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

cord. They consist of the following: Dura - A tough outer membrane Arachnoid - A lacy, weblike middle membrane Subarachnoid space - A delicate, fibrous inner layer that contains many of the blood vessels that feed the brain and spinal cord Risk factors for meningitis include the following: Age of 60 years or greater Age of 5 years or less Diabetes mellitus, renal or adrenal insufficiency, hypoparathyroidism, orcystic fibrosis Immunosuppression, which increases the risk of opportunistic infections and acute bacterial meningitis Human immunodeficiency virus (HIV) infection, which predisposes to bacterial meningitis caused by encapsulated organisms, primarily S pneumoniae, and opportunistic pathogens Crowding (eg, military recruits and college dorm residents), which increases the risk of outbreaks of meningococcal meningitis Splenectomy and sickle cell disease, which increase the risk of meningitis secondary to encapsulated organisms Alcoholism and cirrhosis Recent exposure to others with meningitis, with or without prophylaxis Contiguous infection (eg, sinusitis) Dural defect (eg, traumatic, surgical, congenital) Thalassemia major Intravenous (IV) drug abuse Bacterial endocarditis Ventriculoperitoneal shunt Malignancy (increased risk of Listeria species infection) Some cranial congenital deformities Clinically, meningitis manifests with meningeal symptoms (eg, headache, nuchal rigidity, photophobia), as well as pleocytosis (an increased number of white blood cells) in the cerebrospinal fluid (CSF). Depending on the duration of symptoms, meningitis may be classified as acute or chronic. (See Etiology and Clinical Presentation.) Meningitis is anatomically divided into inflammation of the dura, sometimes referred to as pachymeningitis, which is less common, and leptomeningitis, which is more common and is defined as inflammation of the arachnoid tissue and subarachnoid space. (See Anatomy.) Meningitis can also be divided into the following 3 general categories: Pyogenic (bacterial) Granulomatous Lymphocytic The most common cause of meningeal inflammation is irritation caused by bacterial or viral infections. The organisms usually enter the meninges through the bloodstream from other parts of the body. Most cases of bacterial meningitis are localized over the dorsum of the brain; however, under certain conditions, meningitis may be concentrated at the base of the brain, such as with fungal diseases and tuberculosis. (See Etiology.) Pyogenic (bacterial) meningitis consists of inflammation of the meninges and the underlying subarachnoid CSF. If not treated, bacterial meningitis may lead to lifelong debility or death.[1] [2] The disease was uniformly fatal before the antimicrobial era, but with the advent of antimicrobial therapy, the overall mortality rate from bacterial meningitis has decreased. Nonetheless, it remains alarmingly high, being approximately 25%. (See Epidemiology.) The emergence of resistant bacterial strains has prompted changes in antibiotic protocols in some countries, including the United States. Apart from dexamethasone, neuronal cell protectants still hold only future promise as adjunctive therapy. (See Treatment and Management and Medication.)

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

Abscess formation

Chronic mastoiditis and epidural empyema in a patient with bacterial meningitis. This axial computed tomography scan shows sclerosis of the temporal bone (chronic mastoiditis), an adjacent epidural empyema with marked dural enhancement (arrow), and the absence of left mastoid air.

Subdural empyema and arterial infarct in a patient with bacterial meningitis. This contrast-enhanced axial computed tomography scan shows left-sided parenchymal hypoattenuation in the middle cerebral artery territory, with marked herniation and a prominent subdural empyema.

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

Acute bacterial meningitis

Acute bacterial meningitis denotes a bacterial cause of this syndrome. This is usually characterized by an acute onset of meningeal symptoms and neutrophilic pleocytosis. Depending on the specific bacterial cause, the syndrome may be called, for example, any of the following: Pneumococcal meningitis Haemophilus influenzae meningitis Staphylococcal meningitis Meningococcal meningitis Tuberculous meningitis Unlike subacute (1-7 d) or chronic (>7 d) meningitis, which have myriad infectious and noninfectious etiologies, acute meningitis (< 1 d) is almost always a bacterial infection caused by 1 of several organisms. Depending on age and general condition, these gravely ill patients present acutely with signs and symptoms of meningeal inflammation and systemic infection of less than 24 hours' duration (and

usually >12 hours duration). Patients with acute bacterial meningitis may decompensate very quickly, and so they require emergency care, including antimicrobial therapy, ideally within 30 minutes of emergency department (ED) presentation. For more information, see the following:

Meningococcal Meningitis Staphylococcal Meningitis Haemophilus Meningitis Tuberculous Meningitis

Subacute bacterial meningitis

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

Meningitis caused by nonbacterial organisms

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

Viral meningitis
If, after an extensive workup, aseptic meningitis is found to have a viral etiology, it can be reclassified as a form of acute viral meningitis (eg, enterovirus meningitis, herpes simplex virus [HSV] meningitis). Go to Viral Meningitis for complete information on this topic.

Aseptic meningitis
In many cases, a cause for meningitis is not apparent after initial evaluation and is therefore classified as aseptic meningitis. These patients characteristically have an acute onset of meningeal symptoms, fever, and cerebrospinal pleocytosis that is usually prominently lymphocytic. When the cause of aseptic meningitis is discovered, the disease can be reclassified according to its etiology. If appropriate diagnostic methods are performed, a specific viral etiology is identified in 55-70% of cases of aseptic meningitis. However, the condition can also be caused by bacterial, fungal, mycobacterial, and parasitic agents.

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

PATHOPHYSIOLOGY
The brain is naturally protected from the body's immune system by a barrier the meninges create between the bloodstream and the brain. Normally, this protection is an advantage because the barrier prevents the body from attacking itself. However, in meningitis, the barrier can become a problem; once bacteria or other organisms have found their way to the brain, they are somewhat isolated from the immune system and can spread. When the body tries to fight the infection, the problem can worsen; blood vessels become leaky and allow fluid, white blood cells, and other infection-fighting particles to enter the meninges and brain. This process, in turn, causes brain swelling and can eventually result in decreasing blood flow to parts of the brain, worsening the symptoms of infection.[3] Depending on the severity of bacterial meningitis, the inflammatory process may remain confined to the subarachnoid space. In less severe forms, the pial barrier is not penetrated, and the underlying parenchyma remains intact. However, in more severe forms of bacterial meningitis, the pial barrier is broken, and the underlying parenchyma is invaded by the inflammatory process. Thus, bacterial meningitis may lead to widespread cortical destruction, particularly when left untreated. Replicating bacteria, increasing numbers of inflammatory cells, cytokine-induced disruptions in membrane transport, and increased vascular and membrane permeability perpetuate the infectious process in bacterial meningitis and account for the characteristic changes in CSF cell count, pH, lactate, protein, and glucose in patients with this disease. Exudates extend throughout the CSF, particularly to the basal cisterns, damaging cranial nerves (eg, cranial nerve VIII, with resultant hearing loss), obliterating CSF pathways (causing obstructive hydrocephalus), and inducing vasculitis and thrombophlebitis (causing local brain ischemia).

Intracranial pressure and cerebral brain fluid

One complication of meningitis is the development of increased intracranial pressure (ICP). The pathophysiology of this complication is complex and may involve many proinflammatory molecules as well as mechanical elements. Interstitial edema (secondary to obstruction of CSF flow, as in hydrocephalus), cytotoxic edema (swelling of cellular elements of the brain through the release of toxic factors from the bacteria and neutrophils), and vasogenic edema (increased blood brain barrier permeability) are all thought to play a role in the development of increased ICP. Without medical intervention, the cycle of decreasing cerebral brain fluid (CBF), worsening cerebral edema, and increasing ICP proceeds unchecked. Ongoing endothelial injury may result in vasospasm and thrombosis, further compromising CBF, and may lead to stenosis of large and small vessels. Systemic hypotension (septic shock) also may impair CBF, and the patient soon dies from systemic complications or from diffuse CNS ischemic injury.

Cerebral edema
The increased CSF viscosity resulting from the influx of plasma components into the subarachnoid space and diminished venous outflow lead to interstitial edema, and the products of bacterial degradation, neutrophils, and other cellular activation lead to cytotoxic edema. The ensuing cerebral edema (ie, vasogenic, cytotoxic, interstitial) significantly contributes to intracranial hypertension and a consequent decrease in cerebral blood flow. Anaerobic metabolism ensues, which contributes to increased lactate concentration and hypoglycorrhachia. In addition, hypoglycorrhachia results from decreased glucose transport into the spinal fluid compartment. Eventually, if this uncontrolled process is not modulated by effective treatment, transient neuronal dysfunction or permanent neuronal injury results.

The role of cytokines and secondary mediators in bacterial meningitis

Key advances in understanding the pathophysiology of meningitis include insight into the pivotal roles of cytokines (eg, tumor necrosis factor-alpha [TNF-alpha], interleukin [IL]-1), chemokines (IL-8), and other proinflammatory molecules in the pathogenesis of pleocytosis and neuronal damage during occurrences of bacterial meningitis. Increased CSF concentrations of TNF-alpha, IL-1, IL-6, and IL-8 are characteristic findings in patients with bacterial meningitis. (Cytokine levels, including those of IL-6, TNF-alpha, and interferon-gamma, have been found to be elevated in patients with aseptic meningitis.) The proposed events involving these inflammation mediators in bacterial meningitis begin with the exposure of cells (eg, endothelial cells, leukocytes, microglia, astrocytes, and meningeal macrophages) to bacterial products released during replication and death; this exposure incites the synthesis of cytokines and proinflammatory mediators. Data indicate that this process is likely initiated by the ligation of the bacterial components (eg, peptidoglycan, lipopolysaccharide) to pattern-recognition receptors, such as the Toll-like receptors. TNF-alpha and IL-1 are most prominent among the cytokines that mediate this inflammatory cascade. TNF-alpha is a glycoprotein derived from activated monocyte-macrophages, lymphocytes, astrocytes, and microglial cells. IL-1, previously known as endogenous pyrogen, is also produced primarily by activated mononuclear phagocytes and is responsible for the induction of fever during bacterial infections. Both molecules have been detected in the CSF of individuals with bacterial meningitis. In experimental models of meningitis, they appear early during the course of disease and have been detected within 30-45 minutes of intracisternal endotoxin inoculation. Many secondary mediators, such as IL-6, IL-8, nitric oxide, prostaglandins (PGE2), and platelet activation factor (PAF), are presumed to amplify this inflammatory event, either synergistically or independently. IL-6 induces acute-phase reactants in response to bacterial infection. The chemokine IL-8 mediates neutrophil chemoattractant responses induced by TNF-alpha and IL-1. Nitric oxide is a free radical molecule that can induce cytotoxicity when produced in high amounts. PGE2, a product of cyclo-oxygenase (COX), appears to participate in the induction of increased blood-brain barrier permeability. PAF, with its myriad biologic activities, is believed to mediate the formation of thrombi and the activation of clotting factors within the vasculature. However, the precise roles of all these secondary mediators in meningeal inflammation remain unclear. The net result of the above processes is vascular endothelial injury and increased blood-brain barrier permeability, leading to the entry of many blood components into the subarachnoid space. In many patients, this contributes to vasogenic edema and elevated CSF protein levels. In response to the cytokines and chemotactic molecules, neutrophils migrate from the bloodstream and penetrate the damaged blood-brain barrier, producing the profound neutrophilic pleocytosis characteristic of bacterial meningitis.

Bacterial seeding
Bacterial seeding usually occurs by hematogenous spread. Organisms typically enter the meninges through the bloodstream, from other parts of the body. In patients without an identifiable source of infection, local tissue and bloodstream invasion by bacteria colonized in the nasopharynx may be a common source. Many meningitis-causing bacteria are carried in the nose and throat, often without symptoms in the carrier. Most meningeal pathogens are transmitted through the respiratory route, as exemplified by the fact that Neisseria meningitidis (meningococcus) is carried nasopharyngeally and by the nasopharyngeal colonization with Streptococcus pneumoniae(pneumococcus). Certain respiratory viruses are thought to enhance the entry of bacterial agents into the intravascular compartment, presumably by damaging mucosal defenses. Once inside the bloodstream, the infectious agent must escape immune surveillance (eg, antibodies, complement-mediated bacterial killing, and neutrophil phagocytosis). Subsequently, hematogenous seeding into distant sites occurs, including the CNS. The specific pathophysiologic mechanisms by which the infectious agents gain access into the subarachnoid space remain unclear.

Once inside the CNS, the infectious agents likely survive because host defenses (eg, immunoglobulins, neutrophils, complement components) appear to be limited in this body compartment. The presence and replication of infectious agents remain uncontrolled and incite a cascade of meningeal inflammation. This process of meningeal inflammation has been an area of extensive investigation in recent years that has led to a better understanding of meningitis pathophysiology. Bacterial seeding results in increased permeability of the blood-brain barrier, cerebral edema, and the presence of toxic mediators in the CSF. Inflammations are characterized by polymorphonuclear cell infiltration and extensive fibrinous exudation, which extends throughout the CSF, basal cisterns, and cranial nerves. Acute leptomeningitis results in congestion and hyperemia of the pia-arachnoid and distention of the subarachnoid space by the exudates. Once in the CSF, the paucity of antibodies, complement components, and white blood cells allows the bacterial infection to flourish. Bacterial cell wall components initiate a cascade of complement- and cytokine-mediated events that result in increased permeability of the blood-brain barrier, cerebral edema, and the presence of toxic mediators in the CSF.

