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Meningitis - Practice Essentials, Background, Pathophysiology
Meningitis - Practice Essentials, Background, Pathophysiology
Meningitis - Practice Essentials, Background, Pathophysiology
Meningitis
Updated: Nov 16, 2021
Author: Shikha S Vasudeva, MBBS; Chief Editor: Michael Stuart Bronze, MD more...
OVERVIEW
Practice Essentials
Meningitis is a clinical syndrome characterized by inflammation of the meninges.
Acute bacterial meningitis. This axial nonenhanced computed tomography scan shows mild ventriculomegaly and sulcal
effacement.
Fever
Headache
Neck stiffness
Up to 95% of patients with bacterial meningitis have at least two of the four following symptoms:
fever, headache, stiff neck, or altered mental status.
Other symptoms can include nausea, vomiting, photalgia (photophobia), sleepiness, confusion,
irritability, delirium, and coma. Patients with viral meningitis may have a history of preceding
systemic symptoms (eg, myalgias, fatigue, or anorexia).
Epidemiologic factors and predisposing risks such as mosquito bites (West Nile virus in
endemic months, June-October in the United States)
Exposure to a sick contact (small children with febrile illness)
Previous medical treatment and existing conditions
Geographic location and travel history
Season and temperature (enterovirus and West Nile virus in the summer and fall; herpes
simplex virus type 2 year round)
Acute bacterial meningitis in otherwise healthy patients who are not at the extremes of age
presents in a clinically obvious fashion; however, subacute bacterial meningitis often poses a
diagnostic challenge.
General physical findings in viral meningitis are common to all causative agents. Enteroviral
infection is suggested by the following:
Exanthemas
Contact with small children with febrile illnesses
Symptoms of pericarditis, myocarditis, or conjunctivitis
Syndromes of pleurodynia, herpangina, and hand-foot-and-mouth disease
Paradoxic irritability (ie, remaining quiet when stationary and crying when held)
High-pitched cry
Hypotonia
Level of consciousness
Lymphadenopathy
Papilledema
Meningismus
Patients with aseptic meningitis syndrome usually appear clinically nontoxic, with no vascular
instability. They characteristically have an acute onset of meningeal symptoms, fever, and CSF
pleocytosis that is usually prominently lymphocytic.
See Clinical Presentation for more detail.
Diagnosis
The diagnostic challenges in patients with clinical findings of meningitis are as follows:
Assessing whether a treatable CNS infection is present in those with suspected subacute or
chronic meningitis
Serum electrolytes
Syphilis testing
Management
Altered mental status – Seizure precautions and treatment (if necessary), along with airway
protection (if warranted)
Stable with normal vital signs – Oxygen, IV access, and rapid transport to the emergency
department (ED)
Prompt initiation of empiric antibacterial therapy as appropriate for patient age and condition
Hypotension or shock
Hypoxemia
Hyponatremia
Stroke
Most cases of viral meningitis are benign and self-limited, but in certain instances, specific antiviral
therapy may be indicated, if available.
Other types of meningitis are treated with specific therapy as appropriate for the causative
pathogen, as follows:
Background
Infections of the central nervous system (CNS) can be divided into two broad categories: those
primarily involving the meninges (meningitis; see the image below) and those primarily confined to
the parenchyma (encephalitis).
Pneumococcal meningitis in a patient with alcoholism. Courtesy of the CDC/Dr. Edwin P. Ewing, Jr.
The three layers of membranes that enclose the brain and spinal cord.
Other definitions
Acute meningitis is defined as onset of symptoms of meningeal inflammation over the course
of hours to several days
Chronic meningitis is defined as at least 4 weeks of symptoms of inflammation of meninges
Aseptic meningitis refers to a syndrome consistent with signs and symptoms of meningeal
inflammation but with negative routine CSF cultures
Recurrent meningitis is defined as at least two episodes of signs and symptoms of meningeal
inflammation with associated CSF findings separated by a period of full recovery.
Pathophysiology
Most cases of meningitis are caused by an infectious agent that has colonized or established a
localized infection elsewhere in the host. Potential sites of colonization or infection include the skin,
the nasopharynx, the respiratory tract, the gastrointestinal (GI) tract, and the genitourinary tract.
The organism invades the submucosa at these sites by circumventing host defenses (eg, physical
barriers, local immunity, and phagocytes or macrophages).
An infectious agent (ie, a bacterium, virus, fungus, or parasite) can gain access to the CNS and
cause meningeal disease via any of the three following major pathways:
Invasion of the bloodstream and subsequent seeding is the most common mode of spread for most
agents. This pathway is characteristic of meningococcal, cryptococcal, syphilitic, and
pneumococcal meningitis.
Rarely, meningitis arises from invasion via septic thrombi or osteomyelitic erosion from infected
contiguous structures. Meningeal seeding may also occur with a direct bacterial inoculate during
trauma, neurosurgery, or instrumentation. Meningitis in the newborn may be transmitted vertically,
involving pathogens that have colonized the maternal intestinal or genital tract, or horizontally, from
nursery personnel or caregivers at home.
