Medicine:Meningitis

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Short description: Inflammation of the membranes around the brain and spinal cord
Meningitis
Meninges-en.svg
Meninges of the central nervous system: dura mater, arachnoid mater, and pia mater.
SpecialtyInfectious disease, neurology
SymptomsFever, headache, neck stiffness[1]
ComplicationsDeafness, epilepsy, hydrocephalus, cognitive deficits[2][3]
CausesViral, bacterial, other[4]
Diagnostic methodLumbar puncture[1]
PreventionVaccination[2]
MedicationAntibiotics, antivirals, steroids[1][5][6]
Frequency7.7 million (2019)[7]
Deaths236,000 (2019)[7]

Meningitis is acute or chronic inflammation of the protective membranes covering the brain and spinal cord, collectively called the meninges.[8] The most common symptoms are fever, intense headache, vomiting and neck stiffness and occasionally photophobia.[1]

Other symptoms include confusion or altered consciousness, nausea, vomiting, and an inability to tolerate light or loud noises.[1] Young children often exhibit only nonspecific symptoms, such as irritability, drowsiness, or poor feeding.[1] A non-blanching rash (a rash that does not fade when a glass is rolled over it) may also be present.[9]

The inflammation may be caused by infection with viruses, bacteria, fungi or parasites.[10] Non-infectious causes include malignancy (cancer), subarachnoid hemorrhage, chronic inflammatory disease (sarcoidosis) and certain drugs.[4] Meningitis can be life-threatening because of the inflammation's proximity to the brain and spinal cord; therefore, the condition is classified as a medical emergency.[2][6] A lumbar puncture, in which a needle is inserted into the spinal canal to collect a sample of cerebrospinal fluid (CSF), can diagnose or exclude meningitis.[1][6]

Some forms of meningitis are preventable by immunization with the meningococcal, mumps, pneumococcal, and Hib vaccines.[2] Giving antibiotics to people with significant exposure to certain types of meningitis may also be useful.[1] The first treatment in acute meningitis consists of promptly giving antibiotics and sometimes antiviral drugs.[1][5] Corticosteroids can also be used to prevent complications from excessive inflammation.[3][6] Meningitis can lead to serious long-term consequences such as deafness, epilepsy, hydrocephalus, or cognitive deficits, especially if not treated quickly.[2][3]

In 2019, meningitis was diagnosed in about 7.7 million people worldwide,[7] of whom 236,000 died, down from 433,000 deaths in 1990.[7] With appropriate treatment, the risk of death in bacterial meningitis is less than 15%.[1] Outbreaks of bacterial meningitis occur between December and June each year in an area of sub-Saharan Africa known as the meningitis belt.[11] Smaller outbreaks may also occur in other areas of the world.[11] The word meningitis comes from the Greek μῆνιγξ meninx, "membrane", and the medical suffix -itis, "inflammation".[12][13]

Signs and symptoms

Clinical features

Neck stiffness, Texas meningitis epidemic of 1911–12

In adults, the most common symptom of meningitis is a severe headache, occurring in almost 90% of cases of bacterial meningitis, followed by neck stiffness (the inability to flex the neck forward passively due to increased neck muscle tone and stiffness).[14] The classic triad of diagnostic signs consists of neck stiffness, sudden high fever, and altered mental status; however, all three features are present in only 44–46% of bacterial meningitis cases.[14][15] If none of the three signs are present, acute meningitis is extremely unlikely.[15] Other signs commonly associated with meningitis include photophobia (intolerance to bright light) and phonophobia (intolerance to loud noises). Small children often do not exhibit the aforementioned symptoms, and may only be irritable and look unwell.[2] The fontanelle (the soft spot on the top of a baby's head) can bulge in infants aged up to 6 months. Other features that distinguish meningitis from less severe illnesses in young children are leg pain, cold extremities, and an abnormal skin color.[16][17]

Neck stiffness occurs in 70% of bacterial meningitis in adults.[15] Other signs include the presence of positive Kernig's sign or Brudziński sign. Kernig's sign is assessed with the person lying supine, with the hip and knee flexed to 90 degrees. In a person with a positive Kernig's sign, pain limits passive extension of the knee. A positive Brudzinski's sign occurs when flexion of the neck causes involuntary flexion of the knee and hip. Although Kernig's sign and Brudzinski's sign are both commonly used to screen for meningitis, the sensitivity of these tests is limited.[15][18] They do, however, have very good specificity for meningitis: the signs rarely occur in other diseases.[15] Another test, known as the "jolt accentuation maneuver" helps determine whether meningitis is present in those reporting fever and headache. A person is asked to rapidly rotate the head horizontally; if this does not make the headache worse, meningitis is unlikely.[15]

Other problems can produce symptoms similar to those above, but from non-meningitic causes. This is called meningism or pseudomeningitis.[19]

Meningitis caused by the bacterium Neisseria meningitidis (known as "meningococcal meningitis") can be differentiated from meningitis with other causes by a rapidly spreading petechial rash, which may precede other symptoms.[16] The rash consists of numerous small, irregular purple or red spots ("petechiae") on the trunk, lower extremities, mucous membranes, conjunctiva, and (occasionally) the palms of the hands or soles of the feet. The rash is typically non-blanching; the redness does not disappear when pressed with a finger or a glass tumbler. Although this rash is not necessarily present in meningococcal meningitis, it is relatively specific for the disease; it does, however, occasionally occur in meningitis due to other bacteria.[2] Other clues on the cause of meningitis may be the skin signs of hand, foot and mouth disease and genital herpes, both of which are associated with various forms of viral meningitis.[20]

Early complications

Charlotte Cleverley-Bisman developed severe meningococcal meningitis as a young child; in her case, the petechial rash progressed to gangrene and required amputation of all limbs. She survived the disease and became a poster child for a meningitis vaccination campaign in New Zealand.

Additional problems may occur in the early stage of the illness. These may require specific treatment, and sometimes indicate severe illness or worse prognosis. The infection may trigger sepsis, a systemic inflammatory response syndrome of falling blood pressure, fast heart rate, high or abnormally low temperature, and rapid breathing. Very low blood pressure may occur at an early stage, especially but not exclusively in meningococcal meningitis; this may lead to insufficient blood supply to other organs.[2] Disseminated intravascular coagulation, the excessive activation of blood clotting, may obstruct blood flow to organs and paradoxically increase the bleeding risk. Gangrene of limbs can occur in meningococcal disease.[2] Severe meningococcal and pneumococcal infections may result in hemorrhaging of the adrenal glands, leading to Waterhouse-Friderichsen syndrome, which is often fatal.[21]

The brain tissue may swell, pressure inside the skull may increase and the swollen brain may herniate through the skull base. This may be noticed by a decreasing level of consciousness, loss of the pupillary light reflex, and abnormal posturing.[3] The inflammation of the brain tissue may also obstruct the normal flow of CSF around the brain (hydrocephalus).[3] Seizures may occur for various reasons; in children, seizures are common in the early stages of meningitis (in 30% of cases) and do not necessarily indicate an underlying cause.[6] Seizures may result from increased pressure and from areas of inflammation in the brain tissue.[3] Focal seizures (seizures that involve one limb or part of the body), persistent seizures, late-onset seizures and those that are difficult to control with medication indicate a poorer long-term outcome.[2]

Inflammation of the meninges may lead to abnormalities of the cranial nerves, a group of nerves arising from the brain stem that supply the head and neck area and which control, among other functions, eye movement, facial muscles, and hearing.[2][15] Visual symptoms and hearing loss may persist after an episode of meningitis.[2] Inflammation of the brain (encephalitis) or its blood vessels (cerebral vasculitis), as well as the formation of blood clots in the veins (cerebral venous thrombosis), may all lead to weakness, loss of sensation, or abnormal movement or function of the part of the body supplied by the affected area of the brain.[2][3]

Causes

Meningitis is typically caused by an infection. Most infections are due to viruses, and others due to bacteria, fungi, and parasites.[10] Mostly the parasites are parasitic worms,[4] but can also rarely include parasitic amoebae.[22] Meningitis may also result from various non-infectious causes.[4] The term aseptic meningitis refers to cases of meningitis in which no bacterial infection can be demonstrated. This type of meningitis is usually caused by viruses, but it may be due to bacterial infection that has already been partially treated, when bacteria disappear from the meninges, or when pathogens infect a space adjacent to the meninges (such as sinusitis). Endocarditis (an infection of the heart valves which spreads small clusters of bacteria through the bloodstream) may cause aseptic meningitis. Aseptic meningitis may also result from infection with spirochetes, a group of bacteria that includes Treponema pallidum (the cause of syphilis) and Borrelia burgdorferi (known for causing Lyme disease), and may also result from cerebral malaria (malaria infecting the brain).[4]

Bacterial

Streptococcus pneumoniae—a causative bacterium of meningitis (illustration)

The types of bacteria that cause bacterial meningitis vary according to the infected individual's age group.

