The brain and spinal cord are surrounded by three membranes, which from the outside inwards are the dura mater, the arachnoid mater and the pia mater. Between the arachnoid mater and the pia mater, in the subarachnoid space, is found the cerebrospinal fluid (CSF) (Fig. 38.1). This fluid, of which there is ∼︀150 mL^–1 in a normal individual, is secreted by the choroid plexuses and vascular structures which are in the third, fourth and lateral ventricles. CSF passes from the ventricles via communicating apertures to the subarachnoid space, after which it flows over the surface of the brain and the spinal cord (see Fig. 38.1). The amount of CSF is controlled by resorption into the bloodstream by vascular structures in the subarachnoid space, called the arachnoid villi. Infective meningitis is an inflammation of the arachnoid and pia mater associated with the presence of bacteria, viruses, fungi or protozoa in the CSF. Meningitis is one of the most emotive of infectious diseases, and for good reason: even today, infective meningitis is associated with significant mortality and risk of serious sequelae in survivors.

Fig. 38.1 The meninges covering the brain and spinal cord and the flow of cerebrospinal fluid (arrowed)

(modified from Ross and Wilson (1981), by permission of Churchill Livingstone).

Aetiology and epidemiology

In the UK, around 1500 cases of meningitis are notified annually. However, this almost certainly under represents the true incidence of meningitis. Viruses are the most common cause of meningitis, and are often less serious than bacterial or fungal forms of the disease.

Bacterial meningitis

Although bacterial meningitis occurs in all age groups, it is predominantly a disease of young children, with 40–50% of all cases occurring in the first 4 years of life. Two bacteria, N. meningitidis and S. pneumoniae, account for about 75% of cases. However, the pattern of micro-organisms causing meningitis is related to the age of the patient and the presence of underlying disease.

N. meningitidis is the most common cause of bacterial meningitis from infancy through to middle age, with peaks of incidence in the under-5-year age group and in adolescents. There are several serogroups of N. meningitidis, including A, B, C, W135 and Y. In the late twentieth century, serogroups B and C accounted for 60–65% and 35–40% of infections in the UK, respectively. However, with the introduction of vaccination against N. meningitidis serogroup C (MenC) into the routine immunisation programme in 1999, serogroup B now accounts for well over 80% of all meningococcal disease. There is currently no vaccine available for N. meningitidis serogroup B. Serogroups A and W135 predominate in Africa and the Middle East. A quadrivalent vaccine against serogroups A, C, W135 and Y is available to protect travellers to countries of risk. S. pneumoniae is the most common cause of meningitis in adults aged over 45 years, but almost half of all cases of pneumococcal meningitis occur in children aged under 5 years. It has a poorer outcome than meningococcal meningitis. Vaccination against the most common serotypes of S. pneumoniae using a conjugate vaccine was added to the routine childhood immunisation programme in the UK in 2006: the original 7-valent vaccine was then replaced by a 13-valent vaccine in Spring 2010. A different 23-valent polysaccharide vaccine is available for certain patient groups at risk of pneumococcal infection.

Haemophilus influenzae type b (Hib) was once the major cause of bacterial meningitis in children aged 3 months to 5 years, but introduction of routine immunisation in 1992 has almost eliminated Hib disease in the UK and other developed countries.

Although patients with meningococcal or Hib meningitis are potentially infectious, most cases of meningitis due to these bacteria are acquired from individuals who are asymptomatic nasopharyngeal carriers. People living in the same household as a patient with meningococcal disease have a 500–1200-fold increased risk of developing infection if they do not receive chemoprophylaxis (see later). Susceptible young children who are household contacts of a case of Hib disease have a similarly increased risk of becoming infected. Epidemics of meningococcal disease sometimes occur. In developed countries, these take the form of clusters of cases among people living in close proximity (e.g. in schools or army camps) or in a particular geographical area. In Africa, large epidemics with many thousands of cases occur, usually during the dry season.

In the neonatal period, group B streptococci are the most common cause of bacterial meningitis. Other causes of neonatal meningitis include Escherichia coli and other Enterobacteriaceae, Listeria monocytogenes, Staphylococcus aureus and enterococci. In most cases, infection is acquired from the maternal genital tract around the time of delivery, but transmission between patients can also occur in hospitals.

L. monocytogenes is also an occasional cause of meningitis in immunocompromised patients. Meningitis can also occur as a complication of neurosurgery, especially in patients who have ventriculoatrial or ventriculoperitoneal shunts. Coagulase-negative staphylococci are the major causes of shunt-associated meningitis, but other bacteria are important, including Enterobacteriaceae and S. aureus. Meningitis due to S. aureus may also be secondary to trauma, or local or haematogenous spread from another infective focus. Meningitis may also be a feature of multisystem bacterial diseases such as syphilis, leptospirosis and Lyme disease.

The decline in the incidence of tuberculous meningitis in developed countries has mirrored the fall in the incidence of tuberculosis in these countries. Tuberculous meningitis may occur as part of the primary infection or as a result of recrudescence of a previous infection.