Local extension from contiguous extracerebral infection (eg, otitis media, mastoiditis, or sinusitis) is
a common cause. Possible pathways for the migration of pathogens from the middle ear to the
meninges include the following:
The bloodstream
Preformed tissue planes (eg, posterior fossa)
Temporal bone fractures
The oval or round window membranes of the labyrinths
The brain is naturally protected from the body’s immune system by the barrier that the meninges
create between the bloodstream and the brain. Normally, this protection is an advantage because
the barrier prevents the immune system from attacking the brain. However, in meningitis, the
blood-brain barrier can become disrupted; once bacteria or other organisms have found their way
to the brain, they are somewhat isolated from the immune system and can spread.
When the body tries to fight the infection, the problem can worsen; blood vessels become leaky
and allow fluid, WBCs, and other infection-fighting particles to enter the meninges and brain. This
process, in turn, causes brain swelling and can eventually result in decreasing blood flow to parts
of the brain, worsening the symptoms of infection.
[1]
Depending on the severity of bacterial meningitis, the inflammatory process may remain confined
to the subarachnoid space. In less severe forms, the pial barrier is not penetrated, and the
underlying parenchyma remains intact. However, in more severe forms of bacterial meningitis, the
pial barrier is breached, and the underlying parenchyma is invaded by the inflammatory process.
Thus, bacterial meningitis may lead to widespread cortical destruction, particularly when left
untreated.
Exudates extend throughout the CSF, particularly to the basal cisterns, resulting in the following:
Damage to cranial nerves (eg, cranial nerve VIII, with resultant hearing loss)
Obliteration of CSF pathways (causing obstructive hydrocephalus)
Induction of vasculitis and thrombophlebitis (causing local brain ischemia)
One complication of meningitis is the development of increased intracranial pressure (ICP). The
pathophysiology of this complication is complex and may involve many proinflammatory molecules
as well as mechanical elements. Interstitial edema (secondary to obstruction of CSF flow, as in
hydrocephalus), cytotoxic edema (swelling of cellular elements of the brain through the release of
toxic factors from the bacteria and neutrophils), and vasogenic edema (increased blood brain
barrier permeability) are all thought to play a role.
Without medical intervention, the cycle of decreasing CSF, worsening cerebral edema, and
increasing ICP proceeds unchecked. Ongoing endothelial injury may result in vasospasm and
thrombosis, further compromising CSF, and may lead to stenosis of large and small vessels.
Systemic hypotension (septic shock) also may impair CSF, and the patient soon dies as a
consequence of systemic complications or diffuse CNS ischemic injury.
Cerebral edema
The increased CSF viscosity resulting from the influx of plasma components into the subarachnoid
space and diminished venous outflow lead to interstitial edema. The accumulation of the products
of bacterial degradation, neutrophils, and other cellular activation leads to cytotoxic edema.
The ensuing cerebral edema (ie, vasogenic, cytotoxic, and interstitial) significantly contributes to
intracranial hypertension and a consequent decrease in cerebral blood flow. Anaerobic metabolism
ensues, which contributes to increased lactate concentration and hypoglycorrhachia. In addition,
hypoglycorrhachia results from decreased glucose transport into the spinal fluid compartment.
Eventually, if this uncontrolled process is not modulated by effective treatment, transient neuronal
dysfunction or permanent neuronal injury results.
Key advances in understanding the pathophysiology of meningitis include insight into the pivotal
roles of cytokines (eg, tumor necrosis factor alpha [TNF-α] and interleukin [IL]-1), chemokines (IL-
8), and other proinflammatory molecules in the pathogenesis of pleocytosis and neuronal damage
during occurrences of bacterial meningitis.
Increased CSF concentrations of TNF-α, IL-1, IL-6, and IL-8 are characteristic findings in patients
with bacterial meningitis. Cytokine levels, including those of IL-6, TNF-α, and interferon gamma,
are elevated in patients with aseptic meningitis.
The proposed events involving these inflammation mediators in bacterial meningitis begin with the
exposure of cells (eg, endothelial cells, leukocytes, microglia, astrocytes, and meningeal
macrophages) to bacterial products released during replication and death; this exposure incites the
synthesis of cytokines and proinflammatory mediators. This process is likely initiated by the ligation
of the bacterial components (eg, peptidoglycan and lipopolysaccharide) to pattern-recognition
receptors, such as the Toll-like receptors (TLRs).
TNF-α and IL-1 are most prominent among the cytokines that mediate this inflammatory cascade.
TNF-α is a glycoprotein derived from activated monocyte-macrophages, lymphocytes, astrocytes,
and microglial cells.
Nitric oxide is a free radical molecule that can induce cytotoxicity when produced in high amounts.
PGE2, a product of cyclooxygenase (COX), appears to participate in the induction of increased
blood-brain barrier permeability. PAF, with its myriad biologic activities, is believed to mediate the
formation of thrombi and the activation of clotting factors within the vasculature. However, the
precise roles of all these secondary mediators in meningeal inflammation remain unclear.
The net result of the above processes is vascular endothelial injury and increased blood-brain
barrier permeability, leading to the entry of many blood components into the subarachnoid space.
