningitis caused by C immitis is oral fluconazole (400 mg/d). Some physicians initiate therapy with a higher dose of fluconazole (as high as 1000 mg/d) or in combination with intrathecal amphotericin B.
    • Itraconazole (400-600 mg/d) has been reported to be comparably effective.
    • Duration of treatment usually is life long.
  • H capsulatum
    • The optimal treatment of H capsulatum meningitis is unclear.
    • Amphotericin B at 0.7-1 mg/kg/d to complete a total dose of 35 mg/kg has been used.
    • Fluconazole (800 mg/d) for an additional 9-12 months may be used to prevent relapse.
    • Long-term fluconazole maintenance therapy at 800 mg/d may be used for those who relapse despite having received a full course of treatment. Patients with further relapse despite long-term suppression are candidates for intraventricular amphotericin B.
    • Itraconazole, although it has better anti-Histoplasma activity, is not encouraged because of poor CSF penetration.
    • This infection is associated with a poor outcome; 20-40% of patients with meningitis succumb to the infection despite amphotericin B therapy, and 50% of responders relapse following discontinuation of treatment.
  • Candida species
    • The preferred initial therapy for candidal meningitis is amphotericin B (0.7mg/kg/d). Flucytosine (25 mg/kg qid) is usually added and adjusted to maintain serum levels of 40-60 mcg/mL.
    • Azole therapy 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 following 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.
  • S schenckii
    • Amphotericin B is the treatment of choice.
    • Using itraconazole to achieve lifelong suppression may be attempted after initial therapy with amphotericin B.
    • Fluconazole has less anti-Sporothrix activity compared to itraconazole.
    • The duration of treatment in AIDS-related cases is life long.
• Tuberculous meningitis
  • Depending on the resistance pattern in the community and the results of susceptibility testing (once available), always treat tuberculous meningitis with a combination of drugs.
  • Isoniazid (INH) and pyrazinamide (PZA) attain good CSF levels (approximate blood levels). Rifampin (RIF) penetrates the BBB less efficiently but still attains adequate CSF levels.
  • The use of a combination of the first-line drugs (ie, INH, RIF, PZA, ethambutol, streptomycin) is advocated. The dosage is similar to what is used for pulmonary tuberculosis (ie, INH 300 mg qd, RIF 600 mg qd, PZA 15-30 mg/kg qd, ethambutol 15-25 mg/kg qd, streptomycin 7.5 mg/kg q12h).
  • Evidence regarding the appropriate duration of treatment is conflicting. A treatment duration of 12 months is the minimum, and some experts suggest a duration of at least 2 years.
  • The use of corticosteroids is indicated for individuals with stage 2 or stage 3 disease (ie, patients with evidence of neurologic deficits or changes in their mental function). The recommended dose is 60-80 mg/d, which may be tapered gradually during a span of 6 weeks. The rationale lies in the reduction of inflammatory effects associated with mycobacterial killing by the antimicrobial agents.
• Spirochetal meningitis
  • Syphilitic meningitis
    • The treatment of choice for neurosyphilis requires the parenteral administration of aqueous crystalline penicillin G (2-4 million U/d IV q4h) for 10-14 days, often followed with intramuscular (IM) benzathine penicillin G (2.4 million U).
    • Alternatively, administer procaine penicillin G (2.4 million U/d IM) plus probenecid (500 mg PO qid) for 14 days, followed by IM benzathine penicillin G (2.4 million U).
    • Patients with HIV who have neurosyphilis are treated similarly.
    • Repeat CSF examination is performed regularly (eg, every 6 mo) following treatment to document the success of therapy. Failure of the cell count to normalize or the serologic titers to fall may warrant re-treatment.
    • Because penicillin G is considered the medical treatment of choice, patients who are allergic to penicillin should undergo penicillin desensitization in order to receive optimal treatment.
  • Lyme meningitis
    • Neurologic complications of Lyme disease (other than Bell palsy) ideally require parenteral antibiotic administration.
    • The drug of choice is ceftriaxone (2 g/d) for 14-28 days. The alternative therapy is penicillin G (20 million U/d) for 14-28 days.
    • Doxycycline (100 mg PO/IV bid) for 14-28 days or chloramphenicol (1 g qid) for 14-28 days has also been used.
• Parasitic meningitis
  • Primary amebic meningoencephalitis caused by N fowleri is usually fatal. The few survivors reported in the scientific literature have benefited from early diagnosis and treatment with high-dose intravenous and intrathecal amphotericin B or miconazole and rifampin.
  • The treatment for helminthic (ie, A cantonensis, G spinigerum) eosinophilic meningitis has largely been supportive in nature. This includes adequate analgesia, therapeutic CSF aspiration, and the use of anti-inflammatory agents such as corticosteroids. The use of antihelminthic therapy may be contraindicated because clinical deterioration and death may occur following severe inflammatory reactions to the dying worms.