  • In premature babies and newborns up to three months old, common causes are group B streptococci (subtypes III which normally inhabit the vagina and are mainly a cause during the first week of life) and bacteria that normally inhabit the digestive tract such as Escherichia coli (carrying the K1 antigen). Listeria monocytogenes (serotype IVb) can be contracted when consuming improperly prepared food such as dairy products, produce and deli meats,[23][24] and may cause meningitis in the newborn.[25]
  • Older children are more commonly affected by Neisseria meningitidis (meningococcus) and Streptococcus pneumoniae (serotypes 6, 9, 14, 18 and 23) and those under five by Haemophilus influenzae type B (in countries that do not offer vaccination).[2][6]
  • In adults, Neisseria meningitidis and Streptococcus pneumoniae together cause 80% of bacterial meningitis cases. Risk of infection with Listeria monocytogenes is increased in people over 50 years old.[3][6] The introduction of pneumococcal vaccine has lowered rates of pneumococcal meningitis in both children and adults.[26]

A head injury potentially allows nasal cavity bacteria to enter the meningeal space. Similarly, devices in the brain and meninges, such as cerebral shunts, extraventricular drains or Ommaya reservoirs, carry an increased risk of meningitis. In these cases, people are more likely to be infected with Staphylococci, Pseudomonas, and other Gram-negative bacteria.[6] These pathogens are also associated with meningitis in people with an impaired immune system.[2] An infection in the head and neck area, such as otitis media or mastoiditis, can lead to meningitis in a small proportion of people.[6] Recipients of cochlear implants for hearing loss are more at risk for pneumococcal meningitis.[27] In rare cases, Enterococcus spp. can be responsible for meningitis, both community and hospital-acquired, usually as a secondary result of trauma or surgery, or due to intestinal diseases (e.g., strongyloidiasis).[28]

Tuberculous meningitis, which is meningitis caused by Mycobacterium tuberculosis, is more common in people from countries in which tuberculosis is endemic, but is also encountered in people with immune problems, such as AIDS.[29]

Recurrent bacterial meningitis may be caused by persisting anatomical defects, either congenital or acquired, or by disorders of the immune system.[30] Anatomical defects allow continuity between the external environment and the nervous system. The most common cause of recurrent meningitis is a skull fracture,[30] particularly fractures that affect the base of the skull or extend towards the sinuses and petrous pyramids.[30] Approximately 59% of recurrent meningitis cases are due to such anatomical abnormalities, 36% are due to immune deficiencies (such as complement deficiency, which predisposes especially to recurrent meningococcal meningitis), and 5% are due to ongoing infections in areas adjacent to the meninges.[30]

Viral

Viruses that cause meningitis include enteroviruses, herpes simplex virus (generally type 2, which produces most genital sores; less commonly type 1), varicella zoster virus (known for causing chickenpox and shingles), mumps virus, HIV, LCMV,[20] Arboviruses (acquired from a mosquito or other insect), and the influenza virus.[31] Mollaret's meningitis is a chronic recurrent form of herpes meningitis; it is thought to be caused by herpes simplex virus type 2.[32]

Fungal

There are a number of risk factors for fungal meningitis, including the use of immunosuppressants (such as after organ transplantation), HIV/AIDS,[33] and the loss of immunity associated with aging.[34] It is uncommon in those with a normal immune system[35] but has occurred with medication contamination.[36] Symptom onset is typically more gradual, with headaches and fever being present for at least a couple of weeks before diagnosis.[34] The most common fungal meningitis is cryptococcal meningitis due to Cryptococcus neoformans.[37] In Africa, cryptococcal meningitis is now the most common cause of meningitis in multiple studies,[38][39] and it accounts for 20–25% of AIDS-related deaths in Africa.[40] Other less common pathogenic fungi which can cause meningitis include: Coccidioides immitis, Histoplasma capsulatum, Blastomyces dermatitidis, and Candida species.[34]

Parasitic

A parasitic worm is often assumed to be the cause of eosinophilic meningitis when there is a predominance of eosinophils (a type of white blood cell) found in the cerebrospinal fluid. The most common parasites implicated are Angiostrongylus cantonensis, Gnathostoma spinigerum, Schistosoma, as well as the conditions cysticercosis, toxocariasis, baylisascariasis, paragonimiasis, and a number of rarer infections and noninfective conditions.[41]

Rarely, free-living parasitic amoebae can cause naegleriasis, also called amebic meningitis,[22] a type of meningoencephalitis where not only the meninges are affected but also the brain tissue.

Non-infectious

Meningitis may occur as the result of several non-infectious causes: spread of cancer to the meninges (malignant or neoplastic meningitis)[42] and certain drugs (mainly non-steroidal anti-inflammatory drugs, antibiotics and intravenous immunoglobulins).[43] It may also be caused by several inflammatory conditions, such as sarcoidosis (which is then called neurosarcoidosis), connective tissue disorders such as systemic lupus erythematosus, and certain forms of vasculitis (inflammatory conditions of the blood vessel wall), such as Behçet's disease.[4] Epidermoid cysts and dermoid cysts may cause meningitis by releasing irritant matter into the subarachnoid space.[4][30] Rarely, migraine may cause meningitis, but this diagnosis is usually only made when other causes have been eliminated.[4]

Mechanism

The meninges comprise three membranes that, together with the cerebrospinal fluid, enclose and protect the brain and spinal cord (the central nervous system). The pia mater is a delicate impermeable membrane that firmly adheres to the surface of the brain, following all the minor contours. The arachnoid mater (so named because of its spider-web-like appearance) is a loosely fitting sac on top of the pia mater. The subarachnoid space separates the arachnoid and pia mater membranes and is filled with cerebrospinal fluid. The outermost membrane, the dura mater, is a thick durable membrane, which is attached to both the arachnoid membrane and the skull.

