Bacterial meningitis

Bacterial Meningitis
Classification and external resources
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Related topics

• Eosinophilic meningitis
• Leprosy of the CNS
• Tropical and parasitic infections of the CNS
• Congenital infections of the CNS
• Retroviral infections and AIDS
• Bacterial meningitis

Main source

• Brett's Paediatric Neurology 3rd edition

Definition

Meningitis is an inflammatory process affecting predominantly the meninges, arachnoid and pia mater, and is identified by an abnormal number of leucocytes in the CSF. Meningitis may be caused by bacteria, viruses, fungi or protozoa.

The term "aseptic meningitis' is a misnomer, as the picture of meningeal inflammation with increased CSF leucocytes but without evidence of the usual bacterial pathogens is caused by a wide array of infectious and non-infectious processes. These include viral, fungal and protozoal infections, tuberculosis, spirochaete and parameningeal infective foci.

Bacterial meningitis

Incidence and epidemiology

The incidence and epidemiology of bacterial meningitis vary in different countries [1, 2]. All forms of bacterial meningitis are more prevalent in less-developed countries than in Europe or the USA, but countries in which meningococcal meningitis frequently occurs in epidemics have a greatly increased incidence ofthis organism (Table 22.1)

Table 22.1

. The risk of developing meningitis is greatest in the first year of life, and declines progressively throughout childhood. Attack rates are higher in the neonatal period than at any other age (Table 22.2)

Table 22.2

. The usual organisms causing meningitis differ with the age of the child, and it is useful for the purpose of diagnosis and management to separate neonatal meningitis from that occurring in older children [3]

Figure 22.1 shows the organisms responsible for meningitis at different ages. Neonatal meningitis is caused by organisms acquired during passage down the birth canal, from the mother or nursery. E. coli and group B streptococcus are the major pathogens, with other Gram-negative organisms (Klebsiella, Enterobacter and Pseudomonas) and Listeria monocytogenes accounting for most of the other infections [3]. The incidence of group B streptococcal meningitis has increased greatly in the past few decades. From 20-30% of women are colonized with group B streptococci vaginally or rectally [4], and transmission of the organism to the infant occurs in about half of the cases carrying the organism. Nosocomial transmission of group B streptococci has also been documented [5, 6].

Seventy-five per cent of cases of E. coli meningitis are due to strains possessing the Kl antigen. These strains are found in the gastrointestinal tract of half the women of child-bearing age, and are readily transmitted to the infant [7, 8].

The importance of Listeria as a neonatal pathogen varies in different countries, and it is particularly prevalent in France, probably as a result of widespread consumption of certain foods. After acquisition of the organism by ingesting infected food, L. monocytogenes colonizes the genital and gastrointestinal tracts of pregnant women and may be transmitted to the infant before or after rupture of the membranes [9, 10, 11]. Although Haemophilus influenzae type B, Pneu-mococcus and Meningococcus can occasionally occur in the newborn, they are relatively rare. In infants and older children, over 90% of cases of community-acquired bacterial meningitis are caused by three organisms: Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae type B (Fig. 22.1)

Fig 22.1

<abbott1985 valmari1987 trollfors1987 schlech1985</cite>.

Haemophilus influenzae type B is predominantly an infection of younger children, being most prevalent under 2 years of age, and infrequent over the age of 5. This form of meningitis is more common in certain racial groups, including Eskimoes and American Indians, and probably also in blacks. It is more common in crowded populations (lstre et al1985) and affects boys more often than girls [12, 13]. The introduction of the Haemophilus influenzae type B conjugate vaccine to childhood immunization schedules in many developed countries has dramatically altered the pattern of childhood meningitis [14]. Whereas previously H. influenzae accounted for a large proportion of cases of meningitis in under 5-year-olds, following introduction of the HIB vaccine this form of meningitis has largely been eliminated [15]

H. influenzae is commonly carried in the nasopharynx of healthy children. Non-encapsulated strains are present in 80% of children and adults, but H. influenzae type B is only carried by 0.4% of adults, 0.8% of children over 5 years of age, and 3.2% of children under 5 years of age [16, 17]. Infected children appear to be potent sources of infection to household contacts. Ward et al (1979)[18] have studied the risk of H. influenzae infection in household contacts of children with meningitis. The risk was 6% in children less than 1 year of age, 2.1 % in children under 4 and 0.5% in children between 4 and 6 [18]. The secondary attack rate in young children is similar to that in meningococcal meningitis, and indicates the need for antimicrobial prophylaxis for household contacts. Spread of H. influenzae meningitis has also been observed in day care centres and institutions but the precise risks and the indications for prophylaxis are still subjects of debate [19]

S. pneumoniae is the commonest cause of meningitis in the adult population, but also affects children of all ages, with a peak incidence in children of less than 1 year [20]. There are over 80 serotypes of pneu-mococci, and meningitis is most commonly associated with serotypes 1, 3, 6, 7, 14, 17, 18-21 and 23. The risk of developing pneumococcal meningitis is greater in blacks than in whites, irrespective of income group or population density [21]. The incidence is greatly increased in children with sickle-cell disease, in whom 1/24 develop meningitis [22, 23]. Unlike meningococcal or Haemophilus meningitis, pneumococcal meningitis occurs sporadically, and there is no increased risk of household contacts acquiring the illness.