Surgical Care

• In certain cases of increased ICP, repeated lumbar puncture or the insertion of a ventricular drain may be necessary to relieve the effects of increased ICP.
• Consultations with neurosurgical service may be needed when a skull fracture is suspected or an abscess formation is demonstrated.

Consultations

• Consultation with an infectious diseases specialist
• Consultation with a neurosurgeon in cases of severe intracranial hypertension, suspicion of basilar skull fracture, and abscess formation

Diet

No strict dietary restriction is necessary. To diminish the risks of aspiration, nothing by mouth is recommended for patients with altered levels of consciousness.

Medication

This section discusses antimicrobials commonly used to treat meningitis. Antimicrobials recommended for specific pathogens are discussed in Medical Care.

Antimicrobial agents

These agents are used to treat or prevent infection caused by the most likely pathogen suspected or identified.

Ceftriaxone (Rocephin)

Third-generation cephalosporin with broad-spectrum gram-negative activity. Lower efficacy against gram-positive organisms but excellent activity against susceptible pneumococcal organisms. Exerts antimicrobial effect by interfering with synthesis of peptidoglycan, a major structural component of bacterial cell wall. Excellent antibiotic for empiric treatment of bacterial meningitis.

Dosing

Adult

2 g IV q24h

Pediatric

75 mg/kg IV followed by 100 mg/kg/d IV divided bid; not to exceed 4 g/d

Interactions

Probenecid may increase levels by decreasing its elimination half-life; coadministration with ethacrynic acid, furosemide, and aminoglycosides may increase nephrotoxicity

Contraindications

Documented hypersensitivity; neonates with hyperbilirubinemia caused by increased risk of kernicterus

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Adjust dose in renal impairment; caution in breastfeeding women and people with penicillin allergy; caution in gallbladder, biliary tract, liver, or pancreatic disease

Cefotaxime (Claforan)

Third-generation cephalosporin used to treat suspected or documented bacterial meningitis caused by susceptible organisms such as H influenzae or N meningitides. Like other beta-lactam antibiotics, inhibits bacterial growth by arresting bacterial cell wall synthesis.

Dosing

Adult

2-3 g IV q4-6h; not to exceed 12 g/d

Pediatric

<12 years: 200 mg/kg/d IV divided q6h; not to exceed 12 g/d
>12 years: Administer as in adults

Interactions

Probenecid may increase levels by prolonging its half-life; coadministration with furosemide and aminoglycosides may increase nephrotoxicity

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Adjust dose in severe renal impairment; has been associated with severe antibiotic-associated pseudomembranous colitis; may cause transient neutropenia and thrombocytopenia; may cause transient elevation in liver enzymes; caution in penicillin allergy

Penicillin G (Pfizerpen)

Beta-lactam antibiotic. Inhibits bacterial cell wall synthesis, resulting in bactericidal activity against susceptible microorganisms. Active against many gram-positive organisms. DOC for syphilitic meningitis and susceptible organisms (eg, N meningitides, penicillin-susceptible S pneumoniae).

Dosing

Adult

Up to 24 million U/d IV divided q4h or as continuous IV infusion

Pediatric

100,000-400,000 U/kg/d IV divided q4h; not to exceed 24 million U/d

Interactions

Probenecid can increase effects; coadministration of tetracyclines can decrease effects

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in impaired renal function, seizure disorder, and hypersensitivity to cephalosporins

Vancomycin (Vancocin)

Glycopeptide antibiotic active against staphylococci, streptococci, and other gram-positive bacteria. Exerts antibacterial activity by inhibiting biosynthesis of peptidoglycan. DOC for highly penicillin-resistant and ceftriaxone-resistant S pneumoniae and methicillin-resistant S aureus. Component of empiric DOC for CNS-shunt–associated meningitis. Because of poor CSF penetration, higher dose is required for meningitis than for other infections. Use CrCl to adjust dose in renal impairment.

