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 very 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 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 upon mucous surfaces such as the nasal cavity. This is often in turn preceded by viral infections, which break down the normal barrier provided by the mucous 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 less common in adults.[1] 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.[1]
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 acute infection, this means that it is harder for blood to enter the brain, consequently brain cells are deprived of oxygen and undergo apoptosis (automated cell death).[1]
It is recognized that 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.[1][4]
Diagnosis
| 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 |
Blood tests and imaging
In someone 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.[3][27]The most important test in identifying or ruling out meningitis is analysis of the cerebrospinal fluid through lumbar puncture (LP, spinal tap).[28] However, 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.[3][27][29] This applies in 45% of all adult cases.[4] 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,[3] especially if this may be longer than 30 minutes.[27][29] Often, CT or MRI scans are performed at a later stage to assess for complications of meningitis.[1]
In severe forms of meningitis, monitoring of blood electrolytes may be important; for example, hyponatremia is common in bacterial meningitis, due to a combination of factors, including dehydration, the inappropriate excretion of the antidiuretic hormone (SIADH), or overly aggressive intravenous fluid administration.[4][30]
Lumbar puncture
The CSF sample is examined for presence and types of white blood cells, red blood cells, protein content and glucose level.[3] 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.[3] The type of white blood cell predominantly present (see table) indicates whether meningitis is bacterial (usually neutrophil-predominant) or viral (usually lymphocyte-predominant),[3] 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.[23]
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;[28] in the newborn, glucose levels in CSF are normally higher, and a ratio below 0.6 (60%) is therefore considered abnormal.[3] High levels of lactate in CSF indicate a higher likelihood of bacterial meningitis, as does a higher white blood cell count.[28] If lactate levels are less than 35 mg/dl and the person has not previously received antibiotics then this may rule out bacterial meningitis.[32]
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.[3] 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).[10] Serology (identification of antibodies to viruses) may be useful in viral meningitis.[10] 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.[14] 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, particularly in people with AIDS.[33][34]
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).[10]
Postmortem
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; however, neither is as contagious as the common cold or flu.[36] Both can be transmitted through droplets of respiratory secretions during close contact such as kissing, sneezing or coughing on someone, but cannot be spread by only breathing the air where a person with meningitis has been.[36] Viral meningitis is typically caused by enteroviruses, and is most commonly spread through fecal contamination.[36] 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 where the disease burden is highest, however, the vaccine is still too expensive.[37][38] 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.[10]Meningococcus vaccines exist against groups A, C, W135 and Y.[39] In countries where the vaccine for meningococcus group C was introduced, cases caused by this pathogen have decreased substantially.[37] A quadrivalent vaccine now exists, which combines all four vaccines. Immunization with the ACW135Y vaccine against four strains is now a visa requirement for taking part in Hajj.[40] 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.[37][39] 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.[39] 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,[41] 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.[42][43]
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.[37][44] 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.[44] 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.[37]
Antibiotics
Short-term antibiotic prophylaxis is another method of prevention, particularly of meningococcal meningitis. In cases of meningococcal meningitis, prophylactic treatment of 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.[27][45] Resistance to rifampicin has been noted to increase after use, which has caused some to recommend considering other agents.[45] While antibiotics are frequently used in an attempt to prevent meningitis in those with a basilar skull fracture there is insufficient evidence to determine whether this is beneficial or harmful.[46] This applies to those with or without a CSF leak.[46]Management
Meningitis is potentially life-threatening and has a high mortality rate if untreated;[3] delay in treatment has been associated with a poorer outcome.[4] Thus, treatment with wide-spectrum antibiotics should not be delayed while confirmatory tests are being conducted.[29] If meningococcal disease is suspected in primary care, guidelines recommend that benzylpenicillin be administered before transfer to hospital.[7] Intravenous fluids should be administered if hypotension (low blood pressure) or shock are present.[29] Given that meningitis can cause a number of early severe complications, regular medical review is recommended to identify these complications early[29] and to admit the person to an intensive care unit if deemed necessary.[4]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).[4] Seizures are treated with anticonvulsants.[4] Hydrocephalus (obstructed flow of CSF) may require insertion of a temporary or long-term drainage device, such as a cerebral shunt.
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.
In the USA, where resistance to cefalosporins is increasingly found in streptococci, addition of vancomycin to the initial treatment is recommended.[3][4][27] Chloramphenicol, either alone or in combination with ampicillin, however, appears to work equally well.
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.[3] 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.
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.
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.
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. 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.
Steroids
Adjuvant treatment with corticosteroids (usually dexamethasone) has shown some benefits, such as a reduction of hearing loss, and better short term neurological outcomes in adolescents and adults from high income countries with low rates of HIV.Some research has found reduced rates of death[50] while other research has not. They also appear to be beneficial in those with tuberculosis meningitis, at least in those who are HIV negative.
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.
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.
The likely mechanism is suppression of overactive inflammation.[52]
Adjuvant 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.
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, 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.[3]
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.[10] Mild cases of viral meningitis can be treated at home with conservative measures such as fluid, bedrest, and analgesics.[54]Fungal meningitis
Fungal meningitis, such as cryptococcal meningitis, is treated with long courses of high dose antifungals, such as amphotericin B and flucytosine.[33][55] Raised intracranial pressure is common in fungal meningitis, and frequent (ideally daily) lumbar punctures to relieve the pressure are recommended, or alternatively a lumbar drain.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.
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,[1] the severity of the generalized illness, a decreased level of consciousness or an abnormally low count of white blood cells in the CSF.
Meningitis caused by H. influenzae and meningococci has a better prognosis than cases caused by group B streptococci, coliforms and S. pneumonia. In adults, too, meningococcal meningitis has a lower mortality (3–7%) than pneumococcal disease.
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. These occur in about 15% of survivors.
Some of the hearing loss may be reversible. In adults, 66% of all cases emerge without disability. The main problems are deafness (in 14%) and cognitive impairment (in 10%).
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