Meningococcal meningitis is the commonest form of meningitis in the UK (Communicable Disease Report Weekly 1995)[24]. Although the illness affects all ages it is predominantly a disorder of young children and teenagers [25]. Nine different groups of men-ingococci are identified by agglutination tests for capsular cell wall antigens. Group B is the commonest cause of sporadic meningococcal meningitis, whereas groups A and C are the usual causes of epidemics of meningococcal disease. In the UK and the USA most cases of meningococcal meningitis now occur sporadically. However, the organism has the potential for epidemic spread and outbreaks among military recruits and in institutions continue to occur. Major epidemics have occurred in several countries, including Brazil, Finland and countries of sub-Saharan Africa. Meningococci can be isolated from the nasopharynx of 1-15% of the population [26], and the carriage rates increase greatly during epidemics, and in household contacts of affected patients (Ronne et al 1993). The secondary attack rate in family contacts of patients with meningococcal meningitis is 1 %, a thousandfold increase over the risk in the community. The risk for contacts in day care centres and schools is approximately 0.1% [27]

Pathogenesis

Most cases of meningitis follow an initial period of bac-teraemia. After colonization of the upper respiratory tract the organism invades through the nasal mucosa, enters the bloodstream, and meningeal seeding then occurs [28, 29]. A major unanswered question is why most children colonized by the meningeal pathogens remain well, and only a small minority progress to bacteraemia and meningitis. The pathogenic properties of the bacteria are important determinants of the likelihood of developing meningitis, but host factors are also involved, a fact illustrated by the greatly increased susceptibility of the newborn to meningitis. Genetic factors may also play a role in the susceptibility to meningitis. An association between possession of HLA B12 and lack of HLA BW 40 antigens has been reported for invasive H. influenzae infections [30] and diminished antibody responses to H. influenzae capsular antigens have been documented in siblings of children with Haemophilus influenzae meningitis [31]. Children with congenital or acquired asplenia have a greatly increased risk of developing meningitis due to all three meningeal pathogens [22, 32]. Meningococcal infections occur with increased frequency in patients with properdin deficiency and abnormalities of the terminal components of complement [33, 34]. Organisms of low virulence may invade the CNS of children with haematological malignancies, AIDS or congenital immune deficiencies.

Non-haematogenous seeding of the meninges may occur by direct extension from infected sinuses, otitis media or mastoiditis. Osteomyelitis of the skull or compound fracture of the skull may allow staphylococci or skin organisms to enter the CSF. Direct bacterial invasion of the CSF also occurs after fracture of the cribriform plate or paranasal sinuses, and in children with neurocutaneous connections. Recurrent attacks of meningitis may occur in children with neurocutaneous fistulae, dermal sinuses, and middle ear defects causing CSF leakage [35, 36]. Meningitis may follow neurosurgical procedures or CSF shunting and is then usually due to coagulase-negative staphylococci or other skin organisms [37].

The organisms causing neonatal meningitis, E. coli, group B haemolytic streptococci and L. monocytogenes are usually acquired during passage down the birth canal, from the mother or the nursery environment. Colonization of the nasopharynx, umbilicus and gastrointestinal tract precedes invasion of the bloodstream and meninges.

Immunopathogenesis and pathophysiology

see /Immunopathogenesis and pathophysiology

Clinical features

The clinical signs and symptoms of meningitis vary greatly depending on the age of the child and the duration of the illness. The early symptoms include fever, irritability, lethargy, headache and vomiting, and are commonly found in other childhood illnesses such as upper respiratory tract infections, otitis media and viral infections. Later signs are more distinctive, and include stiff neck, positive Kernig's and Brudzinsky's signs, coma and convulsions. There is usually no difficulty in diagnosing meningitis once these signs are present. The challenge is to recognize the few children with early features of meningitis among the many with trivial childhood illnesses which have the same initial symptoms [3]

The diagnosis is more difficult in the neonatal period and in young infants, when the signs are subtle and nonspecific. Fever is present in only half of neonates with meningitis. Lethargy, disinterest in feeding, vomiting or diarrhoea, jaundice and alteration in respiration are common features. Irritability and abnormal muscle tone are present in one-third of neonates with meningitis. Convulsions and a bulging fontanelle are late manifestations. In older children headache, photophobia and confusion are often present, and the parents may note more subtle changes in the child's behaviour. As no one sign is specific for meningitis, a high index of suspicion is necessary in assessing any ill child. CSF examination must be readily undertaken if there is any possibility that the child might have meningitis. The presence of an alternative focus of infection such as otitis media or pneumonia should not always be accepted as the explanation for a child's illness as other infections may coexist with meningitis.

There are two main patterns of presentation of meningitis. The more common is an insidious onset after a febrile illness, with increasing lethargy and drowsiness, and is characteristic of H. influenzae infection. The second is an acute presentation with shock and signs of raised intracranial pressure [38]. Although N. meningitidis is more commonly associated with this pattern of presentation it can occasionally be seen in other forms of meningitis.

Cutaneous manifestations are an important early clue to some forms of meningitis. A rapidly spreading purpuric rash is characteristic of meningococcal septicaemia, but is also occasionally seen with pneumococcal or H. influenzae sepsis. Although viral infections may also cause rashes, the presence of petechiae or an erythematous rash in a septic-appearing child is an indication for prompt investigation and initiation of antibiotic therapy. Cellulitis, particularly buccal or orbital cellulitis characteristic of H. influenzae infection, is another important cutaneous clue to the possibility of meningitis as bacteraemia and meningitis are present at the time of diagnosis in a significant proportion of these children.