ETIOLOGY
Initially, an infectious agent colonizes or establishes a localized infection in the host. This may be in the form of colonization or infection of the skin, nasopharynx, respiratory tract, GI tract, or genitourinary tract. The organism invades the submucosa by circumventing host defenses (eg, physical barriers, local immunity, phagocytes/macrophages). The following 3 major pathways exist by which an infectious agent (ie, bacterium, virus, fungus, and parasite) gains access to the CNS and causes meningeal disease: Invasion of the bloodstream (ie, bacteremia, viremia, fungemia, parasitemia) and subsequent hematogenous seeding of the CNS. A retrograde neuronal (ie, olfactory and peripheral nerves) pathway (eg,Naegleria fowleri, Gnathostoma spinigerum) Direct contiguous spread (ie, sinusitis, otitis media, congenital malformations, trauma, direct inoculation during intracranial manipulation) Invasion of the bloodstream, and subsequent seeding, is the most common mode of spread for most agents (eg, meningococcal, cryptococcal, syphilitic, and pneumococcal meningitis). Rarely, infected contiguous structures invade via septic thrombi or osteomyelitic erosion; meningeal seeding may also occur with a direct bacterial inoculate during trauma, neurosurgery, or instrumentation. Meningitis in the newborn is transmitted vertically from colonized pathogens in the maternal intestinal or genital tract or horizontally from nursery personnel or caregivers at home. Local extension from contiguous extracerebral infection (eg, otitis media, mastoiditis, or sinusitis) is a common cause. Possible pathways for the migration of pathogens from the middle ear to the meninges include the following: A systemic route in the bloodstream Along preformed tissue planes (eg, posterior fossa) Temporal bone fractures The oval or round window membranes of the labyrinths In HIV-positive/AIDS patients, consider cryptococci, Mycobacterium tuberculosis, syphilis, HIV aseptic meningitis, and Listeria species. If the pathogen is unknown after an ED workup, draw a serum/CSF cryptococcal antigen and treat empirically as in adults older than 50 years (pending results of all blood and CSF tests) to cover the bacterial pathogens, particularly S pneumoniae and L monocytogenes, for which this patient population is most at risk . Go to HIV-1 Associated CNS Conditions - Meningitis for complete information on this topic. In patients who have had trauma or neurosurgery, the most common microorganisms are S pneumoniae (if CSF leak is present), Staphylococcus aureus, coliforms, and P aeruginosa. In patients with infected ventriculoperitoneal (atrial) shunt, the most common microorganisms areStaphylococcus epidermidis, S aureus, coliforms, Propionibacterium acnes,and diphtheroids (rare). Consult a neurosurgeon, since early shunt removal is usually necessary for cure. In patients with aseptic meningitis (CSF pleocytosis and normal CSF glucose, negative bacteria on Gram stain), the most common microorganisms are enteroviruses, human herpesvirus-2 (HHV-2), lymphocytic choriomeningitis virus (LCM), HIV, and other viruses. Other etiologies include drugs (NSAIDs, metronidazole, IV immunoglobulin) and, rarely, leptospirosis. Manage by repeating LP if necessary to rule out partially treated bacterial meningitis.

Pachymeningitis

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

Meningitis caused by Haemophilus influenzae

H influenzae is a small, pleomorphic, gram-negative coccobacilli that is frequently found as part of the normal flora in the upper respiratory tract of humans. It can spread from one individual to another by airborne droplets or direct contact with secretions. Meningitis is the most serious acute manifestation of systemic infection withH influenzae. The encapsulated type B strain of this bacterium is the form ofH influenzae that most often causes meningitis. The isolation of H influenzae in adults suggests the presence of an underlying medical disorder, such as the following: Paranasal sinusitis Otitis media Alcoholism CSF leak following head trauma Functional or anatomic asplenia Hypogammaglobulinemia Go to Haemophilus Meningitis for complete information on this topic.

Meningitis caused by Streptococcus pneumoniae

S pneumoniae, a gram-positive coccus, is the most common bacterial cause of meningitis. In addition, it is the most common bacterial agent in meningitis associated with basilar skull fracture and CSF leak. It may be associated with other foci of infection, such as pneumonia, sinusitis, or endocarditis (ie, Austrian syndrome). S pneumoniae is a common colonizer of the human nasopharynx (5-10% of healthy adults and 20-40% of healthy children). It causes meningitis by escaping the local host defenses and phagocytic mechanisms, either through choroid plexus seeding from bacteremia or through direct extension from sinusitis or otitis media. Patients with the following conditions are at increased risk for S pneumoniaemeningitis: Hyposplenism Hypogammaglobulinemia Multiple myeloma Glucocorticoid treatment Defective complement (C1-C4) Diabetes mellitus Renal insufficiency Alcoholism Malnutrition Chronic liver disease Meningitis caused by Streptococcus agalactiae Streptococcus agalactiae (group B streptococci) is a gram-positive coccus that is isolated from the lower gastrointestinal tract. It also colonizes the female genital tract at a rate of 5-40%, which explains why it is the most common (70%) agent of neonatal meningitis. Predisposing risks in adults include the following: Diabetes mellitus Pregnancy Alcoholism

Hepatic failure Renal failure Corticosteroid treatment In 43% of adult cases, however, no underlying disease is present. Meningitis caused by Neisseria meningitides N meningitides is a gram-negative diplococcus that is carried in the nasopharynx of otherwise healthy individuals. It initiates invasion by penetrating the airway epithelial surface. The precise mechanism by which this occurs is unclear, but recent viral or mycoplasmal infection has been reported to disrupt the epithelial surface and facilitate invasion by meningococcus. Most sporadic cases (95-97%) are caused by serogroups B, C, and Y, while the A and C strains are observed in epidemics (< 3% of cases). Currently, it is the leading cause of bacterial meningitis in children and young adults, accounting for 59% of cases. Risk factors for Neisseria meningitis include the following:

Deficiencies in terminal complement components (eg, membrane attack complex, C5-C9), which increases attack rates but is associated with surprisingly lower mortality rates Properdin defects that increase the risk of invasive disease Antecedent viral infection, household crowding, chronic medical illness, corticosteroid use, and active or passive smoking Overcrowding, as is observed in college dormitories (college freshmen living in dormitories are at highest risk) and military facilities, which has been reported for a clustering of cases Meningitis caused by Listeria monocytogenes Listeria monocytogenes is a small gram-positive bacillus that causes 8% of bacterial meningitis cases and is associated with one of the highest mortality rates (22%). It is widespread in nature and has been isolated in the human stool of 5% of healthy adults. Most human cases appear to be food-borne. It is a common food contaminant, with a recovery rate of up to 70% from raw meat, vegetables, and meats. Outbreaks have been associated with consumption of contaminated coleslaw, milk, cheese, and alfalfa tablets. At-risk groups include the following: Pregnant women Infants and children Elderly individuals (>60 y) Patients with alcoholism Adults who are immunosuppressed (eg, steroid use, transplant recipients, patients with acquired immunodeficiency syndrome [AIDS]) Individuals with chronic liver and renal disease Individuals with diabetes Persons with iron-overload conditions (eg, hemochromatosis or transfusion-induced iron overload)

Meningitis caused by gram-negative bacilli

As a group, gram-negative bacilli can cause meningitis in certain groups of patients. Aerobic gramnegative bacilli include Escherichia coli, Klebsiella pneumoniae, Serratia marcescens, Pseudomonas aeruginosa, andSalmonella species. E coli are a common agent of meningitis among neonates. Other predisposing risk factors for meningitis associated with gram-negative bacilli include the following: Neurosurgical procedures or intracranial manipulation Old age Immunosuppression High-grade gram-negative bacillary bacteremia Disseminated strongyloidiasis

Disseminated strongyloidiasis has been reported as a classic cause of gram-negative bacillary bacteremia, as a result of the translocation of gut microflora with the Strongyloides stercoralis larva during hyperinfection syndrome. Staphylococcus -associated meningitis Staphylococci species are gram-positive cocci that are part of the normal skin flora. Meningitis caused by staphylococci is associated with the following risk factors: Status post neurosurgery and post trauma Presence of CSF shunts Infective endocarditis and paraspinal infection Staphylococcus epidermidis is the most common cause of meningitis in patients with CNS (ie, ventriculoperitoneal) shunts. Go to Staphylococcal Meningitis for complete information on this topic.

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

L monocytogenes

Brucella species

Rickettsia rickettsii

Ehrlichia species

Mycoplasma pneumoniae

Borrelia burgdorferi

Treponema pallidum

Leptospira species

Mycobacterium tuberculosis

Nocardia species

Parasites

N fowleri

Acanthamoeba species

Balamuthia species

Angiostrongylus cantonensis

G spinigerum

Baylisascaris procyonis

S stercoralis

Taenia solium (cysticercosis)

Fungi

Cryptococcus neoformans

C immitis

Blastomyces dermatitidis

H capsulatum

Candida species

Aspergillus species

Viruses

Enterovirus

Poliovirus

Echovirus

Coxsackievirus A

Coxsackievirus B

Enterovirus 68-71

Herpesvirus

HSV-1 and HSV-2

Varicella-zoster virus

EBV

CMV

HHV*-6

HHV-7

Paramyxovirus

Mumps virus

Measles virus

Togavirus

Rubella virus

Flavivirus

Japanese encephalitis virus

St. Louis encephalitis virus

Bunyavirus

California encephalitis virus

La Crosse encephalitis virus

Alphavirus

Eastern equine encephalitis virus

Western equine encephalitis virus

Venezuelan encephalitis virus

Reovirus

Colorado tick fever virus

Arenavirus

LCM virus**

Rhabdovirus

Rabies virus

Retrovirus

HIV***

*Human herpes virus

**Lymphocytic choriomeningitis

***Human immunodeficiency virus

Enteroviruses account for 90% of cases of aseptic meningitis. The enteroviruses belong to the family Picornaviridae and are further classified as follows: Poliovirus (3 serotypes) Coxsackievirus A (23 serotypes) Coxsackievirus B (6 serotypes) Echovirus (31 serotypes) Newly recognized enterovirus serotypes 68-71 The virus is usually spread by fecal-oral or respiratory routes; infection occurs during summer and fall in temperate climates and year-round in tropical regions. The nonpolio enteroviruses (NPEV) account for approximately 90% of cases of viral meningitis in which a specific pathogen can be identified. Echovirus 30 was reported as the cause of an epidemic in Japan in 1991 and also as the cause of 20% of cases of aseptic meningitis reported to the Centers for Disease Control and Prevention (CDC) in 1991. The Herpesviridae family consists of large, DNA-containing enveloped viruses. Eight members are known to cause human infections, and all have been implicated in meningitis syndromes, with the exception of HHV-8 or Kaposi sarcomaassociated virus. HSV accounts for 0.5-3% of cases of aseptic meningitis; it is most commonly associated with primary genital infection and is less likely during recurrences. HSV-1 is a cause of encephalitis, while HSV-2 more commonly causes meningitis. Although Mollaret syndrome, a recurrent, but benign, aseptic meningitis syndrome, is more frequently associated with HSV-2; HSV-1 has also been implicated as a cause. Epstein-Barr virus (EBV, or HHV-4) and cytomegalovirus (CMV, or HHV-5) may manifest as meningitis during the mononucleosis syndrome. Varicella-zoster virus (VZV), or HHV-3, and CMV are causes of meningitis in immunocompromised hosts, especially patients with acquired immunodeficiency syndrome (AIDS) and transplant recipients. HHV-6 and HHV-7 have been reported to cause meningitis in transplant recipients. The most common arthropod-borne viruses are St. Louis encephalitis virus (a flavivirus), Colorado tick fever virus, and California encephalitis virus (bunyavirus group, including La Crosse encephalitis virus). St. Louis encephalitis virus is a mosquito-borne flavivirus that may cause a febrile syndrome, aseptic meningitis syndrome, and encephalitis. Other members of the flavivirus group that may cause aseptic meningitis include tick-borne encephalitis virus and Japanese encephalitis virus. California encephalitis is a common childhood disease of the CNS that is caused by a virus in the genus Bunyavirus. Most of the cases of California encephalitis are probably caused by mosquito-borne La Crosse encephalitis virus. LCM virus is a member of the arenaviruses, a family of single-stranded, RNA-containing viruses in which rodents are the animal reservoir. The modes of transmission include aerosols and direct contact with rodents.

Outbreaks have also been traced to infected laboratory mice and hamsters. The mumps virus is the most common cause of aseptic meningitis in unimmunized populations, occurring in 30% of all patients with mumps. Following exposure, an incubation period of approximately 5-10 days ensues, followed by a nonspecific febrile illness and an acute onset of aseptic meningitis. This may be associated with orchitis, arthritis, myocarditis, and alopecia. Aseptic meningitis syndrome may be the presenting symptom in a patient with acute HIV infection. This usually is part of the mononucleosis-like acute seroconversion phenomenon. Always suspect HIV as a cause of aseptic meningitis in a patient with risk factors such as intravenous drug use and in individuals who practice high-risk sexual behaviors. Adenovirus (serotypes 1, 6, 7, and 12) has been associated with cases of meningoencephalitis. Chronic meningoencephalitis has been reported with serotypes 7, 12, and 32. The infection is usually acquired through a respiratory route. Go to Aseptic Meningitis for complete information on this topic.