Dosing

Adult

Meningitis: 1 g IV q8h; adjust dose based on measured peak and trough levels, which are dependent on body weight and renal clearance
Nonmeningitis infections: 15-30 mg/kg/d IV in divided doses

Pediatric

40 mg/kg/d IV divided qid

Interactions

Erythema, histaminelike flushing, and anaphylactic reactions may occur when administered with anesthetic agents; when taken concurrently with aminoglycosides, risk of nephrotoxicity may increase above that with aminoglycoside monotherapy; effects in neuromuscular blockade may be enhanced when coadministered with nondepolarizing muscle relaxants

Contraindications

Documented hypersensitivity; history of severe hearing loss

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in renal failure and neutropenia; red man syndrome is caused by IV infusion that is too rapid (dose administered over a few min) but rarely occurs when dose is administered as a 2-h administration or as PO or IP administration; red man syndrome is not an allergic reaction

Ampicillin (Omnipen, Polycillin)

Bactericidal beta-lactam antibiotic that inhibits cell wall synthesis by interfering with peptidoglycan formation. Indicated for L monocytogenes and S agalactiae meningitis, usually in combination with gentamicin.

Dosing

Adult

12 g/d IV divided q3-4h

Pediatric

200 mg/kg/d IV divided q4-6h; not to exceed 12 g/d

Interactions

Probenecid and disulfiram elevate levels; allopurinol decreases effects and has additive effects on ampicillin rash; may decrease effects of PO contraceptives

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Adjust dose in renal failure; evaluate rash and differentiate from hypersensitivity reaction

Gentamicin (Garamycin)

Newer antibiotics are available, but aminoglycosides remain significant in treating severe infections. Aminoglycosides inhibit protein synthesis by irreversibly binding to 30s ribosome. In meningitis or gram-negative meningitides, administer intrathecally because of poor CNS penetration. Dosing regimens are numerous; adjust dose based on CrCl and changes in volume of distribution.

Dosing

Adult

Serious infections and normal renal function: 3 mg/kg/d IV q8h
Loading dose: 1-2.5 mg/kg IV
Maintenance: 1-1.5 mg/kg IV q8h
Extended dosing regimen for life-threatening infections: 5 mg/kg/d IV/IM q6-8h
Follow each regimen by at least a trough level drawn on the third or fourth dose (0.5 h before dosing); may draw a peak level 0.5 h after 30-min infusion

Pediatric

<5 years: 2.5 mg/kg/dose IV/IM q8h
>5 years: 1.5-2.5 mg/kg/dose IV/IM q8h or 6-7.5 mg/kg/d divided q8h; not to exceed 300 mg/d; monitor as in adults

Interactions

Coadministration with other aminoglycosides, cephalosporins, penicillins, and amphotericin B may increase nephrotoxicity; aminoglycosides enhance effects of neuromuscular blocking agents, thus, prolonged respiratory depression may occur; coadministration with loop diuretics may increase auditory toxicity of aminoglycosides; possible irreversible hearing loss of varying degrees may occur (monitor regularly)

Contraindications

Documented hypersensitivity; non–dialysis-dependent renal insufficiency

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Narrow therapeutic index (not intended for long-term therapy); caution in renal failure (not on dialysis), myasthenia gravis, hypocalcemia, and conditions that depress neuromuscular transmission; adjust dose in renal impairment

Antiviral agents

These agents interfere with viral replication; they weaken or abolish viral activity.

Acyclovir (Zovirax)

Prodrug activated by cellular enzymes. Inhibits activity of HSV-1, HSV-2, and varicella zoster virus by competing for viral DNA polymerase and incorporation into viral DNA. Used in HSV meningitis.