Convulsions occur in 20-30% of children with meningitis within 2 days of hospitalization. The seizures are usually generalized and do not necessarily indicate a poor prognosis. Focal seizures and focal neurological signs indicate the possible presence of cortical, venous or arterial thrombosis and cortical infarction and suggest a less favourable prognosis [39]. Febrile convulsions occurring during an upper respiratory tract infection are common, and must always be distinguished from convulsions occurring in meningitis. In older children routine lumbar puncture is unnecessary after a febrile convulsion if meningitis is not suspected clinically. However, in children under 18 months of age in whom the signs of meningitis are subtle, CSF examination may be necessary to exclude meningitis.

Laboratory investigations

Cerebrospinal fluid

The presence of meningitis, and the aetiological agent responsible, are established by examination of the CSF. Lumbar puncture should be considered in any seriously unwell child in whom the diagnosis of meningitis is entertained. Only a small proportion of the lumbar punctures (LPs) performed will give abnormal results. This is an unavoidable consequence of the difficulty in diagnosing meningitis in children on clinical grounds alone, and is justified in that the serious consequences of delayed diagnosis far outweigh the relatively minor discomfort of an LP. Lumbar puncture is generally a safe procedure but there are well recognized contraindications to the procedure: (1) the presence of raised intracranial pressure; (2) severe cardiorespiratory failure which may be accentuated by the procedure; and (3) infection in the area that the needle must traverse [38]. In considering the risks of lumbar puncture in patients with bacterial meningitis and in particular in those with a meningococcal purpuric rash, additional factors should be considered. Elevated intracranial pressure occurs in virtually all patients with bacterial meningitis [40]. It must be stressed that the presence of papilloedema is a late and therefore unreliable sign of severely elevated intracranial pressure. Raised intracranial pressure should be suspected in any patient who has a rapidly declining level of consciousness or severely depressed consciousness; in those with alterations in blood pressure or heart rate; in the presence of cranial nerve palsies; and in patients who show opisthotonic posturing. If any of these features are present the risk of cerebral herniation following lumbar puncture is considerable and the procedure should be deferred. [41]

Meningococcal septicaemia without signs of meningitis may itself be a contraindication to lumbar puncture for the following reasons: patients with a meningococcal purpuric rash are often in a state of septic shock; performing a stressful and perhaps painful procedure may cause an increase in respiratory and cardiovascular workload due to the positioning of the patient, and may result in an acute deterioration in the patient's condition; the patient may also have raised intracranial pressure as a consequence of meningitis and reduced cerebral perfusion as a result of hypotension. Lumbar puncture in these circumstances may result in acute brain stem herniation [41, 42].

The diagnosis of meningococcal infection is usually obvious in patients with a characteristic rash. Bacteriological confirmation can be obtained by blood culture or rapid antigen testing in a high proportion of individuals. Meningococcal infection can also be confirmed sero-logically by the analysis of convalescent serum for a rise in antibodies to meningococcal antigens [43, 44] and by PCR.

The presence or absence of meningitis does not alter the management of patients with meningococcal disease. Although several scoring systems utilize the presence of low CSF white cell counts as a poor prognostic feature, the same poor prognostic implications are derived from a clinical assessment of whether meningism is present and from the child's orientation and level of consciousness. The presence or absence of meningitis does not therefore alter the management of patients with meningococcal septicaemia in whom the diagnosis is suspected from the characteristic rash as the same antibiotic regime will apply to both. If it is felt necessary to obtain laboratory confirmation of meningitis, lumbar puncture should be delayed until circulatory stability has been achieved, and until any features suggesting raised intracranial pressure have been eliminated. The cellular and chemical changes will still be present in the CSF several days after the acute illness.

Based on these considerations, we believe that lumbar puncture should be undertaken with far more caution than has been previously practised. The possible risks of the procedure must be balanced against the benefits of the information which may be derived from the procedure in any patient with evidence of severe meningitis and in all patients with septic shock [43, 45].

When the LP is undertaken sufficient CSF should be removed at the time of LP to permit bacterial culture, microscopy, rapid antigen detection, analysis of protein and sugar and staining for acid-fast organisms. An additional volume should be available for viral culture, serology, fungal culture and cytology, in case the diagnosis is not established by the more routine studies.

The CSF findings characteristic of various inflammatory conditions of the brain and meninges are shown in Table 22.3. Bacterial meningitis is usually easily distinguished from viral meningitis or tuberculous meningitis by the large numbers of polymorphonuclear leucocytes, the elevated CSF protein and low glucose. However, neutrophils may predominate in the early stages of viral meningitis and tuberculous meningitis and are also found in subdural empyema. In well established meningitis the CSF contains hundreds to thousands of cells, but very early in the illness, before the meningeal response is established, the cell numbers may be only minimally increased. Any child whose initial CSF does not indicate bacterial meningitis, but whose clinical condition deteriorates, should have a repeat LP 6-12 hours after the initial examination [46, 47].

The causative organism is often identified on Gram stained smears of the CSF after centrifugation. The likelihood of visualizing the bacteria depends on the number of organisms present. Smears are usually negative when the CSF contains less than 10 cfu/ml, and are almost always positive when more than 10 cfu/ml are present. CSF should always be cultured irrespective of the number of cells or the Gram stain result.