In many cases, this contributes to vasogenic edema and elevated CSF protein levels. In response
to the cytokines and chemotactic molecules, neutrophils migrate from the bloodstream and
penetrate the damaged blood-brain barrier, producing the profound neutrophilic pleocytosis
characteristic of bacterial meningitis.
The inflammatory response and the release of proinflammatory mediators are critical to the
recruitment of excess neutrophils to the subarachnoid space. These activated neutrophils release
cytotoxic agents, including oxidants and metalloproteins that cause collateral damage to brain
tissue.
Pattern recognition receptors, of which TLR A4 (TLRA4) is the best studied, lead to increase in the
myeloid differentiation 88 (MyD88)-dependent pathway and excess production of proinflammatory
mediators. At present, dexamethasone is used to decrease the effects of cellular toxicity by
neutrophils after they are present. Researchers are actively seeking ways to inhibit TLRA4 and
other proinflammatory recognition receptors through genetically engineered suppressors.
[2]
Etiology
Acute Bacterial Meningitis
Bacterial meningitis consists of pyogenic inflammation of the meninges and the underlying
subarachnoid CSF, with a bacterial cause of this syndrome. This is usually characterized by an
acute onset of meningeal symptoms and neutrophilic pleocytosis. If not treated, it may lead to
lifelong disability or death.
[3, 4] Depending on age and general condition, patients with acute
bacterial meningitis present acutely with signs and symptoms of meningeal inflammation and
systemic infection of less than 24 hours’ (and usually >12 hours’) duration.
Bacterial seeding of the meninges usually occurs through hematogenous spread. In patients
without an identifiable source of infection, local tissue and bloodstream invasion by bacteria that
have colonized the nasopharynx may be a common source. Many meningitis-causing bacteria are
carried in the nose and throat, often asymptomatically. Most meningeal pathogens are transmitted
through the respiratory route, including Neisseria meningitidis (meningococcus) and S pneumoniae
(pneumococcus).
Certain respiratory viruses are thought to enhance the entry of bacterial agents into the
intravascular compartment, presumably by damaging mucosal defenses. Once in the bloodstream,
the infectious agent must escape immune surveillance (eg, antibodies, complement-mediated
bacterial killing, and neutrophil phagocytosis).
Subsequently, hematogenous seeding into distant sites, including the CNS, occurs. The specific
pathophysiologic mechanisms by which the infectious agents gain access to the subarachnoid
space remain unclear. Once inside the CNS, the infectious agents likely survive because host
defenses (eg, immunoglobulins, neutrophils, and complement components) appear to be limited in
this body compartment. The presence and replication of infectious agents remain uncontrolled and
incite the cascade of meningeal inflammation described above.
With almost 4100 cases and 500 deaths occurring annually in the United States, bacterial
meningitis continues to be a significant source of morbidity and mortality. The annual incidence in
the United States is 1.33 cases per 100,000 population.
[5]
The specific infectious agents that are involved in bacterial meningitis vary among different patient
age groups, and the meningeal inflammation may evolve into the following conditions:
Ventriculitis
Empyema
Cerebritis
Abscess formation
Streptococcus pneumoniae
Staphylococcus aureus
Streptococcus pyogenes
Streptococcus agalactiae
Viridans streptococci
Enterococcus spp
Haemophilus influenzae
Listeria monocytogens
Cutibacterium acnes
Escherichia coli
Klebsiella pneumoniae
Pseudomonas aeruginosa
Salmonella spp
Acinetobacter spp
Stenotrophomonas maltophilia
Fusobacterium necrophorum
Pasteurella multocida
Capnocytophaga canimorsus
Table 1. Most Common Bacterial Pathogens on Basis of Age and Predisposing Risks (Open Table
in a new window)
Listeria monocytogenes
S agalactiae
E coli
Streptococcus pneumoniae
Neisseria meningitidis
N meningitidis
H influenzae
S pneumoniae
H influenzae
S pneumoniae
N meningitidis
Age >50 years
L monocytogenes
N meningitidis
L monocytogenes
Staphylococcus aureus
S pneumoniae
Group A streptococci
Coagulase-negative staphylococci
S aureus
CSF shunts
Aerobic gram-negative bacilli
Propionibacterium acnes
Some of the more common bacterial pathogens causing meningitis are elaborated below, but any
bacteria is capable of causing meningitis
H influenzae meningitis
H influenzae is a small, pleomorphic, gram-negative coccobacillus that is frequently found as part
of the normal flora in the upper respiratory tract. The organism can spread from one individual to
another in airborne droplets or by direct contact with secretions. Meningitis is the most serious
acute manifestation of systemic infection with H influenzae.
In the past, H influenzae was a major cause of meningitis, and the encapsulated type b strain of
the organism (Hib) accounted for the majority of cases. Since the introduction of Hib vaccine in the
United States in 1990, the overall incidence of H influenzae meningitis has decreased by 35%, with
Hib accounting for fewer than 9.4% of H influenzae cases.