Dosing

Adult

1500 mg/m²/d or 10 mg/kg IV q8h for 14-28 d (encephalitis caused by HSV)

Pediatric

Administer as in adults

Interactions

Concomitant use of probenecid or zidovudine prolongs half-life and increases CNS toxicity

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in renal failure or when using nephrotoxic drugs, can precipitate in renal tubules; may cause delirium, lethargy, and seizures

Ganciclovir (Cytovene)

Synthetic guanine derivative active against CMV. An acyclic nucleoside analog of 2'-deoxyguanosine that inhibits replication of herpes viruses both 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.

Dosing

Adult

Induction: 5 mg/kg IV over 1 h q12h for 14-21 d (do not use PO ganciclovir for induction treatment)
Maintenance PO: 500 mg q4h or 1 g tid for life
Maintenance IV: 5 mg/kg qd for 5-7 d/wk

Pediatric

<3 months: Not established
>3 months: Administer as in adults

Interactions

Concomitant administration with cytotoxic drugs, such as dapsone, vinblastine, Adriamycin, pentamidine, flucytosine, vincristine, amphotericin B, TMP/SMX combinations, or other nucleoside analogs, may result in additive toxicity in bone marrow, spermatogonia, and germinal layers of skin and GI mucosa (coadminister only if potential benefits outweigh risks); coadministration with imipenem and cilastatin may cause generalized seizures (use only if potential benefits outweigh risks); serum creatinine may increase following concurrent use with either cyclosporine or amphotericin B; in the presence of probenecid, ganciclovir renal clearance is reduced; bioavailability may increase when didanosine is administered either 2 h prior to or simultaneously with ganciclovir; bioavailability may decrease in the presence of zidovudine, while bioavailability of zidovudine is increased in the presence of ganciclovir

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Clinical toxicity includes granulocytopenia, anemia, and thrombocytopenia; half-life and plasma/serum concentrations may be increased as a result of reduced renal clearance; dosages >6 mg/kg IV may result in increased toxicity; rapid infusions may result in increased toxicity; initially, reconstituted solutions of IV ganciclovir have a high pH (11); phlebitis or pain may occur at site of IV infusion despite further dilution in IV fluids; should be accompanied by adequate hydration; photosensitization (ie, photoallergy, phototoxicity) may occur

Antifungal agents

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

Amphotericin B, conventional (Amphocin, Fungizone)

Polyene antibiotic produced by a strain of S nodosus; can be fungistatic or fungicidal. Binds to sterols, such as ergosterol, in the fungal cell membrane, causing intracellular components to leak with subsequent fungal cell death. Used to treat severe systemic infection and meningitis caused by susceptible fungi (ie, C albicans, H capsulatum, C neoformans). Also available in liposomal (AmBisome) and lipid-complex (Abelcet) formulations. Amphotericin B does not penetrate the CSF well. Intrathecal amphotericin may be needed in addition.

Dosing

Adult

Conventional: 0.7-1.0 mg/kg/d IV infusion; not to exceed 1.5 mg/kg/d
Liposomal: 3-5 mg/kg/d IV infusion
Lipid-complex: 5 mg/kg/d IV infusion

Pediatric

Administer as in adults

Interactions

Antineoplastic agents may enhance the potential of amphotericin B for renal toxicity, bronchospasm, and hypotension; corticosteroids, digitalis, and thiazides may potentiate hypokalemia; the risk of renal toxicity is increased with cyclosporine

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in renal insufficiency, monitor renal function, serum electrolytes (eg, magnesium, potassium), liver function, CBC count, and hemoglobin concentrations; resume therapy at lowest level (eg, 0.25 mg/kg) when therapy is interrupted for longer than 7 d; hypoxemia, acute dyspnea, and interstitial infiltrates may occur in patients with neutropenia who are receiving leukocyte transfusions (separate time of amphotericin infusion from time of leukocyte transfusion); fever and chills are not uncommon after first few administrations of drug; rare acute reactions may include hypotension, bronchospasm, arrhythmias, and shock

Fluconazole (Diflucan)

Fungistatic activity. Synthetic PO antifungal (broad-spectrum bistriazole) that selectively inhibits fungal cytochrome P-450 and sterol C-14 alpha-demethylation, which prevents conversion of lanosterol to ergosterol, thereby disrupting cellular membranes.