Prior antibiotic treatment may render the CSF sterile, resulting in the dilemma of "partially treated' meningitis. Although antibiotics may prevent the bacteria from growing in culture, they seldom alter the cell number, protein concentration or glucose content of the CSF very much, and it is usually still possible to distinguish between partially treated bacterial meningitis and other forms of culture-negative meningitis [48]

A variety of rapid tests to detect bacterial antigens are available which can be performed on blood, CSF and urine, and which may be helpful in establishing a diagnosis. These include counter current electrophoresis, latex particle agglutination, and enzyme linked immunosorbent assays for the polysaccharide antigens of H. influenzae type B, group B streptococcus, S. pneumoniae and N. meningitidis groups A, B, C, Y and W 135. The latex particle agglutination tests are more sensitive than countercurrent electrophoresis, but are only positive in 85-95% of patients with H. influenzae type B meningitis, 50-75% of those with pneumococcal meningitis, and 35-50% of those with meningococcal infection [49]. The rapid antigen tests are of most help in patients with negative CSF and blood cultures, especially those who have received antibiotics prior to LP.

A number of non-specific tests such as C reactive protein, CSF lactate, CSF pH and LDH determinations have been evaluated as adjuncts to the diagnosis of bacterial meningitis. In general these tests lack specificity and none reliably distinguishes bacterial from non-bacterial meningitis.

Detection of bacterial DNA by PCR is proving to be an extremely sensitive method for confirming the diagnosis in culture negative cases, but is not yet routinely available.

Other investigations

Blood cultures should always be performed in patients with suspected meningitis. Occasionally the blood cultures may reveal the organism in patients with CSF pleocytosis and negative CSF cultures. Urinary tract infection may be the source of meningitis in children with underlying urinary tract abnormalities, in neonates, and in immunosuppressed children. Urine should always be cultured, but treatment should not be delayed if an adequate specimen cannot be promptly obtained. The blood count is of little help in distinguishing between bacterial and non-bacterial meningeal infections, but should be performed to identify the anaemia and throm-bocytopenia which occur frequently in septic children. Coagulation studies and measurement of fibrinogen and fibrin degradation products are necessary in severely ill children, and those with purpura or shock, to identify disseminated intravascular coagulation. Measurement of plasma urea, creatinine and electrolytes is necessary to identify hyponatraemia and inappropriate ADH secretion, which is a common complication of meningitis.

Skull X-ray is not routinely indicated, but X-ray of the chest should be undertaken as pneumonia frequently coexists with meningitis, particularly when pneumococcus or H. influenzae is the cause. CT scanning is not required in uncomplicated cases, but may be required in patients with focal neurological signs, and in those in whom a focal CNS infection such as subdural empyema or brain abscess is suspected (Fig. 22.2).

Treatment

The optimal antibiotic regime for treatment of meningitis in children remains a subject of considerable debate, despite the prevalence of meningitis and the availability of an ever-increasing number of potent antibiotics [50, 51, 52]. This is partly due to the variety of different bacteria which cause meningitis, and the changing patterns of antibiotic sensitivity [53, 54]. In addition, the fact that the mortality and morbidity from meningitis have not altered appreciably in the past few decades has stimulated continued efforts to find better forms of treatment[46, 55].

In selecting an antibiotic regime for initial treatment of meningitis, consideration must be given to: (i) the likely pathogens involved at any age; (ii) the changing patterns of antibiotic resistance; and (iii) the pharmacological properties of the antibiotics available, and in particular their ability to penetrate into the CSF [3, 52].

The age of the affected child is the most important factor in predicting the likely pathogens responsible for meningitis[2, 56]. In the first month of life, the antibiotics chosen must cover group B streptococci, E. coli, other Gram-negative organisms such as Klebsiella, and Listeria monocytogenes, which are the usual organisms responsible. In infants and young children, H. influenzae, S. pneumoniae and N. meningitidis account for the vast majority ofmeningeal infections, and initial antibiotic treatment must adequately cover all three of these pathogens[2, 46]. H. influenzae meningitis becomes less common after age 5, and is very infrequent after age 10. Thus antibiotic treatment for teenage children need not include cover for this organism. Although separation of the pathogens responsible for neonatal meningitis from those affecting older children is a useful guide to appropriate antibiotic therapy, considerable overlap occurs in infants 1-3 months of age who may be affected by both the 'neonatal' pathogens and those affecting older infants [57].

Immunocompromised children are susceptible to a very wide range of meningeal pathogens. Organisms of low virulence as well as those causing meningitis in normalchildren may invade the CNS. Antibiotic treatment in these patients must be individualized and the cover extended to include a greater range of pathogens. In children with neurocutaneous fistulae, CSF shunts and recent neuro-surgical procedures, skin organisms including coagulase-negative staphylococci, Staphylococcus aureus and diph-theroids are common causes of meningitis and treatment must include cover for these bacteria [37, 58].

Properties of the available antibiotics

The ideal antibiotic for treatment of meningitis should (i) have bactericidal activity against all the expected pathogens; (ii) penetrate into the CSF in sufficient concentrations to achieve several times the minimum bactericidal concentration of the infecting agents; and (iii) have a high therapeutic to toxic ratio. Additional factors for consideration include cost and the likelihood of inducing antibiotic resistance [59].

Table 22.4

shows the penetration of commonly used antibiotics into the CSF. Chloramphenicol and tri-methoprim sulphamethoxazole enter the CSF in concentrations 30-50% of the serum concentration, irrespective of whether or not the meninges are inflamed. The penicillins, third-generation cephalosporins and vancomycin enter the CSF adequately only in the presence of meningeal inflammation, and the aminoglycosides, first-generation cephalosporins and erythromycin penetrate poorly even in the presence of inflamed meninges.

