Bacterial Meningitis And Brai... Health Article

Transmission, colonization and invasion of the nasopharyngeal epithelium –transmission occurs via close contact or respiratory droplet spread. Invasion of the epithelium and entry into the bloodstream is a critical step in the pathogenesis of bacterial meningitis. Adherence to the mucosal membrane is established by bacterial substructures including pili and certain outer membrane proteins. The primary immune defence at the mucosal epithelium is secretory IgA, which inhibits binding of bacteria to host cells. Pathogenic organisms, including N. meningitidis , H. influenzae and Strep. pneumoniae secrete IgA I proteinases that cleave antibody, preventing secondary effector activation. Bacteria may cross the epithelium by passing between cells or via endocytic uptake and transport across mucosal cells. The risk of colonization may be increased by damage to the mucosal epithelium by irritants such as cigarette smoke, or by preceding viral illness (e.g. influenza A).

Survival in the bloodstream – pathogenic organisms have evolved several mechanisms to evade the host immune response. They exhibit high-level variation in surface antigens, and many bacterial capsular polysaccharides reduce antibody binding, complement-mediated cell lysis and phagocytosis. Complement activation is avoided by bacteria that express sialic acid on their outer membrane (e.g. Escherichia coli K1, group B streptococci (type III), N. meningitidis groups B and C). In addition, bacterial protease-cleaved IgA I monomers competitively inhibit IgG and IgM binding, to further reduce the efficiency of the host's humoral immune system.

Meningeal invasion –bacteraemia may be rapidly followed by seeding of meningeal pathogens and secondary infection of the meninges. Meningeal pathogens appear to have specificity for receptors on choroid plexus epithelium or cerebral capillaries. The blood–brain barrier is a physical and immunological defence that organisms use various mechanisms to overcome. Bacteria may enter the meningeal space by crossing between endothelial cells, either by disrupting intercellular tight junctions or by causing endothelial cell injury. As a result of inflammatory cell activation following infection, H. influenzae , E. coli and pneumococci have cytotoxic effects on the CNS vasculature. Bacteria may also be taken up endocytically and penetrate the blood–brain barrier by the paracellular route. Intracellular pathogens such as mycobacteria and Salmonella may enter the CSF despite previous mononuclear cell phagocytosis, and may cause meningitis during WBC dia-pedesis across the blood–brain barrier.

Bacterial meningitis may be secondary to infection of adjacent sites, with spread of infection from the sinuses, the middle ear or the mastoid. Meningitis may also follow a breach in the blood–brain barrier following trauma or neurosurgery.

CSF inflammatory response – the subarachnoid space has poor immunological defence, allowing rapid and relatively unhindered growth of bacteria in the CSF. Resident macrophages and peri-pheral granulocytes entering the CSF cannot efficiently phagocytose pathogens because of the exclusion of opsonins such as immuno-globulins and complement components by the blood–brain barrier. Following infection, bacterial wall components including lipopolysaccharide, teichoic acid and peptidoglycans initiate an intense inflammatory response, via cell surface receptors including CD14 and the toll-like receptors. Activation of pro-inflammatory pathways occurs via intracellular signalling molecules such as nuclear factor kappa B. This leads to upregulated production of pro-inflammatory cytokines such as tumour necrosis factor É (TNFÉ) and interleukin-1β, which are released by several cells in the CNS, including glial, endothelial and ependymal cells, astrocytes and resident macrophages. These cytokines trigger release of many other mediators, including interleukins, interferon-γ, platelet-activating factor, chemokines, prostaglandins and nitric oxide. Levels of TNFÉ and other pro-inflammatory cytokines within the CSF are raised within hours of infection and are correlated with disease severity in meningitis.

In addition, oxidative cell injury and cytotoxicity may be caused by reactive oxygen species, which accumulate in the CNS in meningitis. Similarly, nitric oxide production is increased in meningitis. Inflammatory stimulation of the vascular endothelium leads to ac-tivation of the highly active isoform of the enzyme inducible nitric oxide synthase. Pathologically high levels of nitric oxide may be generated, leading to vasodilatation and increased cerebral blood flow, and also to cytotoxic disruption of the blood–brain barrier, which may have a role in the development of cerebral oedema.

Although animal experiments have shown that the meninges cannot be directly infected by Mycobacterium tuberculosis , bacilli appear to gain access to the subarachnoid space via a subcortical or meningeal focus. The clinical sequelae appear to result from vasculitis of intracerebral vessels, which can lead to infarction with hemiplegia or quadriplegia. Hydrocephalus may result from a dense exudate that creates an obstruction to the circulation of CSF at the level of the tentorial opening.

Cerebral oedema and thrombosis –cerebral oedema may be caused by reduced CSF reabsorption by the arachnoid villi and by vasogenic or cytotoxic means, as discussed above. Relative hydrocephalus occurs that, with interstitial oedema, leads to an increase in intracranial pressure, which may eventually lead to a reduction in cerebral blood flow. Bacterial meningitis causes loss of cerebrovascular autoregulation; as a result, cerebral blood flow becomes dependent on mean arterial blood pressure, which may increase to maintain cerebral blood flow.