Chronic meningitis
The agents responsible for chronic meningitis are listed in Table 2 Causes of Chronic Meningitis, below. Table 2. Causes of Chronic Meningitis (Open Table in a new window) Category Agent Bacteria M tuberculosis

B burgdorferi

T pallidum

Brucella species

Francisella tularensis

Nocardia species

Actinomyces species

Fungi

C neoformans

C immitis

B dermatitidis

H capsulatum

Candida albicans

Aspergillus species

Sporothrix schenckii

Parasites

Acanthamoeba species

N fowleri

Angiostrongylus cantonensis

G spinigerum

B procyonis

Schistosoma species

S stercoralis

Echinococcus granulosus

Brucella species are small gram-negative coccobacilli that cause zoonoses as a result of infection with B abortus, B melitensis, B suis, and B canis.Transmission to humans occurs following direct or indirect exposure to infected animals (eg, sheep, goat, cattle). Direct infection of the CNS occurs in fewer than 5% of cases, with most patients presenting with acute or chronic meningitis. Persons at risk include individuals who had contact with infected animals (eg, sheep, goat, cattle) or their products (eg, intake of unpasteurized milk products). Veterinarians, abattoir workers, and laboratory workers dealing with these animals are also at risk. M tuberculosis is an acid-fast bacillus that causes a broad range of clinical illnesses that can affect virtually any organ of the body. It is spread through airborne droplet nuclei, and it infects one third of the world's population. Always consider tuberculous meningitis in the differential diagnoses of patients with aseptic meningitis or chronic meningitis syndromes. Involvement of the CNS with tuberculous meningitis is usually caused by rupture of a tubercle into the subarachnoid space. T pallidum is a slender, tightly coiled spirochete that is usually acquired by sexual contact. Other modes of transmission include direct contact with an active lesion, passage through the placenta, and blood transfusion (rare). B burgdorferi, a tick-borne spirochete, is the agent of Lyme disease, the most common vector-borne disease in the United States. C neoformans is an encapsulated, yeast like fungus that is ubiquitous. It has been found in high concentrations in aged pigeon droppings and pigeon nesting places. The 4 serotypes are designated A through D, with the A serotype causing most human infections. The onset may be acute, especially among patients with AIDS. A large number of cases occur in healthy hosts (eg, with no known T-cell defect); however, approximately 50-80% of cases occur in immunocompromised hosts. At particular risk are individuals with defects of T-cellmediated immunity (eg, those who use steroids, cyclosporine, and other immunosuppressants). Most cases of C neoformans have occurred among individuals with AIDS and among organ transplant recipients. It has also been reported in patients with idiopathic CD-4 lymphopenia, Hodgkin disease, and sarcoidosis. C immitis is a soil-based, dimorphic fungus that exists in mycelial and yeast (spherule) forms. Persons at risk for coccidioidal meningitis include individuals exposed to the endemic regions (eg, tourists and local populations) and those with immune deficiency (ie, AIDS, organ transplantation). B dermatitidis is a dimorphic fungus that has been reported to be endemic in North America (eg, Mississippi and Ohio River basins). It has also been isolated from parts of Central America, South America, the Middle East, and India. The natural habitat of B dermatitidis, a dimorphic fungus, is not well defined. Soil that is rich in decaying matter and environments around riverbanks and waterways have been demonstrated to harbor the fungus during outbreaks and are thought to be risk factors for acquiring the infection. Inhalation of the conidia establishes a pulmonary infection. Dissemination may occur in certain individuals (including individuals with underlying immune deficiency [eg, from HIV or pharmaceutical agents] and extremes of age) and may involve the skin, bones and joints, genitourinary tract, and the CNS. Involvement of the CNS occurs in fewer than 5% of cases. H capsulatum is one of the dimorphic fungi that exist in mycelial and yeast forms. It is usually found in soil. Candida species are ubiquitous in nature. They are normal commensals in humans and are found in the skin, the gastrointestinal tract, and the female genital tract. The most common species is C albicans, but the incidence of non-albicans candidal infections (eg, C tropicalis) is increasing, including species with antifungal resistance (eg, C krusei, C glabrata). Involvement of the CNS usually follows hematogenous dissemination. The most important predisposing risk for acquiring disseminated candidal infection appears to be iatrogenic in nature (eg, use of broadspectrum antibiotics and indwelling devices such as urinary and vascular catheters). AIDS is also

considered a predisposing risk factor. Infection may also follow neurosurgical procedures, such as placement of ventricular shunts. S schenckii is an endemic dimorphic fungus that is often isolated from soil, plants, and plant products. Extracutaneous manifestations may occur, with meningeal sporotrichosis (a rare complication) being the worst complication of S schenckii infections. AIDS is a reported underlying risk factor in many described cases. It is associated with a poor outcome. Infection with free-living amebas is an infrequent but often life-threatening human illness, even in immunocompetent individuals. N fowleri is the only recognized human pathogenic species of Naegleria, and it is the agent of primary amebic meningoencephalitis (PAM). The parasite has been isolated in lakes, pools, ponds, rivers, tap water, and soil. Infection occurs when swimming or playing in the contaminated water sources (eg, inadequately chlorinated water and sources associated with poor decontamination techniques). The N fowleri amebas invade the CNS through the nasal mucosa and cribriform plate. PAM occurs in 2 forms. The first form is an acute onset of high fever, photophobia, headache, and change in mental status, similar to bacterial meningitis, occurring within a week following exposure. Because it is acquired through the nasal area, involvement of the olfactory nerves may manifest as abnormal smell sensation. Death occurs in 3 days in patients who are not treated. The second form, the subacute or chronic form, is an insidious onset of low-grade fever, headache, and focal neurologic signs. Duration of illness is weeks to few months. Acanthamoeba and Balamuthia cause granulomatous amebic encephalitis, which is a subacute opportunistic infection that spreads hematogenously from the primary site of infection (skin or lungs) to the CNS and causes an encephalitis syndrome. A cantonensis, the rat lungworm, can cause eosinophilic meningitis (pleocytosis with >10% eosinophils) in humans. The adult parasite resides in the lungs of rats. Its eggs hatch and the larval stages are expelled in the feces. The larvae develop in the intermediate host, usually land snails, freshwater prawns, and crabs. Humans acquire the infection by ingesting raw mollusks. G spinigerum, a gastrointestinal parasite of wild and domestic dogs and cats, may cause eosinophilic meningoencephalitis. Humans acquire the infection following ingestion of undercooked infected fish and poultry. B procyonis is an ascarid parasite that is prevalent in the raccoon populations in the United States and rarely causes human eosinophilic meningoencephalitis. Human infections occur following accidental ingestion of food products contaminated with raccoon feces. Go to Staphylococcal Meningitis for complete information on this topic.

Additional causes of meningitis

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

EPIDEMIOLOGY
The incidence of meningitis varies with the specific etiologic agent, as well as in conjunction with a nations medical resources. The incidence is presumed to be higher in developing countries because of less access to preventive services, such as vaccination. An incidence rate that is 10-fold higher than that in developed countries has been reported. Meningitis affects people of all races. In the United States, black people have a higher reported rate of meningitis than white people and Hispanic people.

Epidemiology of bacterial meningitis

With almost 8000 cases and 2000 deaths occurring annually, bacterial meningitis continues to be a significant source of morbidity and mortality. The attack rate per year in the United States is reportedly 0.6-4 cases per 100,000 population. Meningococcal meningitis is endemic in parts of Africa, India, and other developing areas. Periodic epidemics occur in the so-called sub-Saharan "meningitis belt," as well as among religious pilgrims traveling to Saudi Arabia for the Hajj. In parts of Africa, widespread epidemics of meningococcal meningitis occur regularly. In 1996, the biggest wave of meningococcal meningitis outbreaks ever recorded arose in West Africa. An estimated 250,000 cases and 25,000 deaths occurred in Niger, Nigeria, Burkina Faso, Chad, and Mali. The incidence of neonatal bacterial meningitis is 0.25-1 case per 1000 live births. In addition, the incidence is 0.15 case per 1000 full-term births and 2.5 cases per 1000 premature births. Approximately 30% of newborns with clinical sepsis have associated bacterial meningitis. The frequency of H influenzae type B (HIB) disease has been markedly reduced, but N meningitidis causes approximately 4 cases per 100,000 children aged 1-23 months. The risk of secondary meningitis is 1% for family contacts and 0.1% for daycare contacts. The rate of meningitis caused by S pneumoniae is 6.5 cases per 100,000 children aged 1-23 months. Previously, HIB, N meningitidis, and S pneumoniae accounted for more than 80% of cases of bacterial meningitis. Since the late 20th century, however, the epidemiology of bacterial meningitis has been substantially changed by multiple developments. An increased incidence of HIV infection worldwide resulted in a correspondingly increased frequency of meningitis caused by encapsulated organisms (primarily S pneumoniae).[4] Even so, the overall incidence of bacterial meningitis declined from 1.9 to 1.5 cases per 100,000 between 1998 and 2003.[5] This was partially due to the widespread use of the HIB vaccination, which decreased the incidence of HIB meningitis by more than 90% (see Table 3 Changing Epidemiology of Acute Bacterial Meningitis in the United States, below), nearly eliminating it in many developed countries where routine HIB vaccination is used. Because the frequency of bacterial meningitis in children has declined, the condition is becoming more of a disease of adults. The median age for persons with bacterial meningitis was 25 years in 1998, while in 1986, it was 15 months.[6] A total of 255 cases of invasive H influenzae disease among children younger than 5 years were reported to the CDC in 1998, in contrast to 20,000 cases among children in 1987. This shift has reportedly been less dramatic in developing countries, where the use of the HIB vaccine is not as widespread. Table 3. Changing Epidemiology of Acute Bacterial Meningitis in the United States* (Open Table in a new window)

Bacteria H influenzae Listeria monocytogenes N meningitidis S agalactiae S pneumoniae

1978-1981 48% 2% 20% 3% 13%

1986 45% 3% 14% 6% 18%

1995 7% 8% 25% 12% 47%

*Nosocomial meningitis is not included. These data include only the 5 major meningeal pathogens. The introduction of conjugate vaccines against 7 serotypes of S pneumoniaehas also substantially reduced the incidence of childhood pneumococcal meningitis. Moreover, the introduction of routine vaccination against meningococcus with the use of serogroup C meningococcal conjugate vaccine may reduce the incidence of N meningitidis infections. Excluding meningococcal meningitis, patients younger than 5 years or older than 60 years are at increased risk for bacterial meningitis, despite the above-mentioned shift in median age for persons with the disease. Newborns are at highest risk for acute bacterial meningitis. After the first month of life, the peak incidence is in infants aged 3-8 months. In addition, statistics show an increased incidence in persons aged 60 years and older, independent of other factors. Annual incidences are 1.7-7.2 cases per 100,000 adults, and the mean annual incidence has been reported as 3.8 cases per 100,000 adults. Of patients with bacterial meningitis, 61% had no previous or present accompanying diseases that may have predisposed them to meningitis. Depending on their age, individuals are also predisposed to other etiologic agents (see Table 4 The Most Common Bacterial Pathogens Based on Age and Predisposing Risks, below). E coli K1 and S agalactiae meningitis are common among the neonatal group, and L monocytogenes meningitis is common among neonates and elderly individuals. (The development of neonatal meningitis is related to labor delivery; it results from colonized pathogens in the maternal intestinal or genital tract, immaturity, and environment.) The attack rate for bacterial meningitis is reportedly 3.3 male cases per 100,000 population, compared with 2.6 female cases per 100,000 population. (In meningitis caused by the mumps virus, males and females are affected equally.) In neonates, the male-to-female ratio is 3:1. The epidemiology of bacterial meningitis continues to evolve as preventive strategies are implemented. Table 4. The Most Common Bacterial Pathogens Based on Age and Predisposing Risks (Open Table in a new window) Risk and/or Predisposing Factor Age 0-4 weeks Bacterial Pathogen Streptococcus agalactiae (group B streptococci)

E coli K1

Listeria monocytogenes

Age 4-12 weeks

S agalactiae

E coli

H influenzae

S pneumoniae

N meningitidis

Age 3 months to 18 years

N meningitidis

S pneumoniae

H influenzae

Age 18-50 years

S pneumoniae

N meningitidis

H influenzae

Age older than 50 years

S pneumoniae

N meningitidis

L monocytogenes

Aerobic gram-negative bacilli

Immunocompromised state

S pneumoniae

N meningitidis

L monocytogenes

Aerobic gram-negative bacilli

Intracranial manipulation, including neurosurgery

Staphylococcus aureus

Coagulase-negative staphylococci

Aerobic gram-negative bacilli, including

P aeruginosa

Basilar skull fracture

S pneumoniae

H influenzae

Group A streptococci

CSF shunts

Coagulase-negative staphylococci

S aureus

Aerobic gram-negative bacilli

Propionibacterium acnes

Epidemiology of specific bacterial pathogens of acute meningitis

H influenzae meningitis primarily affects infants younger than 2 years. S agalactiae has also been reported in adults, primarily affecting individuals older than age 60 years. The overall case-fatality rate in adults is 34%. S pneumoniae is associated with one of the highest mortality rates among the bacterial agents that cause meningitis (19-26%). Go to Haemophilus Meningitis for complete information on this topic.