In bacterial meningitis, bacteria reach the meninges by one of two main routes: through the bloodstream (hematogenous spread) or through direct contact between the meninges and either the nasal cavity or the skin. In most cases, meningitis follows invasion of the bloodstream by organisms that live on mucosal surfaces such as the nasal cavity. This is often in turn preceded by viral infections, which break down the normal barrier provided by the mucosal surfaces. Once bacteria have entered the bloodstream, they enter the subarachnoid space in places where the blood–brain barrier is vulnerable – such as the choroid plexus. Meningitis occurs in 25% of newborns with bloodstream infections due to group B streptococci; this phenomenon is much less common in adults.[2] Direct contamination of the cerebrospinal fluid may arise from indwelling devices, skull fractures, or infections of the nasopharynx or the nasal sinuses that have formed a tract with the subarachnoid space (see above); occasionally, congenital defects of the dura mater can be identified.[2]

The large-scale inflammation that occurs in the subarachnoid space during meningitis is not a direct result of bacterial infection but can rather largely be attributed to the response of the immune system to the entry of bacteria into the central nervous system. When components of the bacterial cell membrane are identified by the immune cells of the brain (astrocytes and microglia), they respond by releasing large amounts of cytokines, hormone-like mediators that recruit other immune cells and stimulate other tissues to participate in an immune response. The blood–brain barrier becomes more permeable, leading to "vasogenic" cerebral edema (swelling of the brain due to fluid leakage from blood vessels). Large numbers of white blood cells enter the CSF, causing inflammation of the meninges and leading to "interstitial" edema (swelling due to fluid between the cells). In addition, the walls of the blood vessels themselves become inflamed (cerebral vasculitis), which leads to decreased blood flow and a third type of edema, "cytotoxic" edema. The three forms of cerebral edema all lead to increased intracranial pressure; together with the lowered blood pressure often encountered in sepsis, this means that it is harder for blood to enter the brain; consequently brain cells are deprived of oxygen and undergo apoptosis (programmed cell death).[2]

Administration of antibiotics may initially worsen the process outlined above, by increasing the amount of bacterial cell membrane products released through the destruction of bacteria. Particular treatments, such as the use of corticosteroids, are aimed at dampening the immune system's response to this phenomenon.[2][3]

Diagnosis

CSF findings in different forms of meningitis[44]
Type of meningitis   Glucose   Protein Cells
Acute bacterial low high PMNs,
often > 300/mm3
Acute viral normal normal or high mononuclear,
< 300/mm3
Tuberculous low high mononuclear and
PMNs, < 300/mm3
Fungal low high < 300/mm3
Malignant low high usually
mononuclear

Diagnosing meningitis as promptly as possible can improve outcomes.[45] There are no specific signs or symptoms that can indicate meningitis, and a lumbar puncture (spinal tap) to examine the cerebrospinal fluid is recommended for diagnosis.[45] Lumbar puncture is contraindicated if there is a mass in the brain (tumor or abscess) or the intracranial pressure (ICP) is elevated, as it may lead to brain herniation. If someone is at risk for either a mass or raised ICP (recent head injury, a known immune system problem, localizing neurological signs, or evidence on examination of a raised ICP), a CT or MRI scan is recommended prior to the lumbar puncture.[6][46][47] This applies in 45% of all adult cases.[3]

There are no physical tests that can rule out or determine if a person has meningitis.[48] The jolt accentuation test is not specific or sensitive enough to completely rule out meningitis.[48]

If someone is suspected of having meningitis, blood tests are performed for markers of inflammation (e.g. C-reactive protein, complete blood count), as well as blood cultures.[6][46] If a CT or MRI is required before LP, or if LP proves difficult, professional guidelines suggest that antibiotics should be administered first to prevent delay in treatment,[6] especially if this may be longer than 30 minutes.[46][47] Often, CT or MRI scans are performed at a later stage to assess for complications of meningitis.[2]

In severe forms of meningitis, monitoring of blood electrolytes may be important; for example, hyponatremia is common in bacterial meningitis.[49] The cause of hyponatremia, however, is controversial and may include dehydration, the inappropriate secretion of the antidiuretic hormone (SIADH), or overly aggressive intravenous fluid administration.[3][49]

Lumbar puncture

Cloudy CSF from a person with meningitis due to Streptococcus
Gram stain of meningococci from a culture showing Gram negative (pink) bacteria, often in pairs

A lumbar puncture is done by positioning the person, usually lying on the side, applying local anesthetic, and inserting a needle into the dural sac (a sac around the spinal cord) to collect cerebrospinal fluid (CSF). When this has been achieved, the "opening pressure" of the CSF is measured using a manometer. The pressure is normally between 6 and 18 cm water (cmH2O);[50] in bacterial meningitis the pressure is usually elevated.[6][46] In cryptococcal meningitis, intracranial pressure is markedly elevated.[51] The initial appearance of the fluid may prove an indication of the nature of the infection: cloudy CSF indicates higher levels of protein, white and red blood cells and/or bacteria, and therefore may suggest bacterial meningitis.[6]

The CSF sample is examined for presence and types of white blood cells, red blood cells, protein content and glucose level.[6] Gram staining of the sample may demonstrate bacteria in bacterial meningitis, but absence of bacteria does not exclude bacterial meningitis as they are only seen in 60% of cases; this figure is reduced by a further 20% if antibiotics were administered before the sample was taken. Gram staining is also less reliable in particular infections such as listeriosis. Microbiological culture of the sample is more sensitive (it identifies the organism in 70–85% of cases) but results can take up to 48 hours to become available.[6] The type of white blood cell predominantly present (see table) indicates whether meningitis is bacterial (usually neutrophil-predominant) or viral (usually lymphocyte-predominant),[6] although at the beginning of the disease this is not always a reliable indicator. Less commonly, eosinophils predominate, suggesting parasitic or fungal etiology, among others.[41]

The concentration of glucose in CSF is normally above 40% of that in blood. In bacterial meningitis it is typically lower; the CSF glucose level is therefore divided by the blood glucose (CSF glucose to serum glucose ratio). A ratio ≤0.4 is indicative of bacterial meningitis;[50] in the newborn, glucose levels in CSF are normally higher, and a ratio below 0.6 (60%) is therefore considered abnormal.[6] High levels of lactate in CSF indicate a higher likelihood of bacterial meningitis, as does a higher white blood cell count.[50] If lactate levels are less than 35 mg/dl and the person has not previously received antibiotics then this may rule out bacterial meningitis.[52]

Various other specialized tests may be used to distinguish between different types of meningitis. A latex agglutination test may be positive in meningitis caused by Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae, Escherichia coli and group B streptococci; its routine use is not encouraged as it rarely leads to changes in treatment, but it may be used if other tests are not diagnostic. Similarly, the limulus lysate test may be positive in meningitis caused by Gram-negative bacteria, but it is of limited use unless other tests have been unhelpful.[6] Polymerase chain reaction (PCR) is a technique used to amplify small traces of bacterial DNA in order to detect the presence of bacterial or viral DNA in cerebrospinal fluid; it is a highly sensitive and specific test since only trace amounts of the infecting agent's DNA is required. It may identify bacteria in bacterial meningitis and may assist in distinguishing the various causes of viral meningitis (enterovirus, herpes simplex virus 2 and mumps in those not vaccinated for this).[20] Serology (identification of antibodies to viruses) may be useful in viral meningitis.[20] If tuberculous meningitis is suspected, the sample is processed for Ziehl–Neelsen stain, which has a low sensitivity, and tuberculosis culture, which takes a long time to process; PCR is being used increasingly.[29] Diagnosis of cryptococcal meningitis can be made at low cost using an India ink stain of the CSF; however, testing for cryptococcal antigen in blood or CSF is more sensitive.[53][54]

A diagnostic and therapeutic difficulty is "partially treated meningitis", where there are meningitis symptoms after receiving antibiotics (such as for presumptive sinusitis). When this happens, CSF findings may resemble those of viral meningitis, but antibiotic treatment may need to be continued until there is definitive positive evidence of a viral cause (e.g. a positive enterovirus PCR).[20]

Postmortem

Histopathology of bacterial meningitis: autopsy case of a person with pneumococcal meningitis showing inflammatory infiltrates of the pia mater consisting of neutrophil granulocytes (inset, higher magnification).

Meningitis can be diagnosed after death has occurred. The findings from a post mortem are usually a widespread inflammation of the pia mater and arachnoid layers of the meninges. Neutrophil granulocytes tend to have migrated to the cerebrospinal fluid and the base of the brain, along with cranial nerves and the spinal cord, may be surrounded with pus – as may the meningeal vessels.[55]

Prevention

For some causes of meningitis, protection can be provided in the long term through vaccination, or in the short term with antibiotics. Some behavioral measures may also be effective.