Chloramphenicol is bactericidal for H. influenzae, N. meningitidis and S. pneumoniae. However, it is bacteriostatic against the aerobic Gram-negative bacilli, and is not generally effective as a single agent in Gram-negative bacillary meningitis, a factor which reduces its usefulness in neonatal meningitis [60]. Although chloramphenicol has been the mainstay of treatment for meningitis beyond the neonatal period for many years, the emergence of chloramphenicol-resistant H. influenzae and the potential for marrow toxicity are drawbacks to its use. The variable metabolism of the drug in the neonatal period and in children with liver dysfunction, and the necessity to monitor serum levels, are additional disadvantages.

Ampicillin was a safe and effective single agent for treatment of meningitis in infants and children until the emergence of beta-lactamase-producing H. influenzae. Ampicillin-resistant H. influenzae are now so prevalent that the drug can no longer be used alone for initial treatment and it is usually administered in combination with chloramphenicol until the antibiotic sensitivities of the causative bacteria are known [61]. Non-beta-lactamase-producing H. influenzae can then be treated with ampicillin alone, and ampicillin or penicillin remain effective treatment for pneumococcal or meningococcal meningitis. The recent increase in penicillin-resistant S. pneumoniae may eventually further limit the use of the penicillins [54].

The first-generation cephalosporins proved unreliable for treatment of meningitis. Furthermore, cefuroxime, a second-generation cephalosporin, although active against H. influenzae, S. pneumoniae and N. meningitidis (as well as against Staph. aureus), has proved unreliable as a single agent for initial treatment of meningitis in older infants and children and its use has been associated with relapses and delayed CSF sterilization. Its lack of reliable activity against the Gram-negative bacilli has limited its use in neonatal meningitis [62, 63].

The third-generation cephalosporins cefotaxime, ceftriaxone and ceftazidime have greatly enhanced the armamentarium against both the neonatal meningeal pathogens and those affecting older children [64, 65, 66]. All three agents are extremely active against S. pneumoniae, H. influenzae (including beta-lactamase producing strains) and N meningitidis, as well as against E. coli, Klebsiella and Proteus. They penetrate into the CSF well, achieve concentrations well above the minimum bactericidal concentrations of the usual pathogens, and resistance to them is rare [3]. In addition, they are very safe, and monitoring of serum concentrations is not required. While the third-generation cephalosporins in many ways appear to be ideal agents for initial treatment of meningitis, they are considerably more expensive than the conventional drugs. Furthermore, they lack activity against L. monocytogenes, and are unreliable against Enterobacter. Only ceftazidime is active against Pseudomonas aeruginosa.

Aminoglycosides have for many years been the only agents available for treatment of Gram-negative bacillary meningitis in the neonatal period, despite their poor penetration into the CSF, potential for renal and ototoxicity and their narrow therapeutic to toxic ratio. It is perhaps surprising that they are effective in neonatal meningitis as they achieve concentrations in the CSF scarcely above the minimum inhibitory concentration of E. coli and other Gram-negative bacilli [67, 68].

Choice of antibiotic for initial therapy(Table 22.5)

Neonatal meningitis

The range of Gram-negative and Gram-positive organisms responsible for meningitis in the neonatal period has necessitated the use of a combination of antibiotics. An aminoglycoside-ampicillin combination has been the standard treatment for over 20 years, despite the poor CSF penetration of the aminoglycoside [46, 51]. Attempts to improve the outcome of neonatal meningitis by direct instillation of the aminoglycoside into the CSF have not been successful [68, 69]. Multicentre trials comparing the outcome of neonatal meningitis treated by the systemic therapy alone, or by systemic antibiotics plus intrathecal aminoglycosides, showed no improvement in outcome when intrathecal aminoglycosides were given by either the lumbar or intraventricular route. In fact, mortality was increased in patients receiving intraventricular antibiotics [69]. Although there are some other reports of successful intraventricular administration of aminoglycosides [70], the invasiveness of the procedure and the possibility that the poor outcome in the infants receiving intraventricular treatment might be due to a direct toxic effect of the antibiotic suggests that intraventricular aminoglycosides should only be used in exceptional circumstances[67].

Chloramphenicol, either as a single agent or in combination with ampicillin, has been used for initial treatment of neonatal meningitis in Europe. However, as this combination is unreliable and potentially antagonistic against Gram-negative bacilli, it should probably not be used [71].

The third-generation cephalosporins should theoretically offer a major advance in the treatment of neonatal meningitis. They are active against the common neonatal pathogens including group B streptococci, E. coli and other Gram-negative bacilli, with the exception of L. mono-cytogenes and enterococci. Their safety and excellent CSF penetration are other advantages. However, there is so far little evidence that the outcome of neonatal meningitis is improved by their use [72, 73]. Most neonatal units now use third-generation cephalosporins as their standard therapy. Cefotaxime has been the one most extensively used, with ceftazidime being used in situations where Pseudomonas aeruginosa is suspected. Ceftriaxone is best avoided as it is excreted in the bile and is more likely to alter the bowel flora [74]. The major drawback in the use of the third-generation cephalosporins in the treatment of neonatal meningitis is their lack of activity against L. monocytogenes and enterococci. They must therefore be used in combination with ampicillin unless infection with these pathogens is unlikely or has been excluded [46]

Meningitis in infants and older children

A combination of chloramphenicol and ampicillin (orpenicillin) remains an acceptable initial therapy for bacterial meningitis beyond the neonatal period [46, 75], particularly in less developed countries where the costs of third generation cephalosporins are prohibitive. Once the identity of the organism is known, ampicillin alone is continued for non-beta-lac-tamase-producing H. influenzae and ampicillin or penicillin for N. meningitidis or S. pneumoniae. Chloramphenicol is used alone for ampicillin-resistant H. influenzae. Although this regime has been of proved effectiveness, the potential toxicity of chloramphenicol, the need to monitor levels and the recent emergence of chloramphenicol-resistant H. influenzae have resulted in alternative regimes being advocated.