[3]
The isolation of H influenzae in adults suggests the presence of an underlying medical disorder,
such as the following:
Paranasal sinusitis
Otitis media
Alcoholism
CSF leak after head trauma
Functional or anatomic asplenia
Hypogammaglobulinemia
Pneumococcal meningitis
Patients with the following conditions are at increased risk for S pneumoniae meningitis:
Hyposplenism
Hypogammaglobulinemia
Multiple myeloma
Glucocorticoid treatment
Defective complement (C1-C4)
Diabetes mellitus
Renal insufficiency
Alcoholism
Malnutrition
Chronic liver disease
Diabetes mellitus
Pregnancy
Alcoholism
Hepatic failure
Renal failure
Corticosteroid treatment
Meningococcal meningitis
Most sporadic cases of meningococcal meningitis (95-97%) are caused by serogroups B, C, and Y,
whereas the A and C strains are observed in epidemics (< 3% of cases). Currently, N
meningitidis is one of the leading causes of bacterial meningitis in children and young adults, but
the incidence has decreased with use of the conjugate meningococcal vaccine.
[6]
L monocytogenes is a common food contaminant, with a recovery rate of up to 70% from raw
meat, vegetables, and meats. Outbreaks have been associated with consumption of contaminated
coleslaw, milk, cheese, and alfalfa tablets.
Pregnant women
Infants and children
Elderly individuals (>60 years)
Patients with alcoholism
Adults who are immunosuppressed (eg, steroid users, transplant recipients, or persons with
AIDS)
Individuals with chronic liver and renal disease
Individuals with diabetes
Persons with iron-overload conditions (eg, hemochromatosis or transfusion-induced iron
overload)
Escherichia coli
Klebsiella pneumoniae
Serratia marcescens
P aeruginosa
Salmonella species
Gram-negative bacilli can cause meningitis in certain groups of patients. E coli is a common agent
of meningitis among neonates. Other predisposing risk factors for meningitis associated with gram-
negative bacilli include the following:
Staphylococcal meningitis
Staphylococci are gram-positive cocci that are part of the normal skin flora. Meningitis caused by
staphylococci is associated with the following risk factors:
Neurosurgery
Head trauma
Presence of CSF shunts
Infective endocarditis and paraspinal infection
S epidermidis is the most common cause of meningitis in patients with CNS (ie,
ventriculoperitoneal) shunts.
Aseptic meningitis
Aseptic meningitis is one of the most common infections of the meninges. Although viruses are the
most common cause of aseptic meningitis, however, aseptic meningitis can also be caused by
bacteria, fungi, and parasites. It is noteworthy that partially treated bacterial meningitis accounts for
a large number of meningitis cases with a negative microbiologic workup.
In many cases, a cause of meningitis is not apparent after initial evaluation, and the disease is
therefore classified as aseptic meningitis. These patients characteristically have an acute onset of
meningeal symptoms, fever, and CSF pleocytosis that is usually prominently lymphocytic.
When the cause of aseptic meningitis is discovered, the disease can be reclassified according to
its etiology. If appropriate diagnostic methods are performed, a specific viral etiology is identified in
55% to 70% of cases of aseptic meningitis. However, the condition can also be caused by
bacterial, fungal, mycobacterial, and parasitic agents.
If, after an extensive workup, aseptic meningitis is found to have a viral etiology, it can be
reclassified as a form of acute viral meningitis (eg, enteroviral meningitis or herpes simplex virus
[HSV] meningitis).
Table 2. Infectious Agents Causing Aseptic Meningitis (Open Table in a new window)
Category Agent
Listeria monocytogenes
Brucella spp
Rickettsia rickettsii
Ehrlichia spp
Mycoplasma pneumoniae
Borrelia burgdorferi
Treponema pallidum
Leptospira spp
Mycobacterium tuberculosis
Nocardia spp
Naegleria fowleri
Acanthamoeba spp
Balamuthia spp
Angiostrongylus cantonensis
Baylisascaris procyonis
Strongyloides stercoralis
Toxocara spp
Cryptococcus neoformans
Coccidioides immitis
Blastomyces dermatitidis
Fungi
Histoplasma capsulatum
Candida spp
Aspergillus spp
Viruses Poliovirus
Echovirus
Enterovirus Coxsackievirus A
Coxsackievirus B
Enterovirus 68-71
Varicella-zoster virus
Epstein-Barr virus
Cytomegalovirus
Mumps virus
Paramyxovirus
Measles virus
Retrovirus HIV
HHV = human herpesvirus; HSV = herpes simplex virus; LCM = lymphocytic choriomeningitis.
Enteroviruses account for of the majority of cases of aseptic meningitis in children. Enteroviruses
belong to the family Picornaviridae and are further classified as follows:
Poliovirus (3 serotypes)
Coxsackievirus A (23 serotypes)
Coxsackievirus B (6 serotypes)
Echovirus (31 serotypes)
Newly recognized enterovirus serotypes 68-71
Enteroviruses are usually spread by fecal-oral or respiratory routes. Infection occurs during
summer and fall in temperate climates and year-round in tropical regions.
The nonpolio enteroviruses (NPEVs) account for approximately 90% of cases of viral meningitis in
which a specific pathogen can be identified.
Echovirus 30 was reported as the cause of an epidemic in Japan in 1991. It was also reported as
the cause of 20% of cases of aseptic meningitis reported to the Centers for Disease Control and
Prevention (CDC) in 1991.