Clinical features: most patients other than infants present with the classical features of:

• headache

• fever

• photophobia

• neck stiffness.

Other presenting features include:

• cranial nerve palsies (most commonly IIIth, IVth, VIth and VIIth)

• focal neurological deficits, including nystagmus, aphasia, ataxia and peripheral nerve palsies

• partial or generalized seizures (20–30%) – tend to be more common in Strep. pneumoniae and Hib meningitis

• signs of raised intracranial pressure (e.g. altered consciousness level, hypertension, bradycardia, abnormal respiratory drive) – papilloedema is a late sign

• purpura or petechiae, in meningococcal septicaemia, with or without the features of septic shock.

Patients should be evaluated carefully at presentation for signs of disseminated infection and shock.

A less specific clinical presentation may be seen in young infants and in the elderly, comprising signs such as lethargy, poor appetite, listlessness, diarrhoea and vomiting.

Reduced consciousness level at presentation is an important factor predicting mortality or neurological morbidity. Studies in both adults and children show a mortality of 5–10% in patients with normal consciousness level and 30–50% in those who present with reduced consciousness or coma. The significance of other clinical features (e.g. onset of seizures, duration of illness before admission) as prognostic indicators is less well established. Laboratory markers of poor prognosis include low peripheral WBC count, thrombocytopenia, absence of CSF pleocytosis and high CSF protein levels.

Tuberculous meningitis also has a more insidious onset. A prodromal period may involve fluctuating fever, lethargy, weight loss, behaviour changes, headache and vomiting. The diagnosis is often not considered until more severe symptoms such as neurological deficit, fluctuating consciousness level and convulsions become apparent.

CSF examination –diagnosis of bacterial meningitis is conventionally by examination of CSF. There is increasing concern that lumbar puncture may be hazardous in some conditions. Lumbar puncture should be performed only if there are no contraindications ( Table 1). Normal CT does not exclude raised intracranial pressure in bacterial meningitis, but can be used to exclude significant space-occupying lesions, which would contraindicate lumbar puncture. It is important to exclude brain abscess in this situation, and therefore CT should be performed and the appearances interpreted in light of the clinical context. However, administration of antibiotics must never be delayed awaiting the scan.

Lumbar puncture should not be performed when a clinical diagnosis of meningococcal meningitis has been made on the presence of a purpuric or petechial rash. Such patients are commonly in compensated septic shock, and the procedure may worsen their cardiovascular or respiratory status. The presence of cells in the CSF is suggestive of an inflammatory process, but many different pathogens may cause meningitis.

Evaluation of the CSF is important in determining the aetiology and then in deciding the most appropriate therapy. Typical CSF findings in acute bacterial meningitis include:

• raised WBC count (usually 100–60,000/μl, predominantly neutrophils)

• reduced CSF glucose (30–40% serum glucose, 0.2–2.2 mmol/litre)

• raised CSF protein (0.5–5 g/litre).

However, though most patients with bacterial meningitis exhibit some or all of these features, CSF culture may be positive when glucose and protein concentrations are normal. Gram-staining of CSF is positive in more than 90% of cases of haematogenously acquired meningitis, but less commonly (50–60%) in cases secondary to neurosurgery.

Blood culture should be performed in all patients with suspected meningitis, and latex agglutination bacterial antigen tests or polymerase chain reaction analysis (to detect bacterial DNA) may be performed on blood or CSF to try to obtain a diagnosis. Such tests remain positive for several days after administration of antibiotics.

Differential diagnosis: viral meningoencephalitis often presents with clinical features similar to those of bacterial meningitis, but patients may exhibit distinct CSF findings. CSF glucose is normal, protein concentration is less significantly elevated (typically 0.5–2 g/litre) and there is CSF lymphocytosis (5–200 WBCs/μl).

Focal infections such as brain abscess and subdural empyema may also cause similar clinical features. Investigations to determine a specific aetiology include CSF examination, with specific stains for mycobacteria and fungi, cytology, antigen detection, serology, viral culture and blood cultures. CT or MRI of the brain is usually performed.

Non-infectious illnesses may cause CNS inflammation. These disorders are relatively uncommon and include malignancy, collagen vascular syndromes and exposure to toxins. CSF findings may be useful ( Table 2).

Management: any patient with severely depressed consciousness, signs of raised intracranial pressure, shock or convulsions should be managed in an ICU. Most of those who do not present with raised intracranial pressure may be managed on a general ward with antibiotics, corticosteroids (see below) and adequate analgesia, providing careful monitoring and review are undertaken.

Initial antibiotic therapy should be determined by the likely pathogen, which depends on the age of the patient ( Table 3). Further management of bacterial meningitis depends on the severity of the clinical presentation.