The third-generation cephalosporins are now widely used as single agents for the treatment of meningitis in children [75, 76]. Cefotaxime and ceftriaxone have been shown to be safe and effective treatment for the three common childhood meningeal pathogens. In most studies the prognosis in patients treated with these drugs is no better than in those treated with standard therapy [65, 66, 77, 78]. However, a recent Finnish study suggested that cefotaxime or ceftriaxone were more effective than ampicillin and chloramphenicol combinations in sterilizing the CSF (Peltola et al 1989). Cefuroxime, a second generation cephalosporin, has also been widely used as single-agent therapy, particularly in Europe. However, reports of delayed CSF sterilization and occasional relapses after treatment have led many American experts to avoidcefuroxime in favour of the third-generation cephalo-sporins [51, 63].

The cost of the third-generation cephalosporins is considerably greater than that of ampicillin-chlo-ramphenicol combination. However, the reduction in nursing and pharmacy time required for administration of one rather than two drugs intravenously, and the avoidance of drug level monitoring, may make the single agent not much more expensive than conventional therapy. In countries where chloramphenicol-resistant H. influenzae are becoming more prevalent the third generation cephalosporins are the obvious choice for initial treatment. The emergence of penicillin-resistant pneumococcae has necessitated altered treatment regimes in some countries such as South Africa, Spain and parts of north America. Although most pneumococcae remain sensitive to third generation cephalosporins, there are currently increases in the incidence of pneumococcae resistant to both cephalosporins and penicillin. These strains are difficult to treat, and Vancomycin is one of the few agents active against them. In areas with a high prevalence of resistant pneumococcae, Vancomycin is often added to Cefotaxime or Ceftriaxone until sensitivities have been established. Vancomycin penetrates into the CSF poorly, and Rifampicin may be helpful in combination with Vancomycin for treatment of resistant pneumococcal infections.

Anti-Inflammatory Treatment

The growing evidence that the damaging process within the brain is mediated by activation of host inflammatory pathways, triggered by the release of endotoxin and other bacterial constituents, has led to the hypothesis that injury to the brain may be reduced by the use of anti-inflammatory treatment [29, 79, 80]. In experimental animals, the inflammatory process can be reduced using agents which act to neutralize endotoxin such as poly-myxin B [81] those which block the binding of endotoxin to macrophages, such as bactericidal permeability increasing factor (BPI)[82] and anti-CD 14 antibodies [83]; antibodies directed against cytokine mediators such as ILl or TNF [84, 85] antibodies directed against neutrophil adhesion molecules [86, 87] or pharmacological agents which inhibit neutrophil and macrophage activation, such as steroids, pentoxiphylline or non-steroidal anti-inflammatory agents[88, 89, 90].

While several of these anti-inflammatory mediators have shown benefit in animal experiments, convincing evidence for a beneficial effect from steroids has now emerged from a series of clinical trials[43].

The initial studies conducted in the USA demonstrated a clear benefit from the use of dexamethasone in reducing the severity of neurological sequelae, particularly deafness[80]. Subsequent studies in Costa Rica[40], Egypt [90] and Switzerland have all reported a beneficial effect from the use of dexamethasone in reducing neurological sequelae. Most of the patients in these published studies have suffered from H. influenzae or S. pneumoniae meningitis. Firm conclusions of the efficacy of dexamethasone in reducing neurological damage in patients with men-ingococcal meningitis cannot be derived from these studies. However, the pathophysiological events occurring in meningococcal meningitis are unlikely to differ significantly from those that are seen in other forms of bacterial meningitis. For patients who present with meningococcal meningitis without septic shock, treatment with dexamethasone is recommended. The benefit appears to be greatest if it is administered early in the course of the illness, preferably prior to antibiotic administration. Current recommendation would therefore be to administer dexamethasone in a dose of 0.15 mg/kg, 6 hourly for 4 days starting prior to or simultaneously with the first dose of antibiotics.

There have been few side effects documented in patients receiving dexamethasone. In particular there have been no reports of delayed CSF sterilization or treatment failure, although gastrointestinal bleeding has been observed in a small proportion of patients.

Based on studies in animals, a variety of other anti-inflammatory agents are likely to be of benefit in reducing central nervous system injury, but there have been no clinical studies on which to base recommendations for their routine use.

Supportive care and management of complications

There has been increasing recognition that antibiotic administration is only one component of the overall management of patients with severe meningitis. Neurological derangement often coexists with circulatory insufficiency, impaired respiration, metabolic derangement and convulsions. Measures to detect and correct any co-existing physiological derangement are important in improving the prognosis.

All patients with invasive meningococcal infection may deteriorate suddenly. They should therefore be managed in a facility which can readily institute intensive care. Patients with severe meningitis or septicaemia who are first admitted to hospitals which lack intensive care facilities should be stabilized and then transferred to more specialized units by staff experienced in resuscitation and transport of critically ill children.