The Herpesviridae family consists of large, DNA-containing enveloped viruses. Eight members are
known to cause human infections, and all have been implicated in meningitis syndromes, with the
exception of HHV-8 or Kaposi sarcoma–associated virus.
HSV accounts for 0.5% to 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,
whereas HSV-2 more commonly causes meningitis. Although Mollaret syndrome (a recurrent, but
benign, aseptic meningitis syndrome) is more frequently associated with HSV-2, HSV-1 has also
been implicated as a cause.
Epstein-Barr virus (EBV, or HHV-4) and cytomegalovirus (CMV, or HHV-5) infection may manifest
as meningitis in patients with the mononucleosis syndrome. Varicella-zoster virus (VZV, or HHV-3)
and CMV cause meningitis in immunocompromised hosts, especially patients with AIDS and
transplant recipients. HHV-6 and HHV-7 have been reported to cause meningitis in transplant
recipients.
The most common arthropod-borne viruses are West Nile virus, St Louis encephalitis virus (a
flavivirus), Colorado tick fever virus, and California encephalitis virus (bunyavirus group, including
La Crosse encephalitis virus). St Louis encephalitis virus is a mosquito-borne flavivirus that may
cause a febrile syndrome, aseptic meningitis syndrome, and encephalitis. Other members of the
flavivirus group that may cause aseptic meningitis include tick-borne encephalitis virus, Powassan
encephalitis, and Japanese encephalitis virus.
[7]
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.
The mumps virus is the most common cause of aseptic meningitis in unimmunized populations,
occurring in 30% of all patients with mumps. Upon exposure, an incubation period of approximately
5 to 10 days ensues, followed by a nonspecific febrile illness and an acute onset of aseptic
meningitis. This may be associated with orchitis, arthritis, myocarditis, and alopecia.
Patients with acute HIV infection may present with aseptic meningitis syndrome, usually as part of
the mononucleosis like acute seroconversion phenomenon. HIV should always be suspected as a
cause of aseptic meningitis in a patient with risk factors such as IV drug use or high-risk sexual
behaviors. These patients will have negative results on HIV serologic tests (eg, enzyme-linked
immunosorbent assay [ELISA] and Western blot); the diagnosis is made by the detection of serum
HIV RNA on polymerase chain reaction (PCR) testing or of HIV p24 antigen.
Adenovirus (serotypes 1, 6, 7, and 12) has been associated with cases of meningoencephalitis.
Chronic meningoencephalitis has been reported with serotypes 7, 12, and 32. The infection is
usually acquired through a respiratory route.
Astrovirus MLB2, usually a gastrointestinal virus, and Cache Valley virus in an immunosuppressed
individual are newly identified as causes of meningitis.
[8, 9]
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.
Chronic meningitis can be caused by a wide range of infectious and noninfectious etiologies (see
Table 3 below).
Category Agent
Mycobacterium tuberculosis
Borrelia burgdorferi
Treponema pallidum
Francisella tularensis
Nocardia spp
Actinomyces spp
Coccidioides immitis
Blastomyces dermatitidis
Histoplasma capsulatum
Candida albicans
Aspergillus spp
Sporothrix schenckii
Acanthamoeba spp
Naegleria fowleri
Angiostrongylus cantonensis
Gnathostoma spinigerum
Parasites
Baylisascarisprocyonis
Schistosoma spp
Strongyloides stercoralis
Echinococcus granulosus
Brucellae are small gram-negative coccobacilli that cause zoonoses as a result of infection
with Brucella abortus, Brucella melitensis, Brucella suis, or Brucella canis. Transmission to humans
occurs after direct or indirect exposure to infected animals (eg, sheep, goats, or cattle). Direct
infection of the CNS occurs in fewer than 5% of cases, with most patients presenting with acute or
chronic meningitis.
Persons at risk for brucellosis include individuals who had contact with infected animals or their
products (eg, through intake of unpasteurized milk products). Veterinarians, abattoir workers, and
laboratory workers dealing with these animals are also at risk.
M tuberculosis is an acid-fast bacillus that causes a broad range of clinical illnesses that can affect
virtually any organ of the body. It is spread through airborne droplet nuclei, and it infects one third
of the world’s population. Involvement of the CNS with tuberculous meningitis is usually caused by
rupture of a tubercle into the subarachnoid space
Treponema pallidum is a slender, tightly coiled spirochete that is usually acquired by sexual
contact. Other modes of transmission include direct contact with an active lesion, passage through
the placenta, and blood transfusion (rare).
Borrelia burgdorferi, a tick-borne spirochete, is the agent of Lyme disease, the most common
vector-borne disease in the United States. Meningitis may be part of a triad of neurologic
manifestations of Lyme disease that also includes cranial neuritis and radiculoneuritis. Lyme
disease meningitis is typically associated with a facial palsy that can sometimes be bilateral.
Coccidioides immitis is a soil-based, dimorphic fungus that exists in mycelial and yeast (spherule)
forms. Persons at risk for coccidioidal meningitis include individuals exposed to the endemic
regions (eg, tourists and local populations) and those with immune deficiency (eg, persons with
AIDS and organ transplant recipients).