Behavioral

Bacterial and viral meningitis are contagious, but neither is as contagious as the common cold or flu.[56] Both can be transmitted through droplets of respiratory secretions during close contact such as kissing, sneezing or coughing on someone,[56] but bacterial meningitis cannot be spread by only breathing the air where a person with meningitis has been. Viral meningitis is typically caused by enteroviruses, and is most commonly spread through fecal contamination.[56] The risk of infection can be decreased by changing the behavior that led to transmission.

Vaccination

Since the 1980s, many countries have included immunization against Haemophilus influenzae type B in their routine childhood vaccination schemes. This has practically eliminated this pathogen as a cause of meningitis in young children in those countries. In the countries in which the disease burden is highest, however, the vaccine is still too expensive.[57][58] Similarly, immunization against mumps has led to a sharp fall in the number of cases of mumps meningitis, which prior to vaccination occurred in 15% of all cases of mumps.[20]

Meningococcus vaccines exist against groups A, B, C, W135 and Y.[59][60][61] In countries where the vaccine for meningococcus group C was introduced, cases caused by this pathogen have decreased substantially.[57] A quadrivalent vaccine now exists, which combines four vaccines with the exception of B; immunization with this ACW135Y vaccine is now a visa requirement for taking part in Hajj.[62] Development of a vaccine against group B meningococci has proved much more difficult, as its surface proteins (which would normally be used to make a vaccine) only elicit a weak response from the immune system, or cross-react with normal human proteins.[57][59] Still, some countries (New Zealand, Cuba, Norway and Chile ) have developed vaccines against local strains of group B meningococci; some have shown good results and are used in local immunization schedules.[59] Two new vaccines, both approved in 2014, are effective against a wider range of group B meningococci strains.[60][61] In Africa, until recently, the approach for prevention and control of meningococcal epidemics was based on early detection of the disease and emergency reactive mass vaccination of the at-risk population with bivalent A/C or trivalent A/C/W135 polysaccharide vaccines,[63] though the introduction of MenAfriVac (meningococcus group A vaccine) has demonstrated effectiveness in young people and has been described as a model for product development partnerships in resource-limited settings.[64][65]

Routine vaccination against Streptococcus pneumoniae with the pneumococcal conjugate vaccine (PCV), which is active against seven common serotypes of this pathogen, significantly reduces the incidence of pneumococcal meningitis.[57][66] The pneumococcal polysaccharide vaccine, which covers 23 strains, is only administered to certain groups (e.g. those who have had a splenectomy, the surgical removal of the spleen); it does not elicit a significant immune response in all recipients, e.g. small children.[66] Childhood vaccination with Bacillus Calmette-Guérin has been reported to significantly reduce the rate of tuberculous meningitis, but its waning effectiveness in adulthood has prompted a search for a better vaccine.[57]

Antibiotics

Short-term antibiotic prophylaxis is another method of prevention, particularly of meningococcal meningitis. In cases of meningococcal meningitis, preventative treatment in close contacts with antibiotics (e.g. rifampicin, ciprofloxacin or ceftriaxone) can reduce their risk of contracting the condition, but does not protect against future infections.[46][67] Resistance to rifampicin has been noted to increase after use, which has caused some to recommend considering other agents.[67] While antibiotics are frequently used in an attempt to prevent meningitis in those with a basilar skull fracture there is not enough evidence to determine whether this is beneficial or harmful.[68] This applies to those with or without a CSF leak.[68]

Management

Meningitis is potentially life-threatening and has a high mortality rate if untreated;[6] delay in treatment has been associated with a poorer outcome.[3] Thus, treatment with wide-spectrum antibiotics should not be delayed while confirmatory tests are being conducted.[47] If meningococcal disease is suspected in primary care, guidelines recommend that benzylpenicillin be administered before transfer to hospital.[16] Intravenous fluids should be administered if hypotension (low blood pressure) or shock are present.[47] It is not clear whether intravenous fluid should be given routinely or whether this should be restricted.[69] Given that meningitis can cause a number of early severe complications, regular medical review is recommended to identify these complications early[47] and to admit the person to an intensive care unit if deemed necessary.[3]

Mechanical ventilation may be needed if the level of consciousness is very low, or if there is evidence of respiratory failure. If there are signs of raised intracranial pressure, measures to monitor the pressure may be taken; this would allow the optimization of the cerebral perfusion pressure and various treatments to decrease the intracranial pressure with medication (e.g. mannitol).[3] Seizures are treated with anticonvulsants.[3] Hydrocephalus (obstructed flow of CSF) may require insertion of a temporary or long-term drainage device, such as a cerebral shunt.[3] The osmotic therapy, glycerol, has an unclear effect on mortality but may decrease hearing problems.[70]

Bacterial meningitis

Antibiotics

Structural formula of ceftriaxone, one of the third-generation cefalosporin antibiotics recommended for the initial treatment of bacterial meningitis.

Empiric antibiotics (treatment without exact diagnosis) should be started immediately, even before the results of the lumbar puncture and CSF analysis are known. The choice of initial treatment depends largely on the kind of bacteria that cause meningitis in a particular place and population. For instance, in the United Kingdom, empirical treatment consists of a third-generation cefalosporin such as cefotaxime or ceftriaxone.[46][47] In the US, where resistance to cefalosporins is increasingly found in streptococci, addition of vancomycin to the initial treatment is recommended.[3][6][46] Chloramphenicol, either alone or in combination with ampicillin, however, appears to work equally well.[71]

Empirical therapy may be chosen on the basis of the person's age, whether the infection was preceded by a head injury, whether the person has undergone recent neurosurgery and whether or not a cerebral shunt is present.[6] In young children and those over 50 years of age, as well as those who are immunocompromised, the addition of ampicillin is recommended to cover Listeria monocytogenes.[6][46] Once the Gram stain results become available, and the broad type of bacterial cause is known, it may be possible to change the antibiotics to those likely to deal with the presumed group of pathogens.[6] The results of the CSF culture generally take longer to become available (24–48 hours). Once they do, empiric therapy may be switched to specific antibiotic therapy targeted to the specific causative organism and its sensitivities to antibiotics.[6] For an antibiotic to be effective in meningitis it must not only be active against the pathogenic bacterium but also reach the meninges in adequate quantities; some antibiotics have inadequate penetrance and therefore have little use in meningitis. Most of the antibiotics used in meningitis have not been tested directly on people with meningitis in clinical trials. Rather, the relevant knowledge has mostly derived from laboratory studies in rabbits.[6] Tuberculous meningitis requires prolonged treatment with antibiotics. While tuberculosis of the lungs is typically treated for six months, those with tuberculous meningitis are typically treated for a year or longer.[29]

Fluid Therapy

Fluid given intravenously are an essential part of treatment of bacterial meningitis. There is no difference in terms of mortality or acute severe neurological complications in children given a maintenance regimen over restricted-fluid regimen, but evidence is in favor of the maintenance regimen in terms of emergence of chronic severe neurological complications.[72]

Steroids

Additional treatment with corticosteroids (usually dexamethasone) has shown some benefits, such as a reduction of hearing loss, and better short term neurological outcomes[73] in adolescents and adults from high-income countries with low rates of HIV.[74] Some research has found reduced rates of death[74] while other research has not.[73] They also appear to be beneficial in those with tuberculosis meningitis, at least in those who are HIV negative.[75]

Professional guidelines therefore recommend the commencement of dexamethasone or a similar corticosteroid just before the first dose of antibiotics is given, and continued for four days.[46][47] Given that most of the benefit of the treatment is confined to those with pneumococcal meningitis, some guidelines suggest that dexamethasone be discontinued if another cause for meningitis is identified.[6][46] The likely mechanism is suppression of overactive inflammation.[76]

Additional treatment with corticosteroids have a different role in children than in adults. Though the benefit of corticosteroids has been demonstrated in adults as well as in children from high-income countries, their use in children from low-income countries is not supported by the evidence; the reason for this discrepancy is not clear.[73] Even in high-income countries, the benefit of corticosteroids is only seen when they are given prior to the first dose of antibiotics, and is greatest in cases of H. influenzae meningitis,[6][77] the incidence of which has decreased dramatically since the introduction of the Hib vaccine. Thus, corticosteroids are recommended in the treatment of pediatric meningitis if the cause is H. influenzae, and only if given prior to the first dose of antibiotics; other uses are controversial.[6]