Management of Children with Raised Intracranial Pressure

All patients with bacterial meningitis are likely to have raised intracranial pressure as part of their disease process. In a recent study the mean opening pressure at the time of lumbar puncture was 180 ± 70 mm of water, more than twice the upper limit of normal in infants and children[40]. Signs of raised intracranial pressure include an altered level of consciousness, altered pupillary responses, hyper or hypotension, reduction in resting pulse rate and altered respiratory pattern. Papilloedema is often a late sign of raised intracranial pressure. Raised intracranial pressure should be suspected in any patient with severely depressed levels of consciousness and measures should be instituted in order to prevent brain stem compression and herniation. Diagnosis of raised intracranial pressure should be based on clinical suspicion rather than the use of CT or MRI scans [91]. Both methods are insensitive in predicting raised intracranial pressure, while they are useful for excluding alternative diagnoses in neurologically impaired patients[92, 93]. CNS imaging is thus not routinely required in the management of patients with severe meningitis.

The primary therapeutic objective in the management of raised intracranial pressure is to preserve oxygen and nutrient delivery to the brain. Relatively simple interventions to optimize respiration and cardiac output and prevent metabolic abnormalities may be as important as measures to directly reduce intracranial pressure. In patients who are comatose and suffering from raised intracranial pressure, obstruction to the airway, cessation of respiration or convulsions may result in both hypoxia and hypercapnia, which have disastrous effects on brain per-fusion and enhance the development of cerebral oedema. Maintenance of the airway, elective ventilation to optimize respiration and control of convulsions are important interventions. Although most decisions on the use of measures to reduce raised intracranial pressure are taken on the basis of clinical criteria, direct measurement of intracranial pressure has been advocated by some authorities, and should logically be of help in defining the therapeutic interventions required. Unfortunately, there have been no studies which indicate that intracranial pressure monitoring reduces mortality from meningitis [94]

Simple measures to reduce intracranial pressure include nursing the patient in a head-up position of 20-30 degrees from horizontal and nursing in a quiet environment. Other important interventions include the use of osmotic agents, fluid restriction and control of cerebrovascular tone through manipulation of arterial CO 2 concentration. Extra-vascular fluid accumulation and thus intracranial pressure can be reduced through the use of osmotically active agents such as mannitol. An infusion of mannitol in a dose of 0.25-1 g/kg results in rapid shift in fluid from the extravascular to the intravascular space and may be associated with a prompt reduction in intracranial pressure [94]

In view of the rapid action of mannitol, it may be life saving in patients with impending cerebral herniation, and it is often of use while other measures such as airway control, artificial ventilation and fluid restriction are being initiated. The use of mannitol is often combined with fluid restriction to 50-70% of maintenance requirements, together with the use of frusemide or other loop diuretics to maintain plasma osmolality between 295 and 305 mmol/l. In areas of brain with extensive vascular injury, mannitol may accumulate extravascularly, possibly worsening brain oedema. Furthermore, repeated doses may cause a hyperosmolar state. Together with fluid restriction this may impair cardiac output. Mannitol should therefore be used with caution, and prolonged use of this agent should be used only in carefully monitored situations.

In children with Cushing's triad (pupillary changes, hypotension and bradycardia, with or without respiratory insufficiency), or a Glasgow coma score less than 8, urgent endotracheal intubation and artificial ventilation should be carried out, both to protect the airway and to prevent an acute rise in intracranial pressure due to further increases in PaCO2. Use of hyperventilation as a treatment for raised intracranial pressure has been the subject of much recent controversy [95, 96].

Based on the linear correlation between PaCO2 and cerebral blood flow, hyperventilation to reduce PaCO2 may be effective in decreasing the volume within the vascular compartment of the intracranial cavity, and therefore in reducing intracranial pressure. It is not clear, however, whether such reduction in cerebral blood flow is beneficial, as it may reduce the oxygen supply to critically dependent areas. Moreover there is evidence that cerebral autoregulation and CO 2 reactivity are impaired or absent in injured areas of brain. Hyperventilation as a measure to reduce intracranial pressure should therefore be used with caution and with careful monitoring. Modest reductions in PaCO 2 to between 3.5 and 4.5 kPa is usually advocated and should be monitored by repeated blood gases or by enditidal CO 2 measurement. More severe hyperventilation should only be undertaken in cases where there is evidence of impending brain stem herniation.

In general, patients with meningitis should receive a modest restriction of fluid intake. However, many patients who are admitted with bacterial meningitis have been vomiting or have reduced fluid intake in the days preceding admission. Further restriction of fluid intake may severely i mpair circulating volume and reduce cardiac output. Most children with meningococcal meningitis are hypovolaemic at presentation due to increased capillary permeability, reduced fluid intake prior to presentation, and increased fluid losses due to vomiting and fever. Emphasis on the possibility of inappropriate antidiuretic hormone secretion has in the past led to the practice of fluid restriction in all patients with meningitis, even in the face of severe hypovolaemia. Recent studies indicate that the increased levels of antidiuretic hormone, which are seen in individuals with meningitis, represent an appropriate response to dehydration (Powell et al 1990). With adequate rehydration these levels return to normal. Correction of hypovolaemia, preferably with colloid infusions, will improve cardiac output and may have a beneficial effect on cerebral blood flow. In patients with incipient shock, the use of inotropic agents as well as colloid infusions may be important in optimizing cerebral perfusion.