Dosing

Adult

200-800 mg PO qd; not to exceed 1000 mg/d

Pediatric

3-6 mg/kg PO qd for 14-28 d or 6-12 mg/kg qd depending on severity of infection

Interactions

Levels may increase with hydrochlorothiazides; fluconazole levels may decrease with long-term coadministration of rifampin; may increase concentrations of theophylline, phenytoin, tolbutamide, cyclosporine, glyburide, and glipizide; effects of anticoagulants may increase with fluconazole coadministration

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Adjust dose for renal insufficiency; monitor closely if rashes develop and discontinue drug if lesions progress; may cause clinical hepatitis, cholestasis, and fulminant hepatic failure (including death) with underlying medical conditions (eg, AIDS, malignancy) and while taking multiple concomitant medications; not recommended for breastfeeding women

Antitubercular agents

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

Rifampin (Rifadin, Rimactane)

Used in combination with other antituberculous drugs. Inhibits DNA-dependent bacterial but not mammalian RNA polymerase. Cross-resistance may occur.

Dosing

Adult

600 mg PO/IV qd

Pediatric

10-20 mg/kg PO/IV; not to exceed 600 mg/d

Interactions

Induces microsomal enzymes, which may decrease effects of acetaminophen, PO anticoagulants, barbiturates, benzodiazepines, beta-blockers, chloramphenicol, PO contraceptives, corticosteroids, mexiletine, cyclosporine, digitoxin, disopyramide, estrogens, hydantoins, methadone, clofibrate, quinidine, dapsone, tazobactam, sulfonylureas, theophyllines, tocainide, and digoxin; blood pressure may increase with coadministration of enalapril; coadministration with isoniazid may result in a higher rate of hepatotoxicity than with either agent alone (discontinue one or both agents if alterations in LFTs occur)

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Obtain CBC counts and baseline clinical chemistries prior to and throughout therapy; in liver disease, weigh benefits against risk of further liver damage; interruption of therapy and high-dose intermittent therapy are associated with thrombocytopenia that is reversible if therapy is discontinued as soon as purpura occurs; if treatment is continued or resumed after appearance of purpura, cerebral hemorrhage or death may occur

Isoniazid (Laniazid, Nydrazid)

First-line antituberculous drug used in combination with other antituberculous drugs to treat meningitis. Usually administered for at least 12-24 mo. Prophylactic dose of pyridoxine (6-50 mg/d) is recommended if peripheral neuropathies secondary to isoniazid therapy develop.

Dosing

Adult

5 mg/kg PO qd (usually 300 mg/d) and 10 mg/kg qd or divided bid in patients with disseminated disease; not to exceed 300 mg/d

Pediatric

10-20 mg/kg PO qd; not to exceed 300 mg/d

Interactions

Higher incidence of isoniazid-related hepatitis can occur with daily alcohol ingestion; aluminum salts may decrease isoniazid serum levels (administer 1-2 h before taking aluminum salts); may increase the effect of anticoagulants with coadministration; may inhibit metabolic clearance of benzodiazepines; carbamazepine toxicity or isoniazid hepatotoxicity may result from concurrent use (monitor carbamazepine concentrations and liver function); coadministration with cycloserine may increase adverse CNS effects (eg, dizziness); acute behavioral and coordination changes may occur with coadministration of disulfiram; coadministration with rifampin after halothane anesthesia may result in hepatotoxicity and hepatic encephalopathy; may inhibit hepatic microsomal enzymes and increase toxicity of hydantoin

Contraindications

Documented hypersensitivity; previous isoniazid-associated hepatic injury or other severe adverse reactions

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Monitor patients with active chronic liver disease

Pyrazinamide (PZA)

Pyrazine analog of nicotinamide that may be bacteriostatic or bactericidal against M tuberculosis, depending on the concentration of drug attained at the site of infection; mechanism of action is unknown.