Adjuvant therapies

In addition to the primary therapy of antibiotics and corticosteroids, other adjuvant therapies are under development or are sometimes used to try and improve survival from bacterial meningitis and reduce the risk of neurological problems. Examples of adjuvant therapies that have been trialed include acetaminophen, immunoglobulin therapy, heparin, pentoxifyline, and a mononucleotide mixture with succinic acid.[78] It is not clear if any of these therapies are helpful or worsen outcomes in people with acute bacterial meningitis.[78]

Viral meningitis

Viral meningitis typically only requires supportive therapy; most viruses responsible for causing meningitis are not amenable to specific treatment. Viral meningitis tends to run a more benign course than bacterial meningitis. Herpes simplex virus and varicella zoster virus may respond to treatment with antiviral drugs such as aciclovir, but there are no clinical trials that have specifically addressed whether this treatment is effective.[20] Mild cases of viral meningitis can be treated at home with conservative measures such as fluid, bedrest, and analgesics.[79]

Fungal meningitis

Fungal meningitis, such as cryptococcal meningitis, is treated with long courses of high dose antifungals, such as amphotericin B and flucytosine.[53][80] Raised intracranial pressure is common in fungal meningitis, and frequent (ideally daily) lumbar punctures to relieve the pressure are recommended,[53] or alternatively a lumbar drain.[51]

Prognosis

Disability-adjusted life year for meningitis per 100,000 inhabitants in 2004.[81]
  •   no data
  •   <10
  •   10–25
  •   25–50
  •   50–75
  •   75–100
  •   100–200
  •   200–300
  •   300–400
  •   400–500
  •   500–750
  •   750–1000
  •   >1000

Untreated, bacterial meningitis is almost always fatal. According to the WHO bacterial meningitis has an overall mortality rate of 16.7% (with treatment).[10] Viral meningitis, in contrast, tends to resolve spontaneously and is rarely fatal. With treatment, mortality (risk of death) from bacterial meningitis depends on the age of the person and the underlying cause. Of newborns, 20–30% may die from an episode of bacterial meningitis. This risk is much lower in older children, whose mortality is about 2%, but rises again to about 19–37% in adults.[2][3]

Risk of death is predicted by various factors apart from age, such as the pathogen and the time it takes for the pathogen to be cleared from the cerebrospinal fluid,[2] the severity of the generalized illness, a decreased level of consciousness or an abnormally low count of white blood cells in the CSF.[3] Meningitis caused by H. influenzae and meningococci has a better prognosis than cases caused by group B streptococci, coliforms and S. pneumoniae.[2] In adults, too, meningococcal meningitis has a lower mortality (3–7%) than pneumococcal disease.[3]

In children there are several potential disabilities which may result from damage to the nervous system, including sensorineural hearing loss, epilepsy, learning and behavioral difficulties, as well as decreased intelligence.[2] These occur in about 15% of survivors.[2] Some of the hearing loss may be reversible.[82] In adults, 66% of all cases emerge without disability. The main problems are deafness (in 14%) and cognitive impairment (in 10%).[3]

Tuberculous meningitis in children continues to be associated with a significant risk of death even with treatment (19%), and a significant proportion of the surviving children have ongoing neurological problems. Just over a third of all cases survives with no problems.[83]

Epidemiology

Demography of meningococcal meningitis.
  meningitis belt
  epidemic zones
  sporadic cases only
Deaths from meningitis per million people in 2012
  •   0–2
  •   3-3
  •   4–6
  •   7–9
  •   10–20
  •   21–31
  •   32–61
  •   62–153
  •   154–308
  •   309–734

Although meningitis is a notifiable disease in many countries, the exact incidence rate is unknown.[20] In 2013 meningitis resulted in 303,000 deaths – down from 464,000 deaths in 1990.[84] In 2010 it was estimated that meningitis resulted in 420,000 deaths,[85] excluding cryptococcal meningitis.[40]

Bacterial meningitis occurs in about 3 people per 100,000 annually in Western countries. Population-wide studies have shown that viral meningitis is more common, at 10.9 per 100,000, and occurs more often in the summer. In Brazil, the rate of bacterial meningitis is higher, at 45.8 per 100,000 annually.[15] Sub-Saharan Africa has been plagued by large epidemics of meningococcal meningitis for over a century,[86] leading to it being labeled the "meningitis belt". Epidemics typically occur in the dry season (December to June), and an epidemic wave can last two to three years, dying out during the intervening rainy seasons.[87] Attack rates of 100–800 cases per 100,000 are encountered in this area,[88] which is poorly served by medical care. These cases are predominantly caused by meningococci.[15] The largest epidemic ever recorded in history swept across the entire region in 1996–1997, causing over 250,000 cases and 25,000 deaths.[89]

Meningococcal disease occurs in epidemics in areas where many people live together for the first time, such as army barracks during mobilization, university and college campuses[2] and the annual Hajj pilgrimage.[62] Although the pattern of epidemic cycles in Africa is not well understood, several factors have been associated with the development of epidemics in the meningitis belt. They include: medical conditions (immunological susceptibility of the population), demographic conditions (travel and large population displacements), socioeconomic conditions (overcrowding and poor living conditions), climatic conditions (drought and dust storms), and concurrent infections (acute respiratory infections).[88]

There are significant differences in the local distribution of causes for bacterial meningitis. For instance, while N. meningitides groups B and C cause most disease episodes in Europe, group A is found in Asia and continues to predominate in Africa, where it causes most of the major epidemics in the meningitis belt, accounting for about 80% to 85% of documented meningococcal meningitis cases.[88]

History

Some suggest that Hippocrates may have realized the existence of meningitis,[15] and it seems that meningism was known to pre-Renaissance physicians such as Avicenna.[90] The description of tuberculous meningitis, then called "dropsy in the brain", is often attributed to Edinburgh physician Sir Robert Whytt in a posthumous report that appeared in 1768, although the link with tuberculosis and its pathogen was not made until the next century.[90][91]

It appears that epidemic meningitis is a relatively recent phenomenon.[92] The first recorded major outbreak occurred in Geneva in 1805.[92][93] Several other epidemics in Europe and the United States were described shortly afterward, and the first report of an epidemic in Africa appeared in 1840. African epidemics became much more common in the 20th century, starting with a major epidemic sweeping Nigeria and Ghana in 1905–1908.[92]

The first report of bacterial infection underlying meningitis was by the Austrian bacteriologist Anton Weichselbaum, who in 1887 described the meningococcus.[94] Mortality from meningitis was very high (over 90%) in early reports. In 1906, antiserum was produced in horses; this was developed further by the American scientist Simon Flexner and markedly decreased mortality from meningococcal disease.[95][96] In 1944, penicillin was first reported to be effective in meningitis.[97] The introduction in the late 20th century of Haemophilus vaccines led to a marked fall in cases of meningitis associated with this pathogen,[58] and in 2002, evidence emerged that treatment with steroids could improve the prognosis of bacterial meningitis.[73][76]<ref name=Swartz