Blastomyces dermatitidis is a dimorphic fungus that has been reported to be endemic in North
America (eg, in the Mississippi and Ohio River basins). It has also been isolated from parts of
Central America, South America, the Middle East, and India. Its natural habitat is not well defined.
Soil that is rich in decaying matter and environments around riverbanks and waterways have been
demonstrated to harbor B dermatitidis during outbreaks and are thought to be risk factors for
acquiring the infection.
Inhalation of the conidia establishes a pulmonary infection. Dissemination may occur in certain
individuals, including those with underlying immune deficiency (eg, from HIV or pharmaceutical
agents) and extremes of age, and may involve the skin, bones and joints, genitourinary tract, and
CNS. Involvement of the CNS occurs in fewer than 5% of cases.
Histoplasma capsulatum is one of the dimorphic fungi that exist in mycelial and yeast forms. It is
usually found in soil and can occasionally cause a chronic meningitis. The preferred means of
making the diagnosis is CSF histoplasma antigen detection.
Candida species are ubiquitous in nature. They are normal commensals in humans and are found
in the skin, the GI tract, and the female genital tract. The most common species is Candida
albicans, but the incidence of non-albicans candidal infections (eg, Candida tropicalis) is
increasing, including species with antifungal resistance (eg, Candida krusei and Candida glabrata).
Involvement of the CNS usually follows hematogenous dissemination. The most important
predisposing risks for acquiring disseminated candidal infection appear to be iatrogenic (eg, the
administration of broad-spectrum antibiotics and the use of indwelling devices such as urinary and
vascular catheters). Prematurity in neonates is considered a predisposing risk factor as well.
Infection may also follow neurosurgical procedures, such as placement of ventricular shunts.
Sporothrix schenckii is an endemic dimorphic fungus that is often isolated from soil, plants, and
plant products. Human infections are characteristically lymphocutaneous. Extracutaneous
manifestations of sporotrichosis may occur, though meningeal sporotrichosis, which is the most
severe form, is a rare complication. AIDS is a reported underlying risk factor in many described
cases and is associated with a poor outcome.
Infection with free-living amoebas is an infrequent but often life-threatening human illness, even in
immunocompetent individuals. N fowleri is the only species of Naegleria recognized to be
pathogenic in humans, and it is the agent of primary amebic meningoencephalitis (PAM). The
parasite has been isolated in lakes, pools, ponds, rivers, tap water, and soil.
Infection occurs when a person is swimming or playing in contaminated water sources (eg,
inadequately chlorinated water and sources associated with poor decontamination techniques).
The N fowleri amebas invade the CNS through the nasal mucosa and cribriform plate.
PAM occurs in two forms. The first is characterized by an acute onset of high fever, photophobia,
headache, and altered mental status, similar to bacterial meningitis, occurring within 1 week after
exposure. Because it is acquired via the nasal area, olfactory nerve involvement may manifest as
abnormal smell sensation. Death occurs in 3 days in patients who are not treated. The second
form, the subacute or chronic form, consists of an insidious onset of low-grade fever, headache,
and focal neurologic signs. Duration of illness is weeks to few months.
Angiostrongylus cantonensis, the rat lungworm, can cause eosinophilic meningitis (pleocytosis with
more than 10% eosinophils) in humans. The adult parasite resides in the lungs of rats. Its eggs
hatch, and the larval stages are expelled in the feces. The larvae develop in the intermediate host,
usually land snails, freshwater prawns, and crabs. Humans acquire the infection by ingesting raw
mollusks.
Gnathostoma spinigerum, a GI parasite of wild and domestic dogs and cats, may cause
eosinophilic meningoencephalitis. Humans acquire the infection after ingesting undercooked
infected fish and poultry.
Baylisascaris procyonis is an ascarid parasite that is prevalent in the raccoon populations in the
United States and rarely causes human eosinophilic meningoencephalitis. Human infections occur
after accidental ingestion of food products contaminated with raccoon feces.
Congenital malformation of the stapedial footplate has been implicated in the development of
meningitis. Head and neck surgery, penetrating head injury, comminuted skull fracture, and
osteomyelitic erosion may infrequently result in direct implantation of bacteria into the meninges.
Skull fractures can tear the dura and cause a CSF fistula, especially in the region of the frontal
ethmoid sinuses. Patients with any of these conditions are at risk for bacterial meningitis.
Epidemiology
Epidemiology of bacterial meningitis
The incidence of meningitis varies according to the specific etiologic agent, as well as in
conjunction with a nation’s medical resources. The incidence is presumed to be higher in
developing countries because of less access to preventive services, such as vaccination. In these
countries, the incidence has been reported to be 10 times higher than that in developed countries.
Meningitis affects people of all races. In the United States, black people have a higher reported
rate of meningitis than white people and Hispanic people
With almost 4100 cases and 500 deaths occurring annually in the United States, bacterial
meningitis continues to be a significant source of morbidity and mortality. The annual incidence in
the United States is 1.33 cases per 100,000 population
During a 1998-2007 survey, the incidence of meningitis declined by 31%,a decrease that can be
credited to vaccination programs. The rate of bacterial meningitis declined by 55% in early 1990s
when Hib conjugate vaccine for infants was introduced. The number of cases of invasive H
influenzae disease among children younger than 5 years that were reported to the CDC declined
from 20,000 in 1987 to 255 in 1998. This shift has reportedly been less dramatic in developing
countries, where the use of Hib vaccine is not as widespread.