Dosing

Adult

15-30 mg/kg PO qd; not to exceed 2 g/d

Pediatric

Administer as in adults

Interactions

None reported

Contraindications

Documented hypersensitivity; severe hepatic damage; acute gout

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Use only in combination with other effective antituberculous agents; inhibits renal excretion of urates; may result in hyperuricemia (usually asymptomatic); perform baseline serum uric acid determinations; discontinue if signs of hyperuricemia with acute gouty arthritis occur; obtain baseline LFTs (closely monitor in liver disease); discontinue if signs of hepatocellular damage appear; caution in history of diabetes mellitus; pyrazinamide is not usually administered in pregnant patients unless they are HIV-infected or drug resistance to other antitubercular drugs is suspected or known (see pregnancy precaution)

Ethambutol (Myambutol)

Diffuses into actively growing mycobacterial cells (eg, tubercle bacilli). Impairs cell metabolism by inhibiting synthesis of one or more metabolites, which, in turn, causes cell death. No cross-resistance demonstrated. Mycobacterial resistance is frequent with previous therapy. Use in these patients in combination with second-line drugs that have not been administered previously. Administer q24h until permanent bacteriological conversion and maximal clinical improvement is observed. Absorption is not significantly altered by food.

Dosing

Adult

No previous antituberculous therapy: 15 mg/kg (7 mg/lb) PO qd
Previous antituberculous therapy: 25 mg/kg (11 mg/lb) PO qd

Pediatric

<13 years: Not recommended
>13 years: Administer as in adults

Interactions

Aluminum salts may delay and reduce absorption (administer several h before or after ethambutol dose)

Contraindications

Documented hypersensitivity; optic neuritis (unless clinically indicated)

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Reduce dose in impaired renal function; may have adverse visual effects that may be reversible if promptly discontinued

Follow-up

Further Inpatient Care

• Vigilant surveillance for the development of complications is required.
• Seizure precautions are indicated, especially for patients with impaired mental function.
• Proper isolation precautions are indicated in cases of invasive meningococcal disease.
• Monitor patients for potential adverse effects of medications, such as hypersensitivity reactions, cytopenia, or liver dysfunction.
• Drug-level monitoring may be needed for some antibiotics such as vancomycin and the aminoglycosides.

Deterrence/Prevention

• Vaccination
  • The use of the HIB vaccination is strongly recommended in susceptible individuals.
  • Vaccination against S pneumoniae is strongly encouraged in susceptible individuals, including individuals older than 65 years and those with chronic cardiopulmonary illnesses.
  • Vaccinations against encapsulated bacterial organisms (eg, S pneumoniae, N meningitidis) are encouraged for those with functional or structural asplenia. Always administer vaccinations expediently to individuals who undergo splenectomy.
  • Offer vaccination with quadrivalent meningococcal polysaccharide vaccine to all high-risk populations, including those with underlying immune deficiencies, those who travel to hyperendemic areas and epidemic areas, and those involved with laboratory work that deals with routine exposure to N meningitidis. College students who live in dormitories or residence halls are at modest risk; inform them about the risk and offer vaccination.
  • Vaccination against N meningitidis is recommended for all adolescents aged 11-18 years. 
  • Vaccination against measles and mumps effectively eliminates aseptic meningitis syndrome caused by these pathogens.
• Chemoprophylaxis
  • Following exposure to an index case, temporary nasopharyngeal carriage is characteristic for H influenzae, N meningitidis, and S pneumoniae. 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 following recommendations on chemoprophylaxis. However, this prophylaxis does not treat incubating invasive disease, and closely monitor individuals at highest risk.
  • H influenzae type b
    • To eliminate nasopharyngeal carriage and to decrease invasion of colonized susceptible individuals, use rifampin (20 mg/kg/d) for 4 days.
    • The index patient may need chemoprophylaxis if the administered treatment does not eliminate carriage.
  • N meningitidis
    • Prophylaxis is suggested for contacts of persons with meningococcal meningitis.
    • These contacts include 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 q12h) for 2 days has been shown to rapidly eradicate the carrier stage, and the prophylaxis persists for as long as 10 weeks following treatment.
    • Alternative agents include ceftriaxone (250 mg IM) as a single dose in adults. It also is the safest choice in pregnant patients. It has been shown to eradicate the carrier state for 14 days. Ciprofloxacin (500-750 mg) as a single dose also is efficacious.