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 "Bacterial Meningitis". U.S. Centers for Disease Control and Prevention (CDC). 1 April 2014. https://www.cdc.gov/meningitis/bacterial.html. 
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 2.16 2.17 2.18 2.19 2.20 2.21 2.22 2.23 2.24 2.25 "Bacterial meningitis in children". Lancet 361 (9375): 2139–48. June 2003. doi:10.1016/S0140-6736(03)13693-8. PMID 12826449. 
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 3.14 3.15 3.16 3.17 3.18 3.19 3.20 "Community-acquired bacterial meningitis in adults". The New England Journal of Medicine 354 (1): 44–53. January 2006. doi:10.1056/NEJMra052116. PMID 16394301. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 "Difficult and recurrent meningitis". Journal of Neurology, Neurosurgery, and Psychiatry 75 Suppl 1 (90001): i16–21. March 2004. doi:10.1136/jnnp.2003.034272. PMID 14978146. 
  5. ↑ 5.0 5.1 "Viral Meningitis". U.S. Centers for Disease Control and Prevention (CDC). 26 November 2014. https://www.cdc.gov/meningitis/viral.html. 
  6. ↑ 6.00 6.01 6.02 6.03 6.04 6.05 6.06 6.07 6.08 6.09 6.10 6.11 6.12 6.13 6.14 6.15 6.16 6.17 6.18 6.19 6.20 6.21 6.22 6.23 6.24 6.25 6.26 6.27 6.28 "Practice guidelines for the management of bacterial meningitis". Clinical Infectious Diseases 39 (9): 1267–84. November 2004. doi:10.1086/425368. PMID 15494903. 
  7. ↑ 7.0 7.1 7.2 7.3 "Global Disease Burden 2019". https://ghdx.healthdata.org/gbd-2019. 
  8. ↑ "Meningitis". Primary Care: Clinics in Office Practice 40 (3): 707–726. September 2013. doi:10.1016/j.pop.2013.06.001. PMID 23958365. 
  9. ↑ "NHS medical conditions meningitis". National Health Service (NHS). 20 October 2017. https://www.nhs.uk/conditions/meningitis/. 
  10. ↑ 10.0 10.1 10.2 "Meningitis". World Health Organization (WHO). https://www.who.int/news-room/fact-sheets/detail/meningitis. 
  11. ↑ 11.0 11.1 "Meningococcal meningitis Fact sheet N°141". World Health Organization (WHO). November 2015. https://www.who.int/mediacentre/factsheets/fs141/en/. 
  12. ↑ Mosby's pocket dictionary of medicine, nursing & health professions (6th ed.). St. Louis: Mosby/Elsevier. 2010. p. traumatic meningitis. ISBN 978-0-323-06604-4. https://books.google.com/books?id=_QGaoiFCIDMC&pg=PT4755. 
  13. ↑ "μῆνιγξ". A Greek-English Lexicon. Oxford: Clarendon Press. 1940. https://www.perseus.tufts.edu/hopper/text?doc=Perseus%3Atext%3A1999.04.0057%3Aentry%3Dmh%3Dnigc. 
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  15. ↑ 15.0 15.1 15.2 15.3 15.4 15.5 15.6 15.7 15.8 15.9 "The rational clinical examination. Does this adult patient have acute meningitis?". JAMA 282 (2): 175–81. July 1999. doi:10.1001/jama.282.2.175. PMID 10411200. 
  16. ↑ 16.0 16.1 16.2 "Management of invasive meningococcal disease in children and young people: summary of SIGN guidelines". BMJ 336 (7657): 1367–70. June 2008. doi:10.1136/bmj.a129. PMID 18556318. 
  17. ↑ Management of invasive meningococcal disease in children and young people. Edinburgh: Scottish Intercollegiate Guidelines Network (SIGN). May 2008. ISBN 978-1-905813-31-5. http://www.sign.ac.uk/pdf/sign102.pdf. 
  18. ↑ "The diagnostic accuracy of Kernig's sign, Brudzinski's sign, and nuchal rigidity in adults with suspected meningitis". Clinical Infectious Diseases 35 (1): 46–52. July 2002. doi:10.1086/340979. PMID 12060874. 
  19. ↑ "Meningitis". World Health Organization (WHO). https://www.who.int/health-topics/meningitis. 
  20. ↑ 20.0 20.1 20.2 20.3 20.4 20.5 20.6 20.7 "Viral meningitis". BMJ 336 (7634): 36–40. January 2008. doi:10.1136/bmj.39409.673657.AE. PMID 18174598. 
  21. ↑ "Rupert Waterhouse and Carl Friderichsen: adrenal apoplexy". The Journal of Emergency Medicine 16 (4): 643–47. 1998. doi:10.1016/S0736-4679(98)00061-4. PMID 9696186. 
  22. ↑ 22.0 22.1 "Amebic Meningitis". U.S. Centers for Disease Control and Prevention (CDC). 12 August 2022. https://www.cdc.gov/meningitis/amebic.html. 
  23. ↑ "Bacterial Meningitis". U.S. Centers for Disease Control and Prevention (CDC). 6 August 2019. https://www.cdc.gov/meningitis/bacterial.html. 
  24. ↑ "Prevent Listeria". U.S. Centers for Disease Control and Prevention (CDC). 17 June 2019. https://www.cdc.gov/listeria/prevention.html. 
  25. ↑ "Listeria (Listeriosis)". U.S. Centers for Disease Control and Prevention (CDC). 22 October 2015. https://www.cdc.gov/listeria/index.html. 
  26. ↑ "Effect of pneumococcal conjugate vaccine on pneumococcal meningitis". The New England Journal of Medicine 360 (3): 244–56. January 2009. doi:10.1056/NEJMoa0800836. PMID 19144940. 
  27. ↑ "Can we prevent cochlear implant recipients from developing pneumococcal meningitis?". Clinical Infectious Diseases 46 (1): e1–7. January 2008. doi:10.1086/524083. PMID 18171202. 
  28. ↑ Zeana, C; Kubin, CJ; Della Latta, P; Hammer, SM (2001). "Vancomycin-resistant Enterococcus faecium meningitis successfully managed with linezolid: case report and review of the literature". Clin Infect Dis 33 (4): 477–482. doi:10.1086/321896. PMID 11462183. 
  29. ↑ 29.0 29.1 29.2 "Tuberculous meningitis". Journal of Neurology, Neurosurgery, and Psychiatry 68 (3): 289–99. March 2000. doi:10.1136/jnnp.68.3.289. PMID 10675209. 
  30. ↑ 30.0 30.1 30.2 30.3 30.4 "Epidemiology, etiology, pathogenesis, and diagnosis of recurrent bacterial meningitis". Clinical Microbiology Reviews 21 (3): 519–37. July 2008. doi:10.1128/CMR.00009-08. PMID 18625686. 
  31. ↑ "Meningitis | Viral". U.S. Centers for Disease Control and Prevention (CDC). 19 February 2019. https://www.cdc.gov/meningitis/viral.html. 
  32. ↑ "Recurrent benign lymphocytic meningitis". Clinical Infectious Diseases 43 (9): 1194–97. November 2006. doi:10.1086/508281. PMID 17029141. 
  33. ↑ "Fungal infections of the nervous system: current perspective and controversies in management". International Journal of Surgery 8 (8): 591–601. 2010. doi:10.1016/j.ijsu.2010.07.293. PMID 20673817. 
  34. ↑ 34.0 34.1 34.2 Clinical neurology of the older adult (2nd ed.). Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. 2008. p. 439. ISBN 978-0-7817-6947-1. https://books.google.com/books?id=c1tL8C9ryMQC&pg=PA439. 
  35. ↑ "Central nervous system infections: meningitis and brain abscess". Infectious Disease Clinics of North America 23 (3): 609–23. September 2009. doi:10.1016/j.idc.2009.04.009. PMID 19665086. 
  36. ↑ "Fungal infections associated with contaminated methylprednisolone injections". The New England Journal of Medicine 368 (26): 2495–500. June 2013. doi:10.1056/NEJMra1212617. PMID 23083312. 
  37. ↑ Essentials of clinical mycology (2nd ed.). New York: Springer. 1 January 2011. p. 77. ISBN 978-1-4419-6639-1. https://books.google.com/books?id=8IySvRT52KkC&pg=PA77. 