[3]
Pneumococcal vaccine and universal screening of pregnant women for group B streptococcus
have further decreased the incidence of meningitis among young children but the burden of
bacterial meningitis is now borne by older adults.
Table 4. Changing Epidemiology of Acute Bacterial Meningitis in United States* (Open Table in a
new window)
1998-
Bacteria 1978-1981 1986 1995
2007
*Nosocomial meningitis is not included; these data include only the 5 major
meningeal pathogens.
In England and Wales the annual incidence of pneumococcal meningitis remained unchanged after
PCV7 introduction but declined by 48% after PCV13 replaced PCV7. The greatest decline in
pneumococcal meningitis incidence (70%) was observed among children < 5 years of age. By
2015–16, PCV13-serotype meningitis was rare, and nearly all cases were caused by non-PCV13
serotypes. PCV has reduced pneumococcal infections caused by vaccine strains, most of which
were resistant, by more than 90% in children. Since PCV introduction among US children in 2000,
the rates of antibiotic-resistant invasive pneumococcal infections caused by vaccine strains
decreased by 97% among children younger than 5 years and by more than 60% among adults.
[4]
Meningococcal disease occurs worldwide, with the highest incidence of disease found in the
meningitis belt of sub-Saharan Africa. Following a mass vaccination campaign with a monovalent
serogroup A meningococcal conjugate vaccine, epidemic due to serogroup A was eliminated but
now more epidemics are primarily due to serogroup C and W. In the United States, meningococcal
disease incidence has steadily declined since 1995 (1.20 cases/100,000 persons) to a historic low
of 0.11 cases/100,000 persons in 2017.
[10] The rates of disease are highest in children younger
than 1 year, with a second peak in adolescence. N meningitidis causes approximately four cases
per 100,000 children aged 1 to 23 months. Among adolescents and young adults, those aged 16
through 23 years have the highest rates of meningococcal disease. Historically, most
meningococcal disease outbreaks on university campuses in the United States were caused by
serogroup C. However, serogroup B has caused all known US university-based outbreaks since
2011, likely in part because of high Men ACWY coverage in adolescents.
[2, 1] The risk for
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 to 23 months.
Aseptic meningitis has a reported incidence of 10.9 cases per 100,000 person-years. It occurs in
individuals of all ages but is more common in children, especially during summer. No racial
differences are reported.
The incidence of viral meningitis has been estimated to range from 0.26 to 17 cases per 100,000
people. During 1988-1999, viral meningitis accounted for 50.2% of all meningitis-associated
hospitalization in the United States. In 2006, more than half (54.6 percent) of all meningitis-related
hospitalizations were attributed to a virus, whereas bacterial meningitis accounted for 21.8 percent
of all meningitis-related hospital stays. Most (71%) of viral meningitis hospitalizations occurred
from May to October. In a study from the United Kingdom, the incidence of viral meningitis from
September 2011 to 2014 was 2.73 per 100,000 and that of bacterial meningitis was 1.24 per
100,000.
In a study from Denmark, the incidence of viral meningitis hospitalization was highest after birth,
with a secondary peak at age 5 years. Khetsuriani et al reported average US annual hospitalization
rates of 213 per 100,000 infants, 14 per 100,000 children aged 1 to 4 years, and 14 per 100,000
youth aged 5 to 19 years.
[11, 12, 13, 14]
Arboviruses are an important cause of aseptic meningitis and encephalitis in the summer and fall
months in the United States. West Nile virus was introduced to the United States in 1999 and has
now spread throughout the continent. In 2012, the largest outbreak of West Nile virus infection to
date occurred in the United States, with 5387 cases reported (about half of which were
neuroinvasive disease, such as meningitis or encephalitis) and a 4.5% mortality.
[17] West Nile
virus can also cause acute flaccid paralysis, retinitis and nephropathy.
Other less common arboviruses include St Louis encephalitis virus, Jamestown canyon virus, La
Crosse encephalitis virus, Powassan encephalitis virus, and Eastern equine encephalitis virus. In
the United States, the last epidemic of St Louis encephalitis was in Monroe, Louisiana, in 2001; 63
cases were reported, with three deaths (4.7% mortality). Infection with the La Crosse encephalitis
virus also usually occurs during the summer and early fall, with symptoms again being typical of
acute aseptic meningitis.
[18]
Infections with the LCM virus occur worldwide. Most human cases occur among young adults
during autumn.
Of fungal causes, B dermatitidis is reportedly endemic in North America (eg, Mississippi and Ohio
River basins). It has also been isolated from parts of Central America, South America, the Middle
East, and India. H capsulatum has been reported from many areas of the world, with the
Mississippi and Ohio River valleys being the most endemic regions in North America.
Of parasitic causes, A cantonensis is common in Southeast Asia and the Pacific Islands. It has
also been found in rats outside this region, particularly in regions of Africa, Puerto Rico, and
Louisiana, presumably introduced by ship-borne rats from endemic areas. G spinigerum is
common in Southeast Asia, China, and Japan but has been reported sporadically worldwide.