Sedation and Control of Convulsions

A child who has a significantly reduced level of consciousness due to bacterial meningitis should not be sedated, even if extremely irritable or combative. Irritability or combativeness may indicate hypoxia due to reduced respiratory drive. The addition of hypnotic or tranquillizing agents may precipitate acute respiratory failure or respiratory arrest, or cause a further rise in intracranial pressure. Simple analgesics or antipyretic agents alone should be used in those children who are not critically ill. Patients who require endotracheal intubation and artificial ventilation should receive a combination of drugs to provide analgesia, amnesia and sedation, together with a muscle relaxant. This combination will decrease intracranial pressure. A commonly used combination is morphine in a dose of 0.02 mg/kg/h, midazolam (2-6 µg/kg/min), and atracurium at 10-30 µg/kg/min.

Barbiturates have been used to treat severely raised intracranial pressure that is refractory to other forms of therapy (Dean et al 1992). However, large doses of agents such as thiopentone may severely impair cardiac output and should only be used in patients with adequate cardiovascular stability and with extremely careful monitoring. Thiopentone is particularly useful for induction of anaesthesia prior to endotracheal intubation in patients with acutely raised intracranial pressure.

Seizures occur within 48 hours of presentation in 20-30% of patients with bacterial meningitis. Seizures are especially dangerous in patients with raised intracranial pressure, as they will result in extreme metabolic demands, an increase in cerebral blood flow and may precipitate a further rise in intracranial pressure. Convulsions may be difficult to detect in patients who are pharmacologically paralyzed for artificial ventilation. In such patients electrical monitoring should be used to detect seizure activity. The use of anticonvulsant treatment in non-ventilated patients may precipitate respiratory arrest and careful observation of respiration and ventilation could be undertaken during the treatment of seizures. Short acting agents such as diazepam or paraldehyde can be used to control acute seizures, and barbiturates or phenytoin are generally used for longer term control.

Other complications

Fever persists for 5 days in the majority of children and for 5-9 days in 13% of patients. Fever persisting beyond 8 or 9 days is often associated with intercurrent infection, another focus such as arthritis or osteomyelitis, thrombophlebitis, subdural effusions or empyema. A diligent search for such complications is necessary in patients with persisting fever. CSF examination after the initial LP is unnecessary unless the condition fails to improve over 24-72 hours of therapy.

Subdural effusions seen on CT scanning are present in a high proportion of children with meningitis, particularly those with H. influenzae meningitis, and are not usually associated with signs or symptoms[97]. They usually resolve spontaneously and aspiration is not required unless there is a clinical suspicion that the fluid is infected, or unless clinical signs of raised intracranial pressure or an intracranial expanding mass lesion are present. Brain abscess rarely follows meningitis due to the usual childhood pathogens, but is not infrequent after neonatal meningitis, and meningitis related to neurosurgical procedures or embolic congenital heart disease.

Prognosis

The mortality from bacterial meningitis has not fallen appreciably in the past two decades and remains at 15-20% for neonatal meningitis and less than 10% for meningitis in infants and older children (Feigin 1987). As many as 50% of survivors have some sequelae of the disease. In a prospective study of the outcome ofH. influenzae meningitis, Sell reported that 28% of children who recovered from meningitis had significant handicaps including hearing loss (10%), language disorders (15%), impaired vision (4%), mental retardation (10%) and seizures (2-8%) (Sell 1983, Tejani et al 1982). Although other studies have also shown that a high proportion of children with meningitis have neurological defects present at the time of discharge from hospital, considerable improvement may occur with time, and an optimistic view should be taken in discussions with the parents. Feigin et al have reported that whereas one-third of children have neurological deficits on discharge from hospital, only 11% had deficits detectable 5 years later [16, 98, 99].

Significant hearing loss is one of the most common sequelae of meningitis, occurring in 2.4-29% of cases. The mechanisms of hearing loss include spread of infection along the auditory canal and cochlear aqueduct, serous or purulent labyrinthitis, as well as cortical vascular damage. Because of the prevalence of deafness all children with meningitis should have their hearing tested on follow-up.

Prevention

In view of the prevalence and catastrophic nature of meningitis in children, prevention by vaccination would be a desirable goal. The success of the conjugate vaccine against Haemophilus influenzae type B in reducing the incidence of HIB meningitis has raised hopes that other forms of meningitis will be preventable in future. However, there remain major difficulties in development of effective vaccines against other meningeal pathogens.

The large number of strains of pneumococcus which may cause meningitis have made vaccination against this organism difficult. Conjugate vaccines against a combination of pneumococcal capsular antigens are currently being evaluated. Effective vaccines against meningococcal groups A and C are available [100, 101] and are recommended for travellers to countries where epidemics of meningococcal meningitis are occurring. However, most cases of sporadic meningococcal meningitis in developed countries are due to group B men-ingococcus, for which no effective vaccine is yet available. The immunogenicity of capsular polysaccharides in young children can be enhanced by coupling them to protein antigens. This strategy may ultimately permit effective vaccines against S. pneumoniae and meningococcus to be developed for use in young children[102].

Close contacts of patients with meningococcal infection should receive prophylaxis with rifampicin as the secondary attack rate in family members is about 1 %. Children under 5 years of age who are in close contact with patients developing H. influenzae B meningitis also have a significant risk of developing meningitis. Rifampicin prophylaxis is therefore recommended for family members of the index case if there are other children under 5 years of age in the family[46, 103].

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