  38. ↑ "Cost-effective diagnostic checklists for meningitis in resource-limited settings". Journal of Acquired Immune Deficiency Syndromes 63 (3): e101–08. July 2013. doi:10.1097/QAI.0b013e31828e1e56. PMID 23466647. 
  39. ↑ Essentials of clinical mycology (2nd ed.). New York: Springer. 1 January 2011. p. 31. ISBN 978-1-4419-6639-1. https://books.google.com/books?id=8IySvRT52KkC&pg=PA31. 
  40. ↑ 40.0 40.1 "Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS". AIDS 23 (4): 525–30. February 2009. doi:10.1097/QAD.0b013e328322ffac. PMID 19182676. 
  41. ↑ 41.0 41.1 "Update on eosinophilic meningoencephalitis and its clinical relevance". Clinical Microbiology Reviews 22 (2): 322–348, Table of Contents. April 2009. doi:10.1128/CMR.00044-08. PMID 19366917. 
  42. ↑ "Neoplastic meningitis". The Lancet. Neurology 5 (5): 443–52. May 2006. doi:10.1016/S1474-4422(06)70443-4. PMID 16632315. 
  43. ↑ "The challenge of drug-induced aseptic meningitis". Archives of Internal Medicine 159 (11): 1185–94. June 1999. doi:10.1001/archinte.159.11.1185. PMID 10371226. 
  44. ↑ Provan, Drew; Krentz, Andrew (2005). Oxford Handbook of Clinical and Laboratory Investigation. Oxford: Oxford University Press. ISBN 978-0-19-856663-2. 
  45. ↑ 45.0 45.1 "Aseptic and Bacterial Meningitis: Evaluation, Treatment, and Prevention". American Family Physician 96 (5): 314–322. September 2017. ISSN 0002-838X. PMID 28925647. https://www.aafp.org/afp/2017/0901/p314.html. Retrieved 18 October 2020. 
  46. ↑ 46.0 46.1 46.2 46.3 46.4 46.5 46.6 46.7 46.8 46.9 "EFNS guideline on the management of community-acquired bacterial meningitis: report of an EFNS Task Force on acute bacterial meningitis in older children and adults". European Journal of Neurology 15 (7): 649–59. July 2008. doi:10.1111/j.1468-1331.2008.02193.x. PMID 18582342. 
  47. ↑ 47.0 47.1 47.2 47.3 47.4 47.5 47.6 "Early management of suspected bacterial meningitis and meningococcal septicaemia in adults". The Journal of Infection 46 (2): 75–77. February 2003. doi:10.1053/jinf.2002.1110. PMID 12634067. http://www.britishinfection.org/drupal/sites/default/files/meningitisJI2003.pdf.  – formal guideline at "Early management of suspected meningitis and meningococcal septicaemia in immunocompetent adults". British Infection Society. December 2004. http://www.meningitis.org/assets/x/51738. 
  48. ↑ 48.0 48.1 "Diagnostic test accuracy of jolt accentuation for headache in acute meningitis in the emergency setting". The Cochrane Database of Systematic Reviews 2020 (6): CD012824. June 2020. doi:10.1002/14651858.CD012824.pub2. ISSN 1469-493X. PMID 32524581. 
  49. ↑ 49.0 49.1 "Fluid therapy for acute bacterial meningitis". The Cochrane Database of Systematic Reviews 2016 (11): CD004786. November 2016. doi:10.1002/14651858.CD004786.pub5. PMID 27813057. PMC 6464853. http://archive.lstmed.ac.uk/8112/1/Cochrane_Fluid%20therapy%20for%20acute%20bacterial%20meningitis.pdf. Retrieved 30 December 2018. "Careful management of fluid and electrolyte balance is also important in the treatment of meningitis... there are different opinions regarding the cause of hyponatraemia... if dehydration, rather than inappropriately increased antidiuresis... fluid restriction is open to question". 
  50. ↑ 50.0 50.1 50.2 "How do I perform a lumbar puncture and analyze the results to diagnose bacterial meningitis?". JAMA 296 (16): 2012–22. October 2006. doi:10.1001/jama.296.16.2012. PMID 17062865. 
  51. ↑ 51.0 51.1 "Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america". Clinical Infectious Diseases 50 (3): 291–322. February 2010. doi:10.1086/649858. PMID 20047480. PMC 5826644. http://cid.oxfordjournals.org/content/50/3/291.long. 
  52. ↑ "Diagnostic accuracy of cerebrospinal fluid lactate for differentiating bacterial meningitis from aseptic meningitis: a meta-analysis". The Journal of Infection 62 (4): 255–62. April 2011. doi:10.1016/j.jinf.2011.02.010. PMID 21382412. 
  53. ↑ 53.0 53.1 53.2 "Cryptococcal meningitis". British Medical Bulletin 72 (1): 99–118. 2004. doi:10.1093/bmb/ldh043. PMID 15838017. 
  54. ↑ "Treatment for HIV-associated cryptococcal meningitis". The Cochrane Database of Systematic Reviews 2018 (7): CD005647. July 2018. doi:10.1002/14651858.CD005647.pub3. CD005647. PMID 30045416. 
  55. ↑ "24.14.1 Bacterial meningitis". Oxford Textbook of Medicine Volume 3 (Fourth ed.). Oxford University Press. 2003. pp. 1115–29. ISBN 978-0-19-852787-9. 
  56. ↑ 56.0 56.1 56.2 "Causes and How It Spreads". U.S. Centers for Disease Control and Prevention (CDC). 7 February 2022. https://www.cdc.gov/meningococcal/about/causes-transmission.html. 
  57. ↑ 57.0 57.1 57.2 57.3 57.4 "Vaccines against bacterial meningitis". British Medical Bulletin 72 (1): 65–81. 2004. doi:10.1093/bmb/ldh041. PMID 15802609. 
  58. ↑ 58.0 58.1 "Worldwide Haemophilus influenzae type b disease at the beginning of the 21st century: global analysis of the disease burden 25 years after the use of the polysaccharide vaccine and a decade after the advent of conjugates". Clinical Microbiology Reviews 13 (2): 302–17. April 2000. doi:10.1128/CMR.13.2.302-317.2000. PMID 10756001. 
  59. ↑ 59.0 59.1 59.2 "Prospects for vaccine prevention of meningococcal infection". Clinical Microbiology Reviews 19 (1): 142–64. January 2006. doi:10.1128/CMR.19.1.142-164.2006. PMID 16418528. 
  60. ↑ 60.0 60.1 "A new MenB (meningococcal B) vaccine". Meningitis Research Foundation. http://www.meningitis.org/menb-vaccine. 
  61. ↑ 61.0 61.1 "First vaccine approved by FDA to prevent serogroup B Meningococcal disease" (Press release). U.S. Food and Drug Administration (FDA). 29 October 2014. Archived from the original on 16 November 2014.
  62. ↑ 62.0 62.1 "Meningococcal vaccine in travelers". Current Opinion in Infectious Diseases 20 (5): 454–60. October 2007. doi:10.1097/QCO.0b013e3282a64700. PMID 17762777. 
  63. ↑ "Detecting meningococcal meningitis epidemics in highly-endemic African countries". Weekly Epidemiological Record 75 (38): 306–309. September 2000. PMID 11045076. 
  64. ↑ "Product development partnerships hit their stride: lessons from developing a meningitis vaccine for Africa". Health Affairs 30 (6): 1058–64. June 2011. doi:10.1377/hlthaff.2011.0295. PMID 21653957. 
  65. ↑ "Epidemic meningitis due to Group A Neisseria meningitidis in the African meningitis belt: a persistent problem with an imminent solution". Vaccine 27 (Suppl 2): B13–19. June 2009. doi:10.1016/j.vaccine.2009.04.062. PMID 19477559. 
  66. ↑ 66.0 66.1 "Pneumococcal meningitis in adults: new approaches to management and prevention". The Lancet. Neurology 5 (4): 332–42. April 2006. doi:10.1016/S1474-4422(06)70409-4. PMID 16545750. 