M tuberculosis is worldwide in distribution, and humans are its only reservoir. In 1997, the
estimated case rates among endemic countries ranged from 62 to 411 cases per 100,000
population.
B burgdorferi is a tick-borne spirochete that is found in the temperate regions of much of the
northern hemisphere. Endemic regions include North America (eg, the northeastern United States,
Minnesota, Wisconsin, and parts of California and Oregon), Europe, and Asia.
The distribution of C immitis is limited to the endemic regions of the Western Hemisphere, within
the north and south 40° latitudes (ie, parts of the southwestern United States, Mexico, and Central
and South America). Persons who have migrated from or traveled to endemic areas may
experience onset of disease in other parts of the world.
S schenckii has been reported worldwide. However, most cases come from the tropical regions of
the Americas.
Prognosis
Patients with bacterial meningitis who present with an impaired level of consciousness,
hypotension, or seizures are at increased risk for neurologic sequelae or death.
[8]
In bacterial meningitis, several risk factors are associated with death and with neurologic disability.
A risk score has been derived and validated in adults with bacterial meningitis. This score includes
the following variables, which are associated with an adverse clinical outcome:"
Older age
Increased heart rate
Lower Glasgow Coma Scale score
Cranial nerve palsies
CSF leukocyte count lower than 1000/μL
Gram-positive cocci on CSF Gram stain
Even with effective antimicrobial therapy, significant neurologic complications occur in as many as
30% of survivors of bacterial meningitis. Close monitoring for the development of these
complications is essential.
Mortality for bacterial meningitis is highest in the first year of life, decreases in midlife, and
increases again in old age. Bacterial meningitis is fatal in one in 10 cases, and one of every seven
survivors is left with a severe handicap, such as deafness or brain injury.
Among bacterial pathogens, S pneumoniae causes the highest mortality (20-30% in adults, 10% in
children) and morbidity (15%) in meningitis. If severe neurologic impairment is evident at the time
of presentation (or if the onset of illness is extremely rapid), mortality is 50% to 90% and morbidity
is even higher, even with immediate medical treatment. Meningitis caused by L monocytogenes or
gram-negative bacilli also has a higher case-fatality rate than meningitis caused by other bacterial
agents.
Reported overall mortality for meningitis from specific bacterial organisms is as follows:
S pneumoniae - 19-26%
H influenzae - 3-6%
N meningitidis - 3-13%
L monocytogenes - 15-29%
Patients with meningococcal meningitis have a better prognosis than do those with pneumococcal
meningitis, with a mortality of 4% to 5%; however, patients with meningococcemia have a poor
prognosis, with a mortality of 20% to 30%.
Advanced bacterial meningitis can lead to brain damage, coma, and death. In 50% of patients,
several complications may develop in the days to weeks after infection. Long-term sequelae are
seen in as many as 30% of survivors and vary with etiologic agent, patient age, presenting
features, and hospital course. Patients usually have subtle CNS changes.
Hearing loss
Cortical blindness
Other cranial nerve dysfunction
Paralysis
Muscular hypertonia
Ataxia
Multiple seizures
Mental motor retardation
Focal paralysis
Ataxia
Subdural effusions
Hydrocephalus
Cerebral atrophy
Risk factors for hearing loss after pneumococcal meningitis are female sex, older age, severe
meningitis, and infection with certain pneumococcal serotypes (eg, 12F).
[19] Delayed
complications include the following:
Seizures are a common and important complication, occurring in approximately one fifth of
patients. The incidence is higher in patients younger than 1 year, reaching 40%. Approximately one
half of patients with this complication have repeated seizures. Patients may die as a result of
diffuse CNS ischemic injury or systemic complications.
The prognosis in patients with meningitis caused by opportunistic pathogens depends on the
underlying immune function of the host. Many patients who survive the disease require lifelong
suppressive therapy (eg, long-term fluconazole for suppression in patients with HIV-associated
cryptococcal meningitis).
The mortality for viral meningitis without encephalitis is less than 1%. In patients with deficient
humoral immunity (eg, agammaglobulinemia), enteroviral meningitis may have a fatal outcome.
Patients with viral meningitis usually have a good prognosis for recovery. The prognosis is worse
for patients at the extremes of age (ie, < 2 or >60 years) and those with significant comorbidities
and underlying immunodeficiency
Patient Education
Patients and parents of young children should be educated about the benefits of vaccination in
preventing meningitis. Vaccination against N meningitidis is recommended for all US college
students.
Close contacts of patients with known or suspected N meningitidis or Hib meningitis may require
education regarding the need for prophylaxis. All contacts should be instructed to come to the
emergency department immediately at the first sign of fever, sore throat, rash, or symptoms of
meningitis. Rifampin prophylaxis only eradicates the organism from the nasopharynx; it is
ineffective against invasive disease.
For patient education information, see the Brain and Nervous System Center and the Children’s
Health Center, as well as Meningitis in Adults, Meningitis in Children, Brain Infection, and Spinal
Tap.
Clinical Presentation