Epidemiology of aseptic meningitis

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

Aseptic meningitis occurs in individuals of all ages, although it is more common in children, especially during summer. No racial differences are reported. Aseptic meningitis tends to occur 3 times more frequently in males than in females. The enteroviruses are distributed worldwide, and the infection rates vary depending on the season of the year and a populations age and socioeconomic status. Most enterovirus infections occur in individuals who are younger than age 15 years, with the highest attack rates in children who are younger than 1 year. Infections with the St. Louis encephalitis virus usually occurs during the summer and early fall, with symptoms being typical of acute aseptic meningitis. In the United States, the last epidemic of St. Louis encephalitis was in Florida in 1990. Twenty-four cases were reported to the CDC in 1998, with most cases originating from Louisiana. Infection with the La Crosse encephalitis virus also usually occurs during the summer and early fall, with symptoms again being typical of acute aseptic meningitis. Infections with the LCM virus occur worldwide; most human cases occur among young adults during autumn. B dermatitidis is reportedly endemic in North America (eg, Mississippi and Ohio River basins). It has also been isolated from parts of Central America, South America, the Middle East, and India. H capsulatum has been reported from many areas of the world, with the Mississippi and Ohio River valleys being the most endemic regions in North America. A cantonensis is common in Southeast Asia and the Pacific Islands. It has also been found in rats outside this region, particularly in regions of Africa, Puerto Rico, and Louisiana, presumably introduced by shipborne rats from endemic areas. G spinigerum is common in Southeast Asia, China, and Japan but has been reported sporadically worldwide. Go to Aseptic Meningitis for complete information on this topic.

Epidemiology of chronic meningitis

Brucella -associated chronic meningitis has a worldwide distribution and is common in the Middle East, India, Mexico, and Central and South America. In the United States following the control of bovine infections, incidence decreased to less than 0.5 cases per 100,000 population, and only 79 cases were reported to the CDC in 1998. M tuberculosis is worldwide in distribution, and humans are its only reservoir. In 1997, the estimated case rates among endemic countries ranged from 62-411 cases per 100,000 population. B burgdorferi is a tick-borne spirochete that occurs in the temperate regions of North America (eg, northeast United States, Minnesota, Wisconsin, parts of California and Oregon), Europe, and Asia. C neoformans has a worldwide distribution. Serotypes B and C of C neoformans have been restricted mostly to tropical and subtropical regions, and serotype B has been isolated from eucalyptus trees. The distribution of C immitis is limited to the endemic regions of the Western Hemisphere, within the north and south 40 latitudes (ie, parts of the southwest United States, Mexico, and Central and South America). S schenckii has been reported worldwide, with most cases coming from the tropical regions of the Americas.

PROGNOSIS

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

Morbidity and mortality for bacterial and viral meningitis

Bacterial meningitis causes long-term sequelae and results in significant mortality beyond the neonatal period. Prolonged or difficult-to-control seizures are predictors of complications. Bacterial meningitis can be extremely serious. Morbidity, mortality, and prognosis depend on the pathogen, the patient's age and condition, and the severity of acute illness.[7] Cerebral infarction and edema are predictors of poor outcome, as are the signs of disseminated intravascular coagulopathy and endotoxic shock. The presence of low-level pleocytosis (< 20 cells) in patients with bacterial meningitis suggests a poorer outcome. Advanced bacterial meningitis can lead to brain damage, coma, and death. Long-term sequelae are seen in as many as 30% of survivors and vary with etiologic agent, patient age, presenting features, and hospital course. Patients usually have subtle CNS changes. Serious complications include the following: Hearing loss Cortical blindness Other cranial nerve dysfunction Paralysis Muscular hypertonia Ataxia Multiple seizures Mental motor retardation Focal paralysis Ataxia Subdural effusions Hydrocephalus Cerebral atrophy Mortality rates for bacterial meningitis are highest in the first year of life, decrease in midlife, and increase again in old age. Bacterial meningitis is fatal in 1 in 10 cases, and 1 in 7 survivors is left with a severe handicap, such as deafness or brain injury. Meningitis caused by S pneumoniae, L monocytogenes, and gram-negative bacilli has a higher casefatality rate compared with meningitis caused by other bacterial agents. The prognosis of meningitis caused by opportunistic pathogens depends on the underlying immune function of the host. Many patients who survive the disease require lifelong suppressive therapy (eg, longterm fluconazole for suppression in patients with HIV-associated cryptococcal meningitis). Despite effective antimicrobial and supportive therapy, mortality rates among neonates remain high, with significant long-term sequelae in survivors. In patients with deficient humoral immunity (eg, agammaglobulinemia), enterovirus meningitis may have a fatal outcome. Among bacterial pathogens, pneumococcal bacteria cause the highest rates of mortality (20-30% in adults, 10% in children) and morbidity (15%) in meningitis. Mortality is 50-90% and morbidity is even

higher if severe neurologic impairment is evident at the time of presentation (or with extremely rapid onset of illness), even with immediate medical treatment. The reported mortality rates for specific bacterial organisms are as follows:

S pneumoniae meningitis - 19-26% H influenzae meningitis - 3-6% N meningitidis meningitis - 3-13% L monocytogenes meningitis - 15-29% Patients with meningococcal meningitis have a better prognosis than do those with pneumococcal meningitis, with a mortality rate of 4-5%; however, patients with meningococcemia have a poor prognosis, with a mortality rate of 20-30%. The mortality rate for viral meningitis (without encephalitis) is less than 1%. In patients with deficient humoral immunity (eg, agammaglobulinemia), enterovirus meningitis may have a fatal outcome. Patients with viral meningitis usually have a good prognosis for recovery. The prognosis is worse for patients at the extremes of age (ie, < 2 y, >60 y) and those with significant comorbidities and underlying immunodeficiency.

CLINICAL PRESENTATION
History
Clues in the patient's clinical history may suggest the specific etiologic agent that caused meningitis to develop. Detailed epidemiologic and predisposing risks should be assessed. For example, in patients whose symptoms have lasted longer than 1 month and who have CSF pleocytosis, 40% of these individuals have tuberculous meningitis, 7% have cryptococcal meningitis, 8% have neoplasms, and 34% remain undiagnosed. (In these patients, defer ED treatment until the organism is identified.)

Exposures
History of exposure to a patient with a similar illness is an important epidemiologic clue when determining etiology (eg, individuals who were in close contact with an index case of meningococcemia). Record evidence of systemic viral infection (ie, myalgias, fatigue, anorexia). Enteroviral infection is suggested by the presence of exanthemas; symptoms of pericarditis, myocarditis, or conjunctivitis; or syndromes of pleurodynia, herpangina, and hand-foot-and-mouth disease. Elicit a history of sexual contact and high-risk behavior from the patient. HSV meningitis is associated with primary genital HSV infection and HIV infection. A history of recurrent bouts of benign aseptic meningitis suggests Mollaret syndrome, which is caused by HSV. Animal contacts should be elicited. Patients with rabies could present atypically with aseptic meningitis; rabies should be suspected in a patient with a history of animal bite (eg, skunk, raccoon, dog, fox, bat). Exposure to rodents suggests infection with LCM virus and Leptospira infection. Laboratory workers dealing with these animals also are at increased risk of contracting LCM. The intake of unpasteurized milk and cheese predisposes to brucellosis andL monocytogenes infection.

Previous medical treatment and existing conditions

As many as 40% of patients with acute or subacute bacterial meningitis have previously been treated with oral antibiotics (presumably due to misdiagnosis at the time of initial presentation). The presence of a ventriculoperitoneal shunt and a history of recent cranial surgery should be elicited. Patients with low-grade ventriculitis associated with a ventriculoperitoneal shunt may have a less dramatic presentation than do patients with acute bacterial meningitis, with headache, nausea, minimal fever, and malaise. The presence of cochlear implants with a positioner has been associated with a higher risk of bacterial meningitis. Multiple etiologies of fever and seizures in patients with alcoholism or cirrhosis make meningitis challenging to diagnose.

Location and travel

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

Season and temperature

The time of 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. Arthropod-borne viruses (eg, St. Louis encephalitis, California encephalitis virus group) occur during the warmer months.

Physical Examination
Distinguishing acute, subacute, and chronic meningitis helps to identify the causative pathogen for these diseases.

Bacterial and viral meningitis

Otherwise healthy patients within age extremes present with clinically obvious acute bacterial meningitis. In contrast, most patients with subacute bacterial meningitis present a diagnostic challenge. Systemic examination occasionally reveals a pulmonary or otitis media co-infection. Signs of meningeal irritation include the following: Nuchal rigidity or discomfort on neck flexion Kernig sign Brudzinski sign Papilledema is present in only one third of meningitis patients with increased ICP; it takes at least several hours to develop. Focal neurologic signs include the following: Isolated cranial nerve abnormalities (principally III, IV, VI, VII) in 10-20% of patients Dramatic increase in complications from lumbar puncture, portending a worse outcome Systemic findings can also be present. Extracranial infection (eg, sinusitis, otitis media, mastoiditis, pneumonia, urinary tract infection) may be noted. Arthritis is seen with N meningitidis but is found less commonly with other bacterial species. Nonblanching petechiae and cutaneous hemorrhages are seen classically with N meningitidis; however, these also can occur with other bacterial and viral infections. Endotoxic shock with vascular collapse is characteristic of severe N meningitidis infection. Altered mental status, from irritability to somnolence, delirium, and coma, can develop. Infants may have the following: Bulging fontanelle (if euvolemic) Paradoxic irritability (ie, quiet when stationary, cries when held) High-pitched cry Hypotonia Examine skin over entire spine for dimples, sinuses, nevi, or tufts of hair, which may indicate a congenital anomaly communicating with the subarachnoid space. Approximately 25% of patients with bacterial meningitis present acutely, well within 24 hours of onset of symptoms. In contrast, patients with subacute bacterial meningitis and most patients with viral meningitis present with neurologic symptoms developing over 1-7 days. Chronic symptoms lasting longer than 1 week suggest the presence of meningitis caused by certain viruses or by tuberculosis, syphilis, fungi (especially cryptococci), or carcinomatosis. About 85% of adults and children with bacterial meningitis exhibit the classic triad of symptoms (ie, fever, headache, and neck stiffness).[5] These symptoms can develop over several hours or over 1-2 days. Fever is the most common manifestation (95%), while the other 2 symptoms are less common. However, in a meta-analysis of 845 patients, the sensitivity and specificity of these classic symptoms were poor. Even so, 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). Other symptoms can include the following:

Nausea Vomiting Photalgia - Discomfort when the patient looks into bright lights (also called photophobia) Sleepiness Confusion Irritability Delirium Coma Increased blood pressure with bradycardia can also be present. Vomiting occurs in 35% of patients. Occasionally, if a patient has been taking antibiotics for another infection, meningitis symptoms can take longer to develop or may be less intense. On physical examination, a skin rash caused by meningococcal meningitis (50%), H influenzae, pneumococcal meningitis, echovirus type 9, orStaphylococcus aureus may be present.[8] Other neurologic signs include the following:

Cranial nerve palsies - Resulting from ICP or the presence of exudates encasing the nerve roots Focal cerebral signs (10-20%) - May develop as a result of ischemia from vascular inflammation and thrombosis Papilledema (< 1%) - Another sign of increased ICP; presence of papilledema suggests not only meningitis but a possible alternate diagnosis (eg, brain abscess) One quarter of affected patients have a fulminant onset within 24 hours of infection, and there may be a history of a respiratory illness within the preceding 7 days (50%). 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. As bacterial meningitis progresses, patients of any age may have seizures (30% of adults and children; 40% of newborns and infants). As many as 40% of patients with acute or subacute bacterial meningitis have previously been treated with oral antibiotics (presumably due to misdiagnosis at time of initial presentation); in patients with partially treated meningitis, seizures may be the sole presenting symptom. Fever and changes in level of alertness or mental status occur less commonly than in untreated meningitis. Atypical presentation may be observed in certain groups. Elderly individuals, especially those with underlying comorbidities (eg, diabetes, renal and liver disease), may present with lethargy and an absence of meningeal symptoms. Patients with neutropenia may present with subtle symptoms of meningeal irritation. Other immunocompromised hosts, including organ and tissue transplant recipients and patients with HIV and AIDS, may also have an atypical presentation. Immunosuppressed patients may not show dramatic signs of fever or meningeal inflammation. A less dramatic presentationheadache, nausea, minimal fever, and malaisemay be found in patients with low-grade ventriculitis associated with a ventriculoperitoneal shunt. Newborns and small infants also may not present with the classic symptoms, or the symptoms may be difficult to detect. An infant may appear only to be slow or inactive, or he or she may be irritable, vomiting, or feeding poorly. Other symptoms in this age group include temperature instability, high-pitched crying, respiratory distress, and/or bulging fontanelles (late sign in one third of neonates). Approximately half of affected adults show signs of meningeal irritation, such as nuchal and/or spinal rigidity and a positive Kernig and/or Brudzinski sign.[8] The Kernig sign is determined in a supine patient by flexing 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. The Brudzinski sign is determined by passively flexing 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. 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.

Systemic findings on physical examination may provide clues to the etiology of a patients meningitis. Morbilliform rash with pharyngitis and adenopathy may suggest a viral etiology (eg, EBV, 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, mononucleosis-like syndrome in EBV, CMV, and HIV) and fungal (eg, disseminated histoplasmosis). The presence of a murmur suggests infective endocarditis with secondary bacterial seeding of the meninges. General physical findings in viral meningitis are common to all causative agents, but some viruses produce unique clinical manifestations that help in focusing the diagnostic approach. The classically taught triad of meningitis consists of fever, nuchal rigidity, and altered mental status, but not all patients have all 3 symptoms, and almost all patients have headache. The examination reveals no focal neurologic deficits in the majority of cases.