Raised intracranial pressure is a medical emergency, and is recognized by:

• reduced or fluctuating consciousness level

• hypertension and relative bradycardia

• unequal, dilated or poorly reacting pupils

• focal neurological signs

• abnormal posturing

• seizures

• papilloedema (may be a very late sign).

In some cases, it can be diffcult to distinguish between the signs of raised intracranial pressure and those of clinical shock with reduced consciousness level and poor peripheral perfusion caused by septicaemia.

When raised intracranial pressure is suspected, basic life support should be maintained and the patient given mannitol, 0.25 g/kg i.v. over 10 minutes, followed by frusemide, 1 mg/kg. Shock should be treated, and further intensive care (including intubation, artificial ventilation, sedation and careful fluid balance) may be required. Seizures should be controlled with lorazepam, 0.1 mg/kg i.v., or midazolam, 0.1 mg/kg, phenytoin, 18 mg/kg loading dose with ECG monitoring, or, if they are persistent, thiopentone in ventilated patients.

Corticosteroids have been shown to be useful in preventing some morbidity associated with some forms of bacterial meningitis. A recent study has shown that early treatment with dexa-methasone may improve the outcome in adults with acute bacterial meningitis without increasing corticosteroid-related adverse events. Adjunctive dexamethasone may reduce sensorineural hearing loss (but not mortality or other neurological sequelae) in children and infants with H. influenzae meningitis. A recent meta-analysis of randomized clinical trials suggested benefit in preventing sequelae in both Hib and pneumococcal meningitis in childhood. Although no data are available for meningococcal meningitis, the pathophysiological events are likely to be similar to those in other forms of bacterial meningitis and in animal models in which anti-inflammatory therapy has been beneficial. Few adverse events have been caused by dexamethasone; in particular, there have been no reported cases of delayed CSF sterilization or treatment failure. In all children with suspected bacterial meningitis after the neo- natal period, the authors' practice is to recommend dexamethasone, 0.4 mg/kg b.d. for 48 hours, given with the first dose of parenteral antibiotics. In adults, dexamethasone, 10 mg, is given every 6 hours intravenously for 4 days; the first dose is administered before or with the first parenteral antibiotic therapy.

Corticosteroids should be used in the management of children with tuberculous meningitis. They have been shown to reduce mortality, long-term neurological complications and permanent sequelae. In a recent study of patients over 14 years of age, adjunctive treatment with dexamethasone reduced mortality in those with tuberculous meningitis, but there was no demonstrable improvement in the combined end-point of death or severe disability after 9 months.

Follow-up of patients recovering from bacterial meningitis should include full neurological assessment and formal audiological testing.

Complications and long-term prognosis: complications of bacterial meningitis vary according to the aetiology, the severity of disease at presentation, and the age and immune status of the patient.

Focal infections including brain abscess and subdural empyema should be considered in patients with persistent fever or focal neurological signs or who deteriorate after the initial illness. Hydrocephalus, subdural effusions, venous thrombosis and vascular spasm may also cause focal neurological deficits and may require neurosurgical intervention.

Early recognition, prompt antibiotic therapy and improvements in medical management have reduced mortality from bacterial meningitis after the neonatal period, to about 5%. Mortality is greater in pneumococcal meningitis. The prognosis is poorest in infants under 6 months of age and in those with a high CSF bacterial load (>10 ⁶ colony-forming units/ml). Severe neuro-developmental sequelae occur in 10–20% of patients who recover from bacterial meningitis. Neurological morbidity is of varying severity and includes hearing loss (most commonly after Hib or pneumococcal infection) and motor abnormalities such as hemiplegia and quadriplegia.

Prevention: primary prevention of bacterial meningitis may be achieved by immunization, and by prevention of secondary cases of meningococcal and H. influenzae disease using chemoprophylaxis.

Vaccines – conjugate vaccines for Hib and group C meningococcus have dramatically reduced the incidence of these pathogen as a cause of bacterial meningitis. The older vaccine against N. meningitidis serogroups A, C, W135 and Y confers protection for up to 3 years to health-care workers and overseas travellers. There is currently no vaccine for the large number of strains of group B meningococcus.

The polyvalent pneumococcal vaccine is derived from the capsular polysaccharide of multiple strains, but is poorly immuno-genic in children under 2 years of age, who are at greatest risk of infection. It is used in older children and adults at high risk of invasive pneumococcal disease, such as those with reduced splenic function (including sickle cell disease), the elderly, and patients with diabetes or other chronic diseases. New polyvalent conjugate vaccines are being introduced that will reduce the burden of pneumococcal meningitis in vaccinated populations.

Chemoprophylaxis is used to prevent transmission or development of disease in close contacts of patients with proven meningococcal or Hib bacterial meningitis. Close collaboration with community and public health teams is important in the administration of antibiotics to family and other close contacts as soon as possible after an index case has been diagnosed. Rifampicin is the drug of choice; ceftriaxone and ciprofloxacin are effective alternatives.