Complications

• Even with effective antimicrobial therapy, significant neurologic complications have been reported to occur in as many as 30% of survivors following an episode of bacterial meningitis. Closely monitor for the development of these complications.
• Cranial nerve palsies and the effects of impaired cerebral blood flow, such as cerebral infarction, are caused by increased ICP.
• Other early complications include the development of venous sinus thrombosis, obstruction of CSF flow, or the formation of subdural empyema and brain abscess.
• The long-term neurologic sequelae can be grouped into 3 categories as follows:
  • Hearing impairment
  • Obstructive hydrocephalus
  • Brain parenchymal damage: This is the most important feared complication of bacterial meningitis. It could lead to sensory and motor deficits, cerebral palsy, learning disabilities, mental retardation, cortical blindness, and seizures.

Prognosis

• Patients with viral meningitis usually have a good prognosis for recovery.
• The prognosis is worse for patients at the extremes of age (ie, <2 y, >60 y) and those with significant comorbidities and underlying immunodeficiency.
• Patients presenting with an impaired level of consciousness are at increased risk for developing neurologic sequelae or dying.
• A seizure during an episode of meningitis also is a risk factor for mortality or neurologic sequelae.
• Acute bacterial meningitis is a medical emergency and delays in instituting effective antimicrobial therapy result in increased morbidity and mortality.
• The presence of low-level pleocytosis (<20 cells) in patients with bacterial meningitis suggests a poorer outcome.
• Meningitis caused by S pneumoniae, L monocytogenes, and gram-negative bacilli has a higher case-fatality rate compared to meningitis caused by other bacterial agents.
• The prognosis of meningitis caused by opportunistic pathogens also depends on the underlying immune function of the host. Many of the survivors require lifelong suppressive therapy (eg, long-term fluconazole for suppression in patients with HIV-associated cryptococcal meningitis).

Patient Education

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

Miscellaneous

Medicolegal Pitfalls

• Failure to recognize and entertain the diagnosis in a patient with fever, meningismus, and headache
• Failure to expediently initiate antibacterial therapy because of delays associated with unnecessary radiographic studies
• Failure to implement prophylactic treatment in exposed individuals (eg, health care workers and family members in close contact with a patient who has invasive meningococcus disease)

Multimedia

Media file 1: Pneumococcal meningitis in a patient with alcoholism. Courtesy of the CDC/Dr. Edwin P. Ewing, Jr.

References

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Keywords

bacterial meningitis, aseptic meningitis, viral meningitis, tuberculous meningitis, syphilitic meningitis, Lyme meningitis, cryptococcal meningitis, fungal meningitis, parasitic meningitis, inflammation of the meninges, headache, nuchal rigidity, photophobia, pleocytosis, acute meningitis, chronic meningitis, Streptococcus pneumoniae meningitis, meningococcal meningitis, Haemophilus influenzae meningitis, Histoplasma meningitis, amebic meningoencephalitis

Contributor Information and Disclosures

Author

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.

Coauthor(s)

Michael R Keating, MD, Consultant, Assistant Professor of Medicine, 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.

Medical Editor

Joseph Richard Masci, MD, Chief of Infectious Diseases, Associate Director, Associate Professor, Department of Internal Medicine, Division of Infectious Diseases, Elmhurst Hospital Center, Mount Sinai School of Medicine
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

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: emedicine $50.00 author of chapter

CME Editor

Eleftherios Mylonakis, MD, Clinical and Research Fellow, Department of Internal Medicine, Division of Infectious Diseases, Massachusetts General Hospital
Eleftherios Mylonakis, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American Society for Microbiology, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Chief Editor

Burke A Cunha, MD, Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital
Burke A Cunha, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Clinical trials

Oral Glycerol and High-Dose Rectal Paracetamol to Improve the Prognosis of Childhood Bacterial Meningitis (GLYIP)

IHPOTOTAM : Induced HyPOthermia TO Treat Adult Meningitis

Study Evaluating Pneumococcal Meningitis in the Paediatric Population in Spain Four Years After the Marketing of Prevenar.

Understanding the Immune Response to Meningitis Vaccines

Disease Burden Of Pneumonia, Meningitis and Bacteremia Among Children in Japan:Pneumonet Japan

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