Chronic meningitis
Perform careful general, systemic, and neurologic examinations, looking especially for a BCG vaccination scar, lymphadenopathy, papilledema and tuberculomas during funduscopy, and meningismus. The presentation of chronic tuberculous meningitis 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 tuberculous meningitis is based on neurologic status, as follows: Stage 1 - No change in mental function with no deficits and no hydrocephalus Stage 2 - Confusion and evidence of neurologic deficit Stage 3 - Stupor and lethargy The median incubation period before the appearance of symptoms in chronic syphilitic meningitis 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 types of aseptic meningitis, with headache, nausea, vomiting, and meningismus. Meningovascular syphilis occurs later in the course of untreated syphilis, and the symptoms are dominated by focal syphilitic arteritis (ie, focal neurologic symptoms associated with signs of meningeal irritation) that spans weeks to months and results in stroke and irreversible damage if left untreated. Patients with HIV have an increased risk of accelerated progression. Although rare during stage I of Lyme disease, CNS involvement (with meningitis) may occur in Lyme disease-associated chronic meningitis and is characterized by the concurrent appearance of erythema migrans at the site of the tick bite. More commonly, aseptic meningitis syndrome occurs 2-10 weeks following the erythema migrans rash. This represents stage 2 of Lyme disease, or the borrelial hematogenous dissemination stage. Headache is the most common symptom of Lyme diseaseassociated chronic meningitis, 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. Infection with C neoformans is characterized by the gradual onset of symptoms, the most common of which is headache. 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. Patients infected with B dermatitidis may present with an abscess or fulminant meningitis, while patients infected with H capsulatum may present with headache, cranial nerve deficits, or changes in mental status months prior to diagnosis.

Helminthic eosinophilic meningitis

Following ingestion of A cantonensis, most patients with symptomatic disease present with nonspecific and self-limited abdominal pain caused by larval migration into the bowel wall. On rare occasions, the larvae can migrate into the CNS and cause eosinophilic meningitis.

Aseptic meningitis
In contrast to patients with bacterial meningitis, patients with aseptic meningitis syndrome usually appear clinically nontoxic, with no vascular instability. In many cases, a cause for meningitis is not apparent after initial evaluation and is therefore classified as aseptic meningitis. These patients characteristically have an acute onset of meningeal symptoms, fever, and cerebrospinal pleocytosis that is usually prominently lymphocytic. Go to Aseptic Meningitis for complete information on this topic.

Complications
Risk factors for hearing loss after pneumococcal meningitis are female gender, older age, severe meningitis, and infection with certain pneumococcal serotypes (eg, 12F serotype).[9] In 50% of patients, several complications may develop in the days to weeks following infection. Immediate complications include the following: Septic shock, including DIC Coma with loss of protective airway reflexes Seizures - 30-40% of children, 20-30% of adults Cerebral edema Septic arthritis Pericardial effusion Hemolytic anemia (H influenzae) Delayed complications include the following: Decreased hearing or deafness Other cranial nerve dysfunctions Multiple seizures Focal paralysis Subdural effusions Hydrocephalus Intellectual deficits Ataxia Blindness Waterhouse-Friderichsen syndrome Peripheral gangrene

Seizures

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

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

Cranial nerve palsy and cerebral infarction

Cranial nerve palsies and the effects of impaired cerebral blood flow, such as cerebral infarction, are caused by increased ICP. In certain cases, repeated lumbar puncture or the insertion of a ventricular drain may be necessary to relieve the effects of this increase. In cerebral infarction, endothelial cells swell, proliferate, and crowd into the lumen of the blood vessel, and inflammatory cells infiltrate the blood vessel wall. Foci of necrosis develop in the arterial and venous walls and induce arterial and venous thrombosis. Venous thrombosis is more frequent than arterial thrombosis, but arterial and venous cerebral infarctions can be seen in 30% of patients.

Brain parenchymal damage

Brain parenchymal damage is the most important and feared complication of bacterial meningitis. It can lead to the following disorders: Sensory and motor deficits Cerebral palsy Learning disabilities Mental retardation Cortical blindness Seizures

Cerebritis

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

Subdural effusion
In children with meningitis who are younger than 1 year, 20-50% of cases are complicated by sterile subdural effusions. Most cases are transient and small to moderate in size. Of these effusions, 2% are infected secondarily and become subdural empyemas. In the empyema, infection and necrosis of the arachnoid membrane permits formation of a subdural collection. Risk factors include young age, rapid onset of illness, low peripheral WBC count, and high CSF protein. Seizures occur more commonly during the acute course of the disease, although long-term sequelae of promptly treated subdural effusions are similar to those of uncomplicated meningitis.

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

reduced secretion of CSF by the choroid plexus, the infective organisms remain in the ventricles and multiply.

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

Differential Diagnoses
Diagnostic Considerations
Diagnoses to consider aside from meningitis include the following: Noninfectious meningitis, including medication-induced meningeal inflammation Meningeal carcinomatosis CNS vasculitis Stroke Encephalitis All causes of altered mental status and coma Leptospirosis Subdural empyema

Differentials
Brain Abscess Delirium Tremens Encephalitis Herpes Simplex Herpes Simplex Encephalitis Neoplasms, Brain Pediatrics, Febrile Seizures Pediatrics, Meningitis and Encephalitis Subarachnoid Hemorrhage

Meningitis Workup
Approach Considerations
The challenges for emergency physicians when treating meningitis are as follows: Early identification and treatment of patients with acute bacterial meningitis Assessing whether a treatable CNS infection is present in those with suspected subacute or chronic meningitis Identifying the causative organism Bacterial meningitis must be first and foremost in the differential diagnosis of patients with headache, neck stiffness, fever, and change in mental status. Acute bacterial meningitis is a medical emergency, and delays in instituting effective antimicrobial therapy result in increased morbidity and mortality. The cornerstone in the diagnosis of meningitis is examination of the CSF. The diagnosis of bacterial meningitis is made by culture to isolate the bacteria in the CSF sample. Other laboratory tests, which may include other culture of blood specimens, are needed to complement the CSF culture. These bacterial cultures are used for identification of the offending bacteria and occasionally its serogroup, as well as for determination of the organisms susceptibility to antibiotics. In general, whenever the diagnosis of meningitis is strongly considered, a lumbar puncture should be promptly performed. The opening pressure should be measured and the fluid sent for cell count (and differential count), chemistry (ie, CSF glucose and protein), and microbiology (ie, Gram stain and cultures). A computed tomography (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 made up of patients with the following risk factors: Newly onset seizures An immunocompromised state Signs suspicious for space-occupying lesions (such as papilledema and focal neurologic signs) Moderate to severe impairment in consciousness Special studies, such as serology and nucleic acid amplification, may also be performed, depending on clinical suspicion of an offending organism. In the absence of focal neurologic deficit, radiographic imaging of the head should not preclude performing a lumbar puncture. 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 bodyassociated infections (eg, ventriculoperitoneal shunts), or an associated abscess formation.

CBC Count with Differential

Complete blood cell (CBC) count with differential demonstrates polymorphonuclear leukocytosis with left shift in bacterial meningitis.

Comprehensive Metabolic Panel

The following should be obtained: Serum electrolytes, to determine dehydration or syndrome of inappropriate secretion of antidiuretic hormone [SIADH]) Serum glucose (which is used in comparison with the CSF glucose)

BUN and/or creatinine and liver profile, to assess organ functioning and adjust antibiotic dosing The serum glucose may be low if glycogen stores are depleted, or they may be high in infected patients with diabetes.

Coagulation Profile
Coagulation profile and platelets are indicated in patients with chronic alcohol use or liver disease or if disseminated intravascular coagulation (DIC) is suspected. (Patients may require platelets or fresh frozen plasma [FFP] prior to lumbar puncture.)

Serum Test for Syphilis

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 [FTAAbs], Treponema pallidumhemoagglutination [TPHA], microhemagglutination-Treponema pallidum[MHATP]) 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.

Serum Test for Procalcitonin

There is increasing data to suggest that serum procalcitonin (PCT) levels can be used as a guide to distinguish between bacterial and aseptic meningitis in children. The results yielded by a serum PCT, combined with other findings, could be helpful in making clinical decisions.[10] In an analysis of retrospective, multicenter, hospital-based cohort studies, Dubos et al confirmed that measurement of the PCT level is the best biological marker to differentiate bacterial meningitis from aseptic meningitis in children in the ED. Sensitivity and specificity of the PCT level in distinguishing between bacterial and aseptic meningitis were 99% and 83%, respectively.[10]

Special Studies
Cultures prior to instituting antibiotics may be helpful if diagnosis is uncertain. These cultures include the following:

Blood - 50% positive in meningitis caused by H influenzae, S pneumoniae, or N meningitidis Nasopharynx Respiratory secretions Urine Skin lesions Latex agglutination or counter immunoelectrophoresis (CIE) of blood, urine, and CSF for specific bacterial antigens is recommended occasionally if diagnosis is challenging or in patients with partially treated meningitis.

Lumbar Puncture
Elevated opening pressure correlates with increased risk of morbidity and mortality in bacterial and fungal meningitis. In bacterial meningitis, elevated opening pressure (reference range is 80-200 mm water) suggests increased ICP from cerebral edema. In viral meningitis, the opening pressure is usually within the reference range. The CSF opening pressure may be elevated at times in cryptococcal meningitis, suggesting increased ICP. The opening CSF pressure is usually elevated in tuberculous meningitis. The CSF cell count varies depending on the offending pathogen. It is usually in the few hundreds (1001000 cells/L) with a predominance of lymphocytes in patients with viral meningitis. Some cases of echovirus, mumps, and HSV meningitis may produce a neutrophilic picture early in the course of disease. Go to Lumbar Puncture for complete information on this topic.

See Table 5 "CSF Picture of Meningitis According to Etiologic Agent " and Table 6 "Comparison of CSF Findings by Type of Organism," below . Table 5. CSF Picture of Meningitis According to Etiologic Agent (Open Table in a new window)
Agent Opening Pressure 200-300 WBC count per L 100-5000; >80% PMNs* 10-300; lymphocytes 100-500; lymphocytes 10-200; lymphocytes 10-300; lymphocytes 0-5; lymphocytes Glucose (mg/dL) Protein (mg/dL) Microbiology

Bacterial meningitis Viral meningitis

< 40

>100

Specific pathogen demonstrated in 60% of Gram stains and 80% of cultures Viral isolation, PCR assays

90-200

Normal, reduced in LCM and mumps Reduced, < 40

Normal but may be slightly elevated Elevated, >100

Tuberculous meningitis Cryptococcal meningitis Aseptic meningitis Normal values

180-300

Acid-fast bacillus stain, culture, PCR

180-300

Reduced

50-200

India ink, cryptococcal antigen, culture

90-200

Normal

Normal but may be slightly elevated 15-40

Negative findings on workup

80-200

50-75

Negative findings on workup

*Polymorphonuclear lymphocytes

Polymerase chain reaction

Table 6. Comparison of CSF Findings by Type of Organism (Open Table in a new window)
Bacterial Meningitis Pressure Increased Viral Meningitis* Normal or mildly increased Fungal Meningitis** Normal or mildly increased in TB. May be increased in fungal. AIDS patients with cryptococcal meningitis have increased risk of blindness, death unless maintained at < 30 cm.

5-15 cm H2 O

Cell count

No cell count result can exclude bacterial meningitis. Typically thousands of PMNs, but may be less dramatic or even normal (classically, in very early meningococcal meningitis and in extremely ill preterm: 0-25 neonates). Lymphocytosis with normal CSF chemistries seen in 15-25%, especially when cell counts < 1000 or if partially treated. Approximately 90% of patients with ventriculoperitoneal shunts have term: 0-22 CSF WBC count >100 cells/mm3 are infected; CSF glucose usually normal, and organisms are less pathogenic. Cell count and chemistries normalize slowly (over days) with antibiotics. >6 months: 0-5

Usually < 500 cells, nearly 100% mononuclear. Up to 48 hours, significant PMN pleocytosis may be indistinguishable from early bacterial meningitis; this is particularly true with eastern equine encephalitis. Presence of nontraumatic

Hundreds of mononuclear cells

RBCs in 80% of HSV meningoencephalitis, although 10% have normal CSF results

mononuclear

cells/mm3

Micro

no organisms

Gram stain 80% sensitive. Inadequate decolorization No organism may mistake H influenzaefor gram-positive cocci. Pretreatment with antibiotics may affect stain uptake, causing gram-positive organisms to appear gram negative and decrease culture yield on average 20%.

India ink 80-90% sensitive for fungi; AFB stain 40% sensitive for TB (increase yield by staining supernate from at least 5 cc CSF)

Glucose

Decreased

Normal

euglycemia: >50% serum

Sometimes decreased. Aside from fulminant bacterial meningitis, the lowest levels of CSF glucose are seen in TB, primary amebic meningoencephalitis, neurocysticercosis

hyperglycemi a: >30% serum

wait 4 h after glucose load

Protein

Usually >150, may be >1000

Mildly increased

Increased; >1000 with relatively benign clinical presentation suggestive of fungal disease

preterm: 65150

term: 20-170

>6 months: 15-45

mg/dL

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

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

Take tube #1 to the chemistry lab for glucose and protein. Take tube #2 to the hematology lab for a cell count with differential. Take tube #3 to the microbiology and immunology lab for Gram stain, bacterial culture, acid-fast bacillus (AFB) stain and tuberculosis cultures, India ink stain, cryptococcal antigen testing, and fungal cultures, CIE, VDRL, and cryptococcal antigen, if indicated. Hold tube #4 for a repeat cell count with differential, if needed (or for other subsequent studies not initially ordered). Research correlates CSF cytokines in children with bacterial meningitis. According to Seupaul, the following 3 diagnostic tests have clinically useful likelihood ratios for the diagnosis of bacterial meningitis in adults: CSF/blood glucose - Ratio of 0.4 or less CSF white blood cell (WBC) count - Count of 500/L or more CSF lactate level level of 31.53 or greater

CSF characteristics of acute 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/L) in the presence of a high bacterial load suggests a poor prognosis.