  67. ↑ 67.0 67.1 "Antibiotics for preventing meningococcal infections". The Cochrane Database of Systematic Reviews 10 (10): CD004785. October 2013. doi:10.1002/14651858.CD004785.pub5. PMID 24163051. 
  68. ↑ 68.0 68.1 "Antibiotic prophylaxis for preventing meningitis in patients with basilar skull fractures". The Cochrane Database of Systematic Reviews 2015 (4): CD004884. April 2015. doi:10.1002/14651858.CD004884.pub4. PMID 25918919. 
  69. ↑ "Fluid therapy for acute bacterial meningitis". The Cochrane Database of Systematic Reviews 2016 (11): CD004786. November 2016. doi:10.1002/14651858.CD004786.pub5. PMID 27813057. PMC 6464853. http://archive.lstmed.ac.uk/8112/1/Cochrane_Fluid%20therapy%20for%20acute%20bacterial%20meningitis.pdf. Retrieved 30 December 2018. 
  70. ↑ "Osmotic therapies added to antibiotics for acute bacterial meningitis". The Cochrane Database of Systematic Reviews 2018 (2): CD008806. February 2018. doi:10.1002/14651858.CD008806.pub3. PMID 29405037. 
  71. ↑ "Third generation cephalosporins versus conventional antibiotics for treating acute bacterial meningitis". The Cochrane Database of Systematic Reviews 2007 (4): CD001832. October 2007. doi:10.1002/14651858.CD001832.pub3. PMID 17943757. 
  72. ↑ "Fluid therapy for acute bacterial meningitis". The Cochrane Database of Systematic Reviews 2016 (11): CD004786. November 2016. doi:10.1002/14651858.CD004786.pub5. ISSN 1469-493X. PMID 27813057. 
  73. ↑ 73.0 73.1 73.2 73.3 "Corticosteroids for acute bacterial meningitis". The Cochrane Database of Systematic Reviews 2015 (9): CD004405. September 2015. doi:10.1002/14651858.CD004405.pub5. PMID 26362566. 
  74. ↑ 74.0 74.1 "Corticosteroid administration and outcome of adolescents and adults with acute bacterial meningitis: a meta-analysis". Mayo Clinic Proceedings 84 (5): 403–09. May 2009. doi:10.4065/84.5.403. PMID 19411436. 
  75. ↑ "Corticosteroids for managing tuberculous meningitis". The Cochrane Database of Systematic Reviews 2016 (4): CD002244. April 2016. doi:10.1002/14651858.CD002244.pub4. PMID 27121755. 
  76. ↑ 76.0 76.1 "Dexamethasone in adults with bacterial meningitis". The New England Journal of Medicine 347 (20): 1549–56. November 2002. doi:10.1056/NEJMoa021334. PMID 12432041. http://dare.uva.nl/personal/pure/en/publications/dexamethasone-in-adults-with-bacterial-meningitis(72435a94-1ea1-488f-9407-345b79b068cc).html. Retrieved 20 October 2018. 
  77. ↑ "Dexamethasone as adjunctive therapy in bacterial meningitis. A meta-analysis of randomized clinical trials since 1988". JAMA 278 (11): 925–31. September 1997. doi:10.1001/jama.1997.03550110063038. PMID 9302246. 
  78. ↑ 78.0 78.1 "Non-corticosteroid adjuvant therapies for acute bacterial meningitis". The Cochrane Database of Systematic Reviews 2021 (11): CD013437. November 2021. doi:10.1002/14651858.CD013437.pub2. ISSN 1469-493X. PMID 34813078. 
  79. ↑ "Meningitis and Encephalitis Fact Sheet". National Institute of Neurological Disorders and Stroke (NINDS). 11 December 2007. http://www.ninds.nih.gov/disorders/encephalitis_meningitis/detail_encephalitis_meningitis.htm. 
  80. ↑ "Fungal meningitis". Seminars in Neurology 20 (3): 307–22. 2000. doi:10.1055/s-2000-9394. PMID 11051295. 
  81. ↑ "Mortality and Burden of Disease Estimates for WHO Member States in 2002" (xls). World Health Organization (WHO). 2002. https://www.who.int/entity/healthinfo/statistics/bodgbddeathdalyestimates.xls. 
  82. ↑ "Hearing loss during bacterial meningitis". Archives of Disease in Childhood 76 (2): 134–38. February 1997. doi:10.1136/adc.76.2.134. PMID 9068303. 
  83. ↑ "Treatment outcomes of childhood tuberculous meningitis: a systematic review and meta-analysis". The Lancet. Infectious Diseases 14 (10): 947–57. October 2014. doi:10.1016/S1473-3099(14)70852-7. PMID 25108337. 
  84. ↑ "Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013". Lancet 385 (9963): 117–71. January 2015. doi:10.1016/S0140-6736(14)61682-2. PMID 25530442. 
  85. ↑ "Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010". Lancet 380 (9859): 2095–128. December 2012. doi:10.1016/S0140-6736(12)61728-0. PMID 23245604. PMC 10790329. https://zenodo.org/record/2557786. Retrieved 23 March 2020. 
  86. ↑ "Cerebrospinal Meningitis in Africa". Bulletin of the World Health Organization 28 Suppl (Suppl): 1–114. 1963. PMID 14259333. 
  87. ↑ "Manson Lecture. Meningococcal meningitis in Africa". Transactions of the Royal Society of Tropical Medicine and Hygiene 93 (4): 341–53. 1999. doi:10.1016/S0035-9203(99)90106-2. PMID 10674069. 
  88. ↑ 88.0 88.1 88.2 World Health Organization (1998). Control of epidemic meningococcal disease, practical guidelines, 2nd edition, WHO/EMC/BA/98. 3. pp. 1–83. https://www.who.int/csr/resources/publications/meningitis/whoemcbac983.pdf. 
  89. ↑ "Meningococcal meningitis : Overview". Weekly Epidemiological Record 78 (33): 294–296. August 2003. PMID 14509123. 
  90. ↑ 90.0 90.1 Walker, Arthur Earl; Laws, Edward R.; Udvarhelyi, George B. (1998). "Infections and inflammatory involvement of the CNS". The Genesis of Neuroscience. Thieme. pp. 219–21. ISBN 978-1-879284-62-3. https://books.google.com/books?id=UaSaRzw8gYEC&pg=PP1. Retrieved 24 August 2020. 
  91. ↑ Observations on the Dropsy in the Brain. Edinburgh: J. Balfour. 1768. 
  92. ↑ 92.0 92.1 92.2 "Editorial: 100 years of epidemic meningitis in West Africa – has anything changed?". Tropical Medicine & International Health 11 (6): 773–80. June 2006. doi:10.1111/j.1365-3156.2006.01639.x. PMID 16771997. 
  93. ↑ "Mémoire sur le Maladie qui a regne à Génève au printemps de 1805" (in fr). Journal de Médecine, de Chirurgie et de Pharmacologie (Bruxelles) 11: 50–53. 1806. 
  94. ↑ "Ueber die Aetiologie der akuten Meningitis cerebro-spinalis" (in de). Fortschrift der Medizin 5: 573–83. 1887. 
  95. ↑ "The results of the serum treatment in thirteen hundred cases of epidemic meningitis". The Journal of Experimental Medicine 17 (5): 553–76. May 1913. doi:10.1084/jem.17.5.553. PMID 19867668. 
  96. ↑ "Bacterial meningitis – a view of the past 90 years". The New England Journal of Medicine 351 (18): 1826–28. October 2004. doi:10.1056/NEJMp048246. PMID 15509815. 
  97. ↑ "Penicillin in the treatment of meningitis". Journal of the American Medical Association 125 (15): 1011–17. 1944. doi:10.1001/jama.1944.02850330009002.  reproduced in "Landmark article Aug 12, 1944: Penicillin in the treatment of meningitis. By D.H. Rosenberg and P.A.Arling". JAMA 251 (14): 1870–76. April 1984. doi:10.1001/jama.251.14.1870. PMID 6366279. 

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