Viral meningitis

Human enteroviruses such as echoviruses and Coxsackie viruses account for about 70% of cases of viral meningitis in the UK. Herpes simplex and varicella zoster viruses account for most other cases. Occasional causes of viral meningitis include mumps virus and human immunodeficiency viruses.

Fungal meningitis

In Europe, fungal meningitis is rare in individuals without underlying disease. Candida species are an occasional cause of shunt-associated meningitis. Cryptococcus neoformans has emerged as an important cause of meningitis in patients with late-stage HIV infection and other severe defects of T-cell function. With greater use of fluconazole for oral candidiasis, and especially the advent of highly active antiretroviral therapy, cryptococcosis has become much less common in developed countries. However, in sub-Saharan African countries with the highest HIV prevalence, cryptococcus is the leading cause of infective meningitis. In certain other areas of the world, infections with fungi such as Coccidioides immitis and Histoplasma capsulatum are endemic.

Pathophysiology

Most cases of bacterial meningitis are preceded by nasopharyngeal colonisation by the causative organism. In most colonised individuals, infection will progress no further, but in susceptible individuals the organism invades the submucosa by circumventing host defences (e.g. physical barriers, local immunity, phagocytes) and gains access to the CNS by invasion of the bloodstream and subsequent haematogenous seeding of the CNS. Other less common routes by which micro-organisms can reach the meninges include:

• direct spread from the nasopharynx

• blood-borne spread from other foci of colonisation or infection

• abnormal communications with the skin or mucous membranes, for example skull fractures, anatomical defects or a meningocoele

• spread from an infected adjacent focus, for example brain abscess, tuberculoma, infected paranasal air sinus or infection of the middle ear.

Once in the subarachnoid space, the infection spreads widely and incites a cascade of meningeal inflammation. The cerebral tissue is not usually directly involved although cerebral abscess may complicate some types of meningitis.

The micro-organisms that most frequently cause meningitis are capable of doing so because they have a variety of virulence factors, including mechanisms for:

• attachment to host mucosal surfaces

• evasion of phagocytosis and other host defences

• meningeal invasion

• disruption of the blood–brain barrier

• induction of pathophysiological changes in the CSF space

• secondary brain damage.

Overall, the net result of infection is vascular endothelial injury and increased blood–brain barrier permeability leading to the entry of many blood components into the subarachnoid space. This contributes to cerebral oedema and elevated CSF protein levels. In response to the cytokine response, neutrophils migrate from the bloodstream into the CSF. Cerebral oedema contributes to intracranial hypertension and a consequent decrease in cerebral blood flow. Anaerobic metabolism ensues, which contributes to increased lactate and decreases glucose concentrations. If this uncontrolled process is not modulated by effective treatment, transient neuronal dysfunction or permanent neuronal injury results.

Clinical manifestations

Acute bacterial meningitis usually presents with sudden-onset headache, neck stiffness, photophobia, fever and vomiting. On examination, Kernig’s sign may be positive. This is resistance to extension of the leg when the hip is flexed, due to meningeal irritation in the lumbar area. Where meningitis is complicated by septicaemia, there may be septic shock. The presence of a haemorrhagic skin rash is highly suggestive, but not pathognomic, of meningococcal infection. Untreated patients with bacterial meningitis deteriorate rapidly, with development of seizures, focal cerebral signs and cranial nerve palsies. Finally, obtundation and loss of consciousness herald death.

In infants with meningitis, the early physical signs are usually non-speciﬁc and include fever, diarrhoea, lethargy, feeding difficulties and respiratory distress. Focal signs such as seizures or a bulging fontanelle usually only occur at a late stage.

Viral meningitis usually presents with acute onset of low-grade fever, headache, photophobia and neck stiffness. Unless they develop encephalitis, patients usually remain alert and oriented.

Although tuberculous and fungal meningitis sometimes present acutely, these infections typically have a more indolent course. The early stages of the diseases are dominated by general symptoms such as malaise, apathy and anorexia. As they progress, symptoms and signs more typical of meningitis usually appear.

Diagnosis

The definitive diagnosis of meningitis is established by detection of the causative organism and/or demonstration of biochemical changes and a cellular response in CSF. CSF is obtained by lumbar puncture, where a needle is inserted between the posterior space of the third and fourth lumbar vertebrae into the subarachnoid space. Before performing lumbar puncture, the possibility of precipitating or aggravating existing brain herniation in patients with intracranial hypertension must be considered. A CT scan should be performed before undertaking lumbar puncture if any neurological abnormalities are present.

In health, the CSF is a clear colourless fluid which, in the lumbar region of the spinal cord, is at a pressure of 50–150 mmH₂O. There may be up to 5 cells/μL, the protein concentration is up to 0.4 g/L and the glucose concentration is at least 60% of the blood glucose (usually 2.2–4.4 mmol/L). Table 38.1 shows how the cell count and biochemical measurements can be helpful in determining the type of organism causing meningitis.