CSF characteristics of viral meningitis

In viral meningitis, the opening pressure is 90-200 mm H2 0, and the WBC count is 10-300 lymphocytes/L. Although the glucose concentration is typically normal, in LCM, HSV, mumps, and polio, it can be below normal. The protein concentration tends to be slightly elevated, but it can be within the reference range.

CSF characteristics of fungal meningitis

The diagnosis of cryptococcal meningitis relies on the identification of the pathogen in the CSF. The CSF is characterized by a lymphocytic pleocytosis (10-200 lymphocytes), a reduced glucose level, and an elevated protein level. 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.

CSF characteristics of eosinophilic/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 ameboid movement, using wet preparations of the CSF has been used for diagnosis. Alternatively, the ameba 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.

CSF characteristics of Lyme meningitis

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.

CSF characteristics of tuberculous meningitis

The CSF of patients with tuberculous meningitis is characterized by a predominantly lymphocytic pleocytosis, usually in the hundreds. Go to Tuberculous Meningitis for complete information on this topic.

CSF glucose study

In bacterial meningitis, 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 glucose levels as a result of underlying diabetes mellitus, and the predictive value of the CSF and blood glucose ratio may not be accurate in these circumstances. The CSF glucose level is usually within the reference range in viral meningitis, but some cases of LCM, HSV, mumps, and polio may cause low CSF glucose levels. In tuberculous meningitis, a characteristic hypoglycorrhagia (glucose < 40 mg/dL) is present, and the protein level is usually elevated, especially if a CSF block is present.

CSF protein study

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

CSF Gram stain and acid-fast bacilli stain

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. 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.

CSF culture and antigen testing

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 the CSF bacterial antigen assay 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 the bacterial antigen test does not rule out meningitis (50-95% sensitivity). C neoformans may be cultured from the CSF in cryptococcal meningitis. 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. In syphilitic meningitis, 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). 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. 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.

Viral isolation from the CSF

The isolation of viruses from the CSF 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.

Blood cultures
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 in which 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.

Nucleic acid amplification

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.

Serology
The demonstration of a 4-fold rise in antibodies between acute and convalescent sera traditionally has been used to document meningeal infection in many viral pathogens.

Go to Lumbar Puncture for complete information on this topic.

Chest Radiography
As many as 50% of patients with pneumococcal meningitis also have evidence of pneumonia on initial chest radiograph. This association occurs in fewer than 10% of patients with meningitis caused by H influenzae or N meningitidis and in approximately 20% of patients with meningitis caused by other organisms. Go to Imaging in Bacterial Meningitis for complete information on this topic.

CT Scanning and MRI

CT scans of the head and magnetic resonance imaging (MRI) of the brain generally do not aid in the diagnosis of meningitis. Some patients may show meningeal enhancement, but its absence does not rule out the condition. 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. Presence of papilledema and inability to fully assess fundi or neurologic status are indications for CT scan prior to lumbar puncture. Obtain blood cultures and initiate treatment before imaging studies and lumbar puncture in patients with suspected bacterial meningitis. Results may be normal or demonstrate small ventricles, effacement of sulci, and contrast enhancement over convexities. Late findings include venous infarction and communicating hydrocephalus. Rule out brain abscess, sinus or mastoid infection, skull fracture, and congenital anomalies. Acute bacterial meningitis is shown in the CT and MRI scans (all from the same patient) below.

Acute bacterial meningitis. This axial nonenhanced computed tomography scan

shows mild ventriculomegaly and sulcal effacement

Acute bacterial meningitis. This axial

T2-weighted magnetic resonance image shows only mild ventriculomegaly. Acute bacterial meningitis. This contrast-enhanced, axial T1-weighted magnetic resonance image shows leptomeningeal enhancement (arrows).

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. Go to Imaging in Bacterial Meningitis for complete information on this topic.

Meningeal Biopsy
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 does the CSF acid-fast bacilli smear.

Meningitis Treatment & Management

Approach Considerations
The performance of radiographic imaging should not defer the institution of empiric antimicrobial therapy. The emergence of bacterial resistance, especially penicillin-resistant S pneumoniae, has been increasing worldwide, and the reported rates are 41-56% in Southeast Asia and the Far East. In the United States in 1998, the CDC conducted a study on 3335 isolates from 8 states and found 10.2% intermediate penicillin resistant (minimum inhibitory concentration [MIC] of 0.1-1 mcg/mL) and 13.6% highly resistant (MIC >2 mcg/mL) strains. The geographic distribution of this resistance is variable, and knowledge of this is important when deciding on local empiric antibiotic therapy (see Medication).

Initial Care in Meningitis

Evaluate and treat the patient for shock or hypotension, and infuse crystalloid until he or she is euvolemic. Consider seizure precautions, treat seizures according to the usual protocol, and consider airway protection in patients with altered mental status. For alert patients in stable condition who have normal vital signs, administer oxygen, establish IV access, and transport them rapidly to the ED. In acute meningitis, regardless of presentation, perform CSF examination to identify the causative organism and susceptibilities. Institute treatment as early as possible in the disease course, since delay in instituting treatment may contribute significantly to morbidity and mortality. The patient's condition and ED organization may warrant a watchful wait for 8-12 hours and then a reexamination of the CSF (sooner if patient's condition deteriorates). If initial granulocytosis changes to mononuclear predominance, CSF glucose remains normal, and the patient continues to look well, the infection is most likely nonbacterial.

Treatment of Acute Meningitis

In acutely ill patients, perform an LP (if appropriate) and administer the first dose(s) of antibiotics with or without steroids within 30 minutes of presentation to the ED. Consider instituting ED triage protocol to identify patients at risk. Initiate empiric therapy if LP cannot be performed within 30 minutes. Begin empiric therapy prior to a head CT scan if a focal neurologic deficit is present. If no mass effect is present, perform LP to obtain microbiology studies. Treat systemic complications of acute bacterial meningitis, including the following: Hypotension and/or shock Hypoxemia Hyponatremia (SIADH) Cardiac arrhythmias and ischemia Cerebrovascular accident (CVA) Exacerbation of chronic diseases Look for signs of hydrocephalus and increasing ICP. Manage fever and pain, control straining and coughing, avoid seizures, and avoid systemic hypotension. In otherwise stable patients, sufficient care includes elevating the head and monitoring neurologic status. When more aggressive maneuvers are indicated, some authorities favor early use of diuresis (ie, furosemide 20 mg IV, mannitol 1 g/kg IV), provided circulatory volume is protected. Hyperventilation in intubated patients, with a goal of PaCO2 of 25-30 mm Hg, may briefly lower ICP; hyperventilation with PaCO2 of less than 25 mm Hg may decrease CBF disproportionately and lead to

CNS ischemia. Consider placing an ICP monitor in comatose patients or in those with signs of increased ICP. With elevated ICP, remove CSF until pressure decreases by 50% and maintain at less than 300 mm water. Aggressively control seizures if present, since seizure activity increases ICP (ie, lorazepam 0.1 mg/kg IV and IV load with phenytoin 15 mg/kg or phenobarbital 5-10 mg/kg).

Treatment of Subacute Meningitis

Most patients with subacute bacterial meningitis present more of a diagnostic challenge than do individuals with acute illness. In patients with subacute bacterial meningitis, CSF examination constitutes the critical step in documenting the presence or absence of a CNS infection and the type of infecting organism. If the patient's condition is serious and antibiotics have been given (arguably masking symptoms and hindering growth of organisms on culture), assume that a bacterial infection is present, provide adequate antibiotic coverage, and admit the patient.

Antibiotic Therapy
Bacterial meningitis is a neurologic emergency that is associated with significant morbidity and mortality. The initiation of empiric antibacterial therapy is therefore essential for better outcome. Ideal ED antibiotic therapy is based on a clearly identified organism on CSF Gram stain. Age and underlying conditions dictate empiric treatment in an ED patient without trauma or CNS instrumentation. Information presented in this article is taken from the 2003 edition of The Sanford Guide to Antimicrobial Therapy.[11] (See Table 7, Table 8, and Table 9, below.) Table 7. Recommended Empiric Antibiotics According to Predisposing Factors for Patients With Suspected Bacterial Meningitis (Open Table in a new window) Predisposing Feature Age 0-4 weeks Age 1-3 months Age 3 months to 50 years Older than 50 years Antibiotic(s) Ampicillin plus cefotaxime or an aminoglycoside Ampicillin plus cefotaxime plus vancomycin* Ceftriaxone or cefotaxime plus vancomycin* Ampicillin plus ceftriaxone or cefotaxime plus vancomycin* Ampicillin plus ceftazidime plus vancomycin* Vancomycin plus ceftazidime

Impaired cellular immunity Neurosurgery, head trauma, or CSF shunt

*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. Table 8. Recommended Empiric Antibiotics for Patients With Suspected Bacterial Meningitis and Known CSF Gram Stain Results (Open Table in a new window) Gram Stain Morphology Gram-positive cocci Gram-negative cocci Antibiotic(s) Vancomycin plus ceftriaxone or cefotaxime Penicillin G*

Gram-positive bacilli Gram-negative bacilli

Ampicillin plus an aminoglycoside Broad-spectrum cephalosporin plus an aminoglycoside

*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).

Table 9. Specific Antibiotics and Duration of Therapy for Patients With Acute Bacterial Meningitis (Open Table in a new window) Durati on

Bacteria

Susceptibility

Antibiotic(s)

(Days)

S pneumoniae

Penicillin MIC < 0.1 mg/L MIC 0.1-1 mg/L MIC >2 mg/L

Penicillin G

10-14

Ceftriaxone or cefotaxime Ceftriaxone or cefotaxime

Ceftriaxone MIC >0.5 Ceftriaxone or cefotaxime plus vancomycin mg/L or rifampin H influenzae Beta-lactamasenegative Beta-lactamasepositive N meningitidis ... Ampicillin 7

Ceftriaxone or cefotaxime

Penicillin G or ampicillin Ampicillin or penicillin G plus an aminoglycoside

7 14-21

L ... monocytogenes

S agalactiae

...

Penicillin G plus an aminoglycoside, if warranted Ceftriaxone or cefotaxime plus an aminoglycoside Ceftazidime plus an aminoglycoside

14-21

Enterobacteriac ... eae P aeruginosa ...

21

21

Institute empiric antimicrobial therapy (ie, antibacterial treatment, or antivirals and antifungal therapy in selected cases) as soon as possible. This is usually based on the known predisposing factors and/or initial CSF Gram stain results. Appropriate antibiotic treatment for the most common types of bacterial meningitis should reduce the risk of death to less than 15%, although the risk is higher among elderly patients. 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 targeted treatment. Monitor for the occurrence of complications from the disease (eg, hydrocephalus, seizures, hearing defects) and its treatment (eg, drug toxicity, hypersensitivity).

Antibiotic therapy - Neonate to age 1 month

In neonates to age 1 month, the most common microorganisms are group B or D streptococci, Enterobacteriaceae (eg, E coli), and L monocytogenes. Primary treatment is a combination of ampicillin (age 0-7 d: 50 mg/kg IV q8h; age 8-30 d: 50-100 mg/kg IV q6h) plus cefotaxime 50 mg/kg IV q6h (up to 12 g/d). Alternative treatment is ampicillin (age 0-7 d: 50 mg/kg IV q8h; age 8-30 d: 50-100 mg/kg IV q6h) plus gentamicin (age 0-7 d: 2.5 mg/kg IV or IM q12h; age 8-30 d: 2.5 mg/kg IV or IM q8h). Most authorities recommend adding acyclovir 10 mg/kg IV q8h for herpes simplex encephalitis.

Antibiotic therapy - Age 1-3 months

In infants (1-3 mo), primary treatment is cefotaxime (50 mg/kg IV q6h, up to 12 g/d) or ceftriaxone (initial dose: 75 mg/kg, 50 mg/kg q12h up to 4 g/day) plus ampicillin (50-100 mg/kg IV q6h). Alternative treatment is chloramphenicol (25 mg/kg PO or IV q12h) plus gentamicin (2.5 mg/kg IV or IM q8h). If prevalence of cephalosporin-resistant S pneumoniae (DRSP) is greater than 2%, add vancomycin (15 mg/kg IV q8h). Strongly consider dexamethasone (0.4 mg/kg IV q12h for 2 d or 0.15 mg/kg IV q6h for 4 d) starting 15-20 minutes before first dose of antibiotics.

Antibiotic therapy - Age 3 months to 7 years

In older infants or young children (3 mo - 7 y), the most common microorganisms are S pneumoniae, N meningitidis, and H influenzae. Primary treatment is either cefotaxime (50 mg/kg IV q6h up to 12 g/d) or ceftriaxone (initial dose: 75 mg/kg, then 50 mg/kg q12h up to 4 g/d). If prevalence of DRSP is greater than 2%, add vancomycin (15 mg/kg IV q8h). In countries with low prevalence of DRSP, consider penicillin G (250,000 U/kg/d IM/IV in 3-4 divided doses). Due to DRSP, penicillin G is no longer recommended in the US.

Alternative treatment (or if severely penicillin allergic) is chloramphenicol (25 mg/kg PO/IV q12h) plus vancomycin (15 mg/kg IV q8h). Strongly consider dexamethasone (0.4 mg/kg IV q12h for 2 d or 0.15 mg/kg IV q6h for 4 d) starting 15-20 minutes before the first dose of antibiotics.

Antibiotic therapy - Age 7-50 years

In an older child or an otherwise healthy adult (7-50 y), the most common microorganisms are S pneumoniae, N meningitidis, and L monocytogenes. In areas where prevalence of DRSP is greater than 2%, primary treatment is either cefotaxime (pediatric dose: 50 mg/kg IV q6h up to 12 g/d; adult dose: 2 g IV q4h) or ceftriaxone (pediatric dose: initial dose: 75 mg/kg, then 50 mg/kg q12h up to 4 g/day; adult dose: 2 g IV q12h) plus vancomycin (pediatric dose: 15 mg/kg IV q8h; adult dose: 750-1000 mg IV q12h or 10-15 mg/kg IV q12h). Some add rifampin (pediatric dose: 20 mg/kg/d IV; adult dose: 600 mg PO qd). If Listeria species is suspected, add ampicillin (50 mg/kg IV q6h). Alternative treatment (or if severely penicillin allergic) is chloramphenicol (12.5 mg/kg IV q6h: not bactericidal) or clindamycin (pediatric dose: 40 mg/kg/day IV in 3-4 doses; adult dose: 900 mg IV q8h: active in vitro but no clinical data) or meropenem (pediatric dose: 20-40 mg/kg IV q8h; adult dose: 1 g IV q8h: active in vitro but few clinical data; avoid imipenem, as it is proconvulsant). In areas with low prevalence of DRSP, use cefotaxime (pediatric dose: 50 mg/kg IV q6h up to 12 g/d; adult: 2 g IV q4h) or ceftriaxone (pediatric dose: 75 mg/kg initial dose then 50 mg/kg q12h up to 4 g/d; adult: 2 g IV q12h) plus ampicillin (50 mg/kg IV q6h). Alternative treatment (or if severely penicillin allergic) is chloramphenicol (12.5 mg/kg IV q6h) plus trimethoprim/sulfamethoxazole (TMP/SMX; TMP 5 mg/kg IV q6h) or meropenem (pediatric dose: 20-40 mg/kg IV q8h; adult dose: 1 g IV q8h). Data are limited on the need for dexamethasone in adults, although there is support for its use in developed countries when S. pneumoniae is the suspected organism. Administer the first dose of dexamethasone (0.4 mg/kg q12h IV for 2 d or 0.15 mg/kg q6h for 4 d) 15-20 minutes before first dose of antibiotics.

Antibiotic therapy - Age 50 years and older

In adults older than 50 years or adults with disabling disease or alcoholism, the most common microorganisms are S pneumoniae, coliforms, H influenzae, Listeria species, Pseudomonas aeruginosa, and N meningitidis. Primary treatment if the prevalence of DRSP is greater than 2% is either cefotaxime (2 g IV q4h) or ceftriaxone (2 g IV q12h) plus vancomycin (750-1000 mg IV q12h or 10-15 mg/kg IV q12h). If CSF Gram stain shows gram-negative bacilli, use ceftazidime (2 g IV q8h). In areas of low prevalence of DRSP, use cefotaxime (2 g IV q4h) or ceftriaxone (2 g IV q12h) plus ampicillin (50 mg/kg IV q6h). Other options for treatment include meropenem, TMP/SMX, and doxycycline. Data are limited on the need for dexamethasone in adults, although there is support for its use in developed countries when S pneumoniae is the suspected organism and suspicion for TB or fungal etiologies is low. Administer the first dose of dexamethasone (0.4 mg/kg q12h IV for 2 d or 0.15 mg/kg q6h for 4 d) 15-20 minutes before the first dose of antibiotics. Go to the following articles for complete information on these topics:

Meningococcal Meningitis Staphylococcal Meningitis Haemophilus Meningitis

Steroid Therapy
The present understanding of the pathogenesis of bacterial meningitis has led to multiple therapeutic trials that involve the means to attenuate the detrimental effects of the hosts 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. Clinical data, however, indicate that steroid use may offer benefit in certain cases of acute bacterial meningitis. Therefore, pharmacologic interventions to reduce the degree of inflammation may improve outcome. Strongly consider the use of steroids as adjunctive treatment for 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.

Dexamethasone
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. Controversy surrounds the administration of dexamethasone, which is given with or just before antibiotics. [12] Dexamethasone may interrupt the cytokine-mediated neurotoxic effects of bacteriolysis, which are at maximum in the first days of antibiotic use. A meta-analysis of 10 years of clinical trials confirmed that dexamethasone decreases morbidity, especially incidence and severity of neurosensory hearing loss, for H influenzae meningitis and suggested comparable benefit for S pneumoniae meningitis in childhood. No adequate adult studies exist, although the pathophysiology is presumably similar. Meta-analysis suggests that limiting dexamethasone therapy to 2 days may be optimal. Studies conducted in Europe have continued to support the use of dexamethasone in developed (as opposed to developing) countries, perhaps related to the relative incidence of TB meningitis. Theoretically, anti-inflammatory effects of steroids decrease blood-brain barrier permeability and impede penetration of antibiotics into CSF. Decreased CSF levels of vancomycin have been confirmed in steroidtreated animals but not in human studies. Many authorities believe that all other antibiotics achieve minimal inhibitory concentrations (MICs) in CSF regardless of steroid use. Dexamethasone may not clinically impede even vancomycin. 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. In a meta-analysis, dexamethasone had no effect in any of the prespecified subgroups, including specific causative organisms, predexamethasone antibiotic treatment, HIV status, or age. The meta-analysis was also unable to show a significant reduction in death or neurologic disability.[13] In developing countries, the use of oral glycerol (rather than dexamethasone) has been studied as adjunctive therapy in the treatment of bacterial meningitis in children. In limited studies, it appears to reduce the incidence of neurologic sequelae with few side effects.[14]

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. Go to Viral Meningitis for complete information on this topic.

Herpes simplex meningitis

The antiviral management of HSV 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.

CMV meningitis
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.

HIV meningitis
Instituting highly active antiretroviral therapy (HAART) may be necessary for patients with HIV meningitis that occurs during an acute seroconversion syndrome. Go to HIV-1 Associated CNS Conditions - Meningitis for complete information on this topic.

Fungal Meningitis (AIDS-Related Cryptococcal Meningitis)

For initial 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 used in patients with or who are predisposed to develop renal dysfunction (amphotericin B liposome 3-4 mg/kg/d or amphotericin B lipid complex 5 mg/kg/d). For consolidation therapy, administer fluconazole (400 mg/d for 8 wk). Itraconazole is an alternative if fluconazole is not tolerated. For 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. The 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 policy makers and national departments of health in such countries should consider adding drugs that are typically unavailable in such settings (eg, flucytosine) for HIV treatment programs.[15] Go to HIV-1 Associated CNS Conditions - Meningitis for complete information on this topic.

Fungal Meningitis (NonAIDS- and NonTransplant-Related Cryptococcal Meningitis)

For induction and consolidation therapy, administer amphotericin B (0.7-1 mg/kg/d) plus flucytosine (100 mg/kg/d) for at least 4 weeks. This may be extended to 6 weeks in neurological complications. Then, administer fluconazole (400 mg/d) for a minimum of 8 weeks. A lumbar puncture is recommended after 2 weeks to document sterilization of the CSF. If the infection persists, longer induction therapy is recommended (6 weeks). Solid organ transplant recipients with cryptococcal meningitis should be treated with liposomal amphotericin B (3-4 mg/kg/d IV) or amphotericin B lipid complex (5 mg/kg/d IV) plus flucytosine (100 mg/kg/d in 4 divided doses) for at least 2 weeks of induction therapy. This is followed by consolidation treatment using fluconazole at 400-800 mg/d orally for 8 weeks, and then maintenance treatment with fluconazole at 200 mg/d orally for 6-12 months.

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

Histoplasma capsulatum
The recommended treatment of H capsulatum meningitis is liposomal amphotericin B at 5-mg/kg/d IV for a total of 175 mg/kg given over 4-6 weeks, followed by oral itraconazole 200-300 mg twice to thrice daily for at least 1 year or until the resolution of CSF abnormalities and Histoplasma antigen levels. Blood levels of itraconazole should be measured to ensure good absorption of the oral drug. This infection is associated with a poor outcome; 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 (0.7 mg/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.

Sporothrix 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 than itraconazole. The duration of treatment in AIDS-related cases is lifelong.

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 blood-brain barrier 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. Go to Tuberculous Meningitis for complete information on this topic.

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

Parasitic Meningitis
Primary amebic meningoencephalitis (PAM), caused by N fowleri, is usually fatal. The few survivors reported in the scientific literature benefitted 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 antiinflammatory 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.

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.

Prevention
Vaccination and chemoprophylaxis are 2 means of preventing meningitis.

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

Vaccinations against encapsulated bacterial organisms (eg, S pneumoniae, N meningitidis) are encouraged for people 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. One vaccine protects against 4 strains of N meningitidis. As of February 2008, the Advisory Committee on Immunization Practices no longer recommends routine immunization of children, but they continue to recommend routine immunization of teenagers and all children/adults at increased risk.[16] Vaccination against measles and mumps effectively eliminates aseptic meningitis syndrome caused by these pathogens.

Chemoprophylaxis
Following exposure to an index case, it is typical for an individual to temporarily carry H influenzae, N meningitidis, and S pneumoniaenasopharyngeally. An association between carriage and the risk of disease has been described, especially for N meningitidis and H influenzae. This is the basis for the recommendations on chemoprophylaxis. However, this prophylaxis does not treat incubating invasive disease, and closely monitor individuals at highest risk. To eliminate nasopharyngeal carriage of H influenzae type b 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. 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.

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

Long Term Monitoring

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.

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

Antimicrobial Agents
Class Summary
These agents are used to treat or prevent infection caused by the most likely pathogen suspected or identified.
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Ceftriaxone (Rocephin)
Ceftriaxone is a third-generation cephalosporin with broad-spectrum gram-negative activity. It has lower efficacy against gram-positive organisms but has excellent activity against susceptible pneumococcal organisms. It exerts an antimicrobial effect by interfering with the synthesis of peptidoglycan, a major structural component of the bacterial cell wall. It is an excellent antibiotic for the empiric treatment of bacterial meningitis.
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Ceftazidime (Ceptaz, Fortaz)

Ceftazidime is a third-generation cephalosporin with broad-spectrum activity against gram-negative organisms, lower efficacy against gram-positive organisms, and higher efficacy against resistant organisms. By binding to 1 or more of the penicillin-binding proteins, it arrests bacterial cell wall synthesis and inhibits bacterial replication.
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Cefotaxime (Claforan)
Cefotaxime is a third-generation cephalosporin that is used to treat suspected or documented bacterial meningitis caused by susceptible organisms, such as H influenzae or N meningitidis. Like other betalactam antibiotics, cefotaxime inhibits bacterial growth by arresting bacterial cell wall synthesis.
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Penicillin G (Pfizerpen)
A beta-lactam antibiotic, penicillin G inhibits bacterial cell wall synthesis, resulting in bactericidal activity against susceptible microorganisms. It is active against many gram-positive organisms and is the DOC for syphilitic meningitis and susceptible organisms (eg, N meningitidis, penicillin-susceptible S pneumoniae).
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Ampicillin (Omnipen, Polycillin)

A bactericidal beta-lactam antibiotic, ampicillin inhibits cell wall synthesis by interfering with peptidoglycan formation. The drug is indicated for L monocytogenes and S agalactiae meningitis, usually in combination with gentamicin.
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Vancomycin (Vancocin)
Vancomycin is a glycopeptide antibiotic that is active against staphylococci, streptococci, and other grampositive bacteria. It exerts antibacterial activity by inhibiting biosynthesis of peptidoglycan and is the DOC for highly penicillin-resistant and ceftriaxone-resistant S pneumoniae and methicillin-resistant S aureus. It is a component of empiric DOC for CNS-shuntassociated meningitis. Because of poor CSF penetration, a higher dose of vancomycin is required for meningitis than for other infections. Use CrCl to adjust the dose in renal impairment.
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Gentamicin (Garamycin)
Newer antibiotics are available, but aminoglycosides, such as gentamicin, 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 the dose based on CrCl and changes in the volume of distribution.
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Chloramphenicol (Chloromycetin)
Chloramphenicol binds to 50 S bacterial-ribosomal subunits and inhibits bacterial replication by inhibiting protein synthesis. It is effective against gram-negative and gram-positive bacteria.
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Trimethoprim/sulfamethoxazole (Bactrim, Bactrim DS)

Trimethoprim/sulfamethoxazole inhibits bacterial synthesis of dihydrofolic acid by competing with paraaminobenzoic acid, inhibiting folic acid synthesis. This results in inhibition of bacterial replication.
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Meropenem (Merrem)
A broad-spectrum carbapenem antibiotic, meropenem inhibits cell wall synthesis and has bactericidal activity. It is effective against most gram-positive and gram-negative bacteria. Meropenem has slightly increased activity against gram-negative organisms and slightly decreased activity against staphylococci and streptococci compared with imipenem.
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Doxycycline (Doryx, Bio-Tab)

Doxycycline inhibits protein synthesis and, therefore, bacterial growth by binding with 30S and possibly 50S ribosomal subunits of susceptible bacteria.
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Ciprofloxacin (Cipro)
Ciprofloxacin is a fluoroquinolone that inhibits bacterial DNA synthesis and, consequently, growth by inhibiting DNA gyrase and topoisomerases, which are required for replication, transcription, and translation of genetic material. Quinolones have broad activity against gram-positive and gram-negative aerobic organisms. Ciprofloxacin has no activity against anaerobes. Continue treatment for at least 2 days (7-14 d typical) after signs and symptoms have disappeared.
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Clindamycin (Cleocin)
Clindamycin is a semisynthetic antibiotic produced by a 7(S)-chloro-substitution of 7(R)-hydroxyl group of the parent compound lincomycin. It inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. It widely distributes in the body without penetration of the CNS. Clindamycin is protein bound and excreted by the liver and kidneys. It is effective against gram-positive aerobic and anaerobic bacteria (except enterococci).