Table 38.1 Cellular and biochemical responses in different forms of infective meningitis

In bacterial and fungal meningitis, organisms may be visible in Gram-stained smears of the CSF. The common causes of bacterial meningitis are easily distinguished from each other by their Gram stain appearance. Special stains, such as the Ziehl–Neelsen method, are necessary to visualise mycobacteria. However, only small numbers of mycobacteria are present in the CSF in tuberculous meningitis and direct microscopy is often unrevealing. Although cryptococci can be visualised by Gram staining, they are often more easily seen with India ink staining, which highlights their prominent capsules.

Regardless of the microscopic findings, CSF should be cultured to try to confirm the identity of the causative organism and to facilitate further investigations such as antibiotic sensitivity testing and typing. Special cultural techniques are required for mycobacteria, fungi and viruses. Cultures of other sites are sometimes helpful. In suspected bacterial meningitis, blood for culture should always be obtained. Bacteraemia occurs in only 10% of patients with meningococcal meningitis but is more common in most other forms of meningitis. In suspected meningococcal disease, culture of a nasopharyngeal swab may be helpful because antibiotic penetration at this site is less. It increases the chances of isolating meningococci when antibiotics were administered to the patient before presentation to hospital.

Non-culture-based methods are increasingly used to investigate the aetiology of meningitis. In particular, molecular amplification techniques such as polymerase chain reaction (PCR) are now widely used to detect meningococci, pneumococci, Mycobacterium tuberculosis and various viruses, including herpes simplex viruses and enteroviruses.

Serum antibodies to N. meningitidis and various viruses may be detected, but these investigations usually depend on demonstration of seroconversion between two samples collected a week or more apart, and are therefore undertaken more for public health than clinical reasons. Patients with tuberculous meningitis may have a positive Mantoux test or an interferon-gamma release assay.

Drug treatment

Acute bacterial meningitis is a medical emergency that requires urgent administration of antibiotics. Other considerations in some forms of meningitis include the use of adjunctive therapy such as steroids, and the administration of antibiotics to prevent secondary cases.

Antimicrobial therapy

Pharmacokinetic considerations

The antimicrobial therapy of meningitis requires attainment of adequate levels of bactericidal agents within the CSF. The principal route of entry of antibiotics into CSF is by the choroid plexus; an alternative route is via the capillaries of the central nervous system into the extracellular fluid and hence into the ventricles and subarachnoid space (see Fig. 38.1). The passage of antibiotics into CSF is dependent on the degree of meningeal inflammation and integrity of the blood–brain barrier created by capillary endothelial cells, as well as the following properties of the antibiotic:

• lipid solubility (the choroidal epithelium is highly impermeable to lipid-insoluble molecules)

• ionic dissociation at blood pH

• protein binding

• molecular size

• concentration of the drug in the serum.

Antimicrobials fall into three categories according to their ability to penetrate the CSF:

• those that penetrate even when the meninges are not inflamed, for example chloramphenicol, metronidazole, isoniazid and pyrazinamide

• those that generally penetrate only when the meninges are inflamed, and used in high doses, for example most β-lactam antibiotics, the quinolones and rifampicin

• those that penetrate poorly under all circumstances, including the aminoglycosides, vancomycin and erythromycin.

Recommended regimens

Clinical urgency determines that empirical antimicrobial therapy will usually have to be prescribed before the identity of the causative organism or its antibiotic sensitivities are known. Consideration of the epidemiological features of the case, together with microscopic examination of the CSF, is often helpful in identifying the likely pathogen. However, empiric therapy is usually with broad-spectrum antimicrobial therapy to cover all likely pathogens, at least until definitive microbiological information is available. For the purpose of selecting empiric antimicrobial therapy, patients with acute bacterial meningitis can be categorised into four broad groups: neonates and infants aged below 3 months; immunocompetent older infants, children and adults; immunocompromised patients; and those with ventricular shunts.

Antibiotics for meningitis in neonates and infants aged below 3 months

The most important pathogens in neonates include group B streptococci, E. coli and other Enterobacteriaceae, L. monocytogenes. In many centres, a third-generation cephalosporin such as cefotaxime or ceftazidime, along with amoxicillin or ampicillin, is the empiric therapy of choice for neonatal meningitis (Galiza and Heath, 2009). Cephalosporins penetrate into CSF better than aminoglycosides, and their use in Gram-negative bacillary meningitis has contributed to a reduction in mortality to less than 10%. Other centres continue to use an aminoglycoside, such as gentamicin, together with benzylpenicillin, ampicillin or amoxicillin as empiric therapy. This approach remains appropriate, especially in countries such as the UK where group B streptococci are by far the predominant cause of early-onset neonatal meningitis. Whichever empiric regimen is used, therapy can be altered as appropriate once the pathogen has been identified. Suitable dosages are shown in Table 38.2.

Table 38.2 Suitable antibiotic regimens for treatment of acute bacterial meningitis in different age groups

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