Antiviral Agents
Class Summary
These agents interfere with viral replication; they weaken or abolish viral activity.
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Acyclovir (Zovirax)
A prodrug activated by cellular enzymes, acyclovir inhibits the activity of HSV-1, HSV-2, and varicellazoster virus by competing for viral DNA polymerase and incorporation into viral DNA. Acyclovir is used in HSV meningitis.
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Ganciclovir (Cytovene)
Ganciclovir is a synthetic guanine derivative active against CMV. An acyclic nucleoside analog of 2'deoxyguanosine, it inhibits the replication of herpes viruses in vitro and in vivo. levels of ganciclovirtriphosphate 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.
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Foscarnet
Foscarnet is an organic analog of inorganic pyrophosphate that inhibits the replication of known herpesviruses, including CMV, HSV-1, and HSV-2. It inhibits viral replication at the pyrophosphatebinding site on virus-specific DNA polymerases. Foscarnet is used to treat CMV meningitis in immunocompromised hosts at induction doses of 60 mg/kg IV q8h and maintenance doses of 90-120 mg/kg IV q24h.

Antifungal Agents
Class Summary
These agents are used in the management of infectious diseases caused by fungi.

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Amphotericin B, conventional (Amphocin, Fungizone)

A polyene antibiotic produced by a strain of S nodosus, this drug can be fungistatic or fungicidal. It binds to sterols, such as ergosterol, in the fungal cell membrane, causing intracellular components to leak with subsequent fungal cell death. The drug is used to treat severe systemic infection and meningitis caused by susceptible fungi (ie, C albicans, H capsulatum, C neoformans). It is 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.
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Fluconazole (Diflucan)
Fluconazole has fungistatic activity. It is a 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.
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Flucytosine (Ancobon)
Flucytosine is converted to fluorouracil after penetrating fungal cells and inhibits RNA and protein synthesis. It is active against candidal and cryptococcal species and is used in combination with amphotericin B.
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Itraconazole (Sporanox)
Itraconazole has fungistatic activity. It is a synthetic triazole antifungal agent that slows fungal cell growth by inhibiting cytochrome P-450-dependent synthesis of ergosterol, a vital component of fungal cell membranes.

Antitubercular Agents
Class Summary
These agents are used in the management of mycobacterial disease in combination with other antitubercular agents.
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Rifampin (Rifadin, Rimactane)

Rifampin is used in combination with other antituberculous drugs. It inhibits DNA-dependent bacterial, but not mammalian, RNA polymerase. Cross-resistance may occur.
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Isoniazid (Laniazid, Nydrazid)

Isoniazid is a first-line antituberculous drug that is used in combination with other antituberculous drugs to treat meningitis. It is usually administered for at least 12-24 months. A prophylactic dose of pyridoxine (650 mg/d) is recommended if peripheral neuropathies secondary to isoniazid therapy develop.

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Pyrazinamide (PZA)
Pyrazinamide is a pyrazine analog of nicotinamide; it may be bacteriostatic or bactericidal against M tuberculosis, depending on the drug concentration attained at the site of infection. Pyrazinamide's mechanism of action is unknown.
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Ethambutol (Myambutol)
Ethambutol diffuses into actively growing mycobacterial cells (eg, tubercle bacilli). It impairs cell metabolism by inhibiting the synthesis of 1 or more metabolites, which in turn causes cell death. No cross-resistance has been demonstrated. Mycobacterial resistance is frequent with previous therapy. Use in these patients in combination with second-line drugs that have not been administered previously. Administer every 24 hours until permanent bacteriological conversion and maximal clinical improvement is observed. Absorption is not significantly altered by food.
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Streptomycin
Streptomycin has bactericidal action and inhibits bacterial protein synthesis. Susceptible organisms include M tuberculosis, Pasteurella pestis, Pasteurella tularensis, H influenzae, Haemophilus ducreyi, donovanosis (granuloma inguinale), Brucella species, Klebsiella pneumonia, Escherichia coli, Proteus species, Aerobacter species, Enterococcus faecalis, and Streptococcus viridans (in endocarditis, with penicillin). Streptomycin is always given as part of total anti-TB regimen.

Vaccines
Class Summary
These agents are used to induce active immunity against pathogens responsible for meningitis.

Meningococcal vaccine (Groups A/C/Y/W-135)

This vaccine is composed of capsular polysaccharide antigens (groups A, C, Y, and W-135) of Neisseria meningitidis. Meningococcal vaccine may be used to prevent and control outbreaks of serogroup C meningococcal disease according to CDC guidelines. It induces formation of bactericidal antibodies to meningococcal antigens. The vaccine is used for active immunization against invasive meningococcal disease caused by inclusive serogroups. Although the vaccine induces antibody response for serogroup A in individuals as young as age 3 months, it is poorly immunogenic for serogroup C in recipients who are younger than age 18-24 months.

Pneumococcal vaccine 23-valent

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

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

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Dexamethasone
Dexamethasone has many pharmacologic benefits such as stabilizing cell and lysosomal membranes. It increases surfactant synthesis, increases serum vitamin A concentrations, inhibits prostaglandin and proinflammatory cytokines (eg, TNF-alpha, IL-6, IL-2, and IFN-gamma). 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.

Diuretic Agents
Class Summary
These agents are used to reduce intracranial pressure and treat cerebral edema.
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Furosemide (Lasix)
Furosemide is a loop diuretic that increases the excretion of water by interfering with the chloride-binding co-transport system, which, in turn, inhibits sodium and chloride reabsorption in the ascending loop of Henle and distal renal tubule. The proposed mechanism for furosemide in lowering intracranial pressure include (1) lowering cerebral sodium uptake, (2) affecting water transport into astroglial cells by inhibiting the cellular membrane cation-chloride pump, and (3) decreasing cerebrospinal fluid production by inhibiting carbonic anhydrase.
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Mannitol (Osmitrol)
Mannitol may reduce subarachnoid-space pressure by creating an osmotic gradient between cerebrospinal fluid in arachnoid-space and plasma. Doses of 1 g/kg IV have been used.

Anticonvulsants
Class Summary
Anticonvulsants help to aggressively control seizures if present in acute meningitis, because seizure activity increases intracranial pressure.
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Lorazepam (Ativan)
Lorazepam is a sedative hypnotic with a short onset of effect and a relatively long half-life. By increasing the action of gamma-aminobutyric acid (GABA), which is a major inhibitory neurotransmitter in the brain, it may depress all levels of the CNS, including limbic and reticular formation. Doses of lorazepam 0.1 mg/kg IV have been used to control seizures.
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Phenytoin (Dilantin)

Phenytoin works on the motor cortex, where it may inhibit the spread of seizure activity. The activity of brain stem centers responsible for the tonic phase of grand mal seizures may also be inhibited. Doses should be individualized. Doses of 15 mg/kg have been used.
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Phenobarbital
Phenobarbital elevates the seizure threshold, limits the spread of seizure activity, is a sedative. Doses of 5-10 mg/kg have been recommended.

http://emedicine.medscape.com/article/232915-overview

Pathophysiology

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Understanding the pathophysiology of meningococcal infection and the principles of management

The principles of management of meningitis and septicaemia are best understood by having a basic knowledge of their pathophysiology40. The section below is a summary. For more detailed information see references section.

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Clinical pathophysiology of meningococcal septicaemia

back to top^Increased

Vascular Permeability

When meningococci invade the bloodstream, endotoxin is released from the bacteria. This triggers an inflammatory response, with release of inflammatory mediators, which is directed against the endothelial surface lining the blood vessels. One of the main functions of the endothelium is regulation of vascular permeability, and disturbance of this function causes the endothelial lining to become 'leaky', allowing increased passage of protein and water from the intravascular to extra-vascular compartments, causing a 'capillary leak syndrome'. The patient becomes hypovolaemic due to reduction in circulating volume, thus reducing cardiac output.

In compensation for reduced circulating volume, heart rate and contractility increase, and perfusion to skin and the splanchnic circulation is reduced. Therefore signs of hypovolaemia in sepsis include: Tachycardia Tachypnoea Cool peripheries Reduced urine output Irritability or lethargy. Note that in the early phases of septic shock blood pressure is maintained by these compensatory mechanisms. This means that early in shock, children are alert as blood flow to the brain is being maintained at the cost of the other organs.

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dysfunction

Endotoxin and inflammatory mediators (such as IL6)41, together with other poorly defined 'myocardial depressant factors' reduce myocardial contractility. In addition, a myocardial cytotoxic process causes myocardial cell necrosis. Hypovolaemia and myocardial dysfunction contribute to progression of shock. In addition, nitric oxide and other vasoactive mediators cause a relative 'vasoparesis' and relative inotrope unresponsiveness. Progression of shock leads to tissue hypoxia and capillary leak leads to pulmonary oedema resulting in tachypnoea and hypoxia. Eventually, compensatory mechanisms fail and blood pressure falls. This is a late and serious sign in septic shock in children.

back to top^Disseminated

intravascular coagulation

Endotoxin and the inflammatory response leads to activation of the coagulation cascade and down-regulation of anticoagulant and fibrinolytic pathways, leading to a procoagulant state. Clotting times are prolonged and thrombocytopenia occurs. Microvascular thrombosis contributes to multiple organ failure and purpura fulminans. Amputations: When purpura fulminans occurs, some tissues are irreversibly destroyed due to thrombosis within the microvasculature, combined with vasoconstriction and ischaemia in peripheries. Haemorrhagic necrosis in skin and clotting in small vessels can lead to loss of skin, digits or limbs.

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Specific organ dysfunction in shock

Respiratory failure (arterial PO2 <10kPa in air or PCO2 >6) Common in shock. Capillary leak into lung parenchyma acute pulmonary oedema. Clinically: tachypnoea, chest wall retraction, hypoxia. Metabolic derangement Septicaemia causes profound acidosis and derangements in metabolism, which may affect myocardial function and need correcting. Hypoglycaemia is common. Hypokalaemia, hypocalcaemia, hypomagnesaemia and hypophosphataemia all occur. Coagulopathy (purpuric rash) Coagulopathy occurs early in patients with septicaemia. The laboratory findings of disseminated intravascular coagulation(DIC) are common in such patients. Coagulopathy is generally associated with the presence of a purpuric rash, but significant coagulopathy may infrequently occur in the absence of purpura.

Neurological dysfunction In septicaemia, patients may be alert until late in the illness. Falling conscious level results from impaired cerebral blood flow and disturbed brain metabolism due to hypotension, hypoxia and acidosis. Myocardial failure Depressed myocardial function is multifactorial, including endotoxin, cytokines, multiple metabolic derangements, hypoxia, and hypovolaemia. Clinically: tachycardia, gallop rhythm, cool peripheries and eventually hypotension. Renal failure Little or no urine output (<1ml/kg/hour) is a very early sign in septic shock, initially due to hypovolaemia. If shock persists then renal failure may occur. Serum creatinine 2 times upper limit of normal for age or 2-fold increase in baseline creatinine indicates renal dysfunction.

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Clinical pathophysiology of meningitis

Meningococcal meningitis generally has a better prognosis than septicaemia. Meningococci reach the brain from the bloodstream, implying that the patients immune response has prevented bacterial proliferation in the blood and not suffered overwhelming sepsis. This is because organisms are handled differently in these patients, which is probably due to differences in their inflammatory response to infection as well as different bacterial characteristics. Deaths do occur, however due to the severity of the inflammatory process within the brain. Once bacteria penetrate the blood-brain barrier, endotoxin and inflammatory mediators initiate a CSF inflammatory response, causing leakage of protein and fluid out of the cerebral vasculature. In addition, the processes delineated in septicaemia occur in brain blood vessels, causing cerebral oedema and cerebral vascular thrombosis. As a consequence there is an increase in brain water content and an increase in intracranial pressure. Both the increased pressure and thrombosis may lead to a reduction in cerebral perfusion, and consequently cerebral infarction and sometimes brain death.

An Overview of Meningitis Research

http://meningitis.emedtv.com/meningitis/meningitisresearch.html
Doctors and scientists are hard at work conducting meningitis research. Meningitis research studies are designed to answer important questions and to find out whether new approaches are safe and effective. Meningitis research already has led to many advances, and researchers continue to search for more effective methods for dealing with meningitis.

Current Areas of Focus in Meningitis Research

Current research efforts include investigating new chemotherapy-based treatment for neoplastic meningitis (caused by cancer) and gaining a better understanding of how the central nervous system responds to inflammation and the role of T cells (blood cells involved in immune system response) in suppressing infection in the brain.

In other meningitis research, scientists hope to better understand the molecular mechanisms involved in the protection and disruption of the blood-brain barrier, which could lead to the development of new treatments for several neuroinflammatory diseases such as meningitis.

Other scientists involved with meningitis research hope to define, at a molecular level, how certain viruses overcome the body's defense mechanism and interact with target host cells.

Additional meningitis research is looking at possible neuroprotective medicines. A possible therapeutic approach under investigation involves testing medicines that block the damage that accumulates after the infection and inflammation of meningitis. (This damage can lead to potential complications, including dementia and loss of cognitive function.)