Infections of the Nervous System: Butterworths International Medical Reviews

UK

1

Introduction

Peter G.E. Kennedy and Richard T. Johnson

Publisher Summary

This chapter discusses important aspects of infectious diseases of the nervous system. Three striking developments on the subject of central nervous system (CNS) infections are: (1) understanding of disease processes provided by new technologies; (2) new pathogens and the widening spectrum of disease caused by familiar pathogens; and (3) new therapeutic tools. The pathogenesis of many infective neurological diseases has been clarified by the use of powerful molecular biological techniques and by new methods of imaging the human brain. The remarkable diversity of infectious agents that can affect the nervous system has been increasingly recognized by clinicians and scientists alike. Agents such as spirochetes and fungi are known to cause neurological disease. Spirochete Borrelia burgdorferi has been shown to cause Lyme disease and some of its neurological features are reminiscent of neurosyphilis. Significant advances in the treatment of infectious neurological diseases have also been noteworthy. In general, there are two kinds of treatment—(1) established, well-recognized therapy for newly recognized diseases, and (2) newly developed treatment for diseases, which have been recognized for many years.

Three striking developments on the subject of central nervous system (CNS) infections have been evident over the last decade. These include: understanding of disease processes provided by new technologies; new pathogens and the widening spectrum of disease caused by familiar pathogens; and new therapeutic tools.

First, the pathogenesis of many infective neurological diseases has been clarified by the use of powerful molecular biological techniques and by new methods of imaging the human brain. Genetic mapping, monoclonal antibodies, immunocytochemistry, and in situ and Southern blot hybridization have been used to investigate the factors controlling neurovirulence of bacteria and viruses; they have provided new information on the mechanisms of the demyelinating encephalomyelitis that can follow viral infections, and they have given new insight into the protean neurological manifestations of varicella-zoster virus infections and slow infections of the nervous system. Computerized tomography has clarified both the pathogenesis and the management of tuberculous meningitis and neurocysticercosis, and dispelled the assumption that brain oedema is the central problem in cerebral malaria. Magnetic resonance imaging may provide non-invasive diagnosis for postinfectious encephalomyelitis and progressive multifocal leucoencephalopathy and detect early central nervous system involvement in the acquired immunodeficiency syndrome (AIDS).

Second, the remarkable diversity of infectious agents that can affect the nervous system has been increasingly recognized by clinicians and scientists alike. Agents such as spirochaetes and fungi have been known to cause neurological disease for many decades. The range of species within these different groups has proved to be wider than anticipated in the past; thus the spirochaete Borrelia burgdorferi has been shown to cause Lyme disease, and some of its neurological features are reminiscent of neurosyphilis. The increased therapeutic immunosuppression and cytotoxic drugs have amplified the importance and the range of fungal infections, as well as selective viral and bacterial infections. Botulism has recently been recognized to occur not only from contaminated food, but also from the absorption by toxin formed in the gastrointestinal tract. It has become the only documented cause of the sudden infant death syndrome.

AIDS, which probably represents the most formidable challenge which the world’s public health services have ever had to face, has highlighted the extent to which an unusual organism can cause neurological disease and immunosuppression in individuals. Whether, as many suspect, the causative agent in human immunodeficiency virus (HIV) became prevalent in man by extending its host specificity from the African green monkey, or whether it became a human pathogen via some other mechanism is not yet known. However, it is clear from retrospective and epidemiological studies that the disease is new. In view of the estimates of the likely incidence of AIDS over the next decade, one can only hope that intensive current investigative, preventative and therapeutic measures employed by scientists, governments and public health services will have a significant impact in halting the spread of this disease. It is particularly sobering to note that many of the neurological complications may occur in individuals who do not have established AIDS, but the AIDS-related complex, or those with seropositivity for human immunodeficiency virus alone without other manifestations of the syndrome.

Third, significant advances in the treatment of infectious neurological diseases have also been noteworthy. In general, these have been of two main kinds: established, well-recognized therapy for newly recognized diseases, and newly developed treatment for diseases which have been recognized for many years. In the first category can be included penicillin therapy for Lyme disease, in which a good clinical response can be anticipated in the majority of patients. The second category includes recent antiviral therapy such as acyclovir for herpes simplex encephalitis and the remarkable efficacy of the helminthicide praziquantel in treating CNS cysticercosis. In addition, each new generation of antibiotics has potential relevance to the treatment of acute and chronic bacterial infections of the CNS. It can be readily appreciated that these three advances are not mutually exclusive. For example, an increasing understanding of pathogenesis is likely to lead to more rational therapy. Thus, the recent demonstration of a lack of cerebral oedema in patients with cerebral malaria has led most clinicians to abandon dexamethasone therapy in this condition.

It has been our intention in this volume to choose topics which reflect these various developments. In particular, we wished to illustrate the major theme of the series, namely to highlight areas or subjects in which significant advances have been made which also have relevance to the treatment of patients. We believe that this volume covers a number of important aspects of infectious diseases of the nervous system, but in view of the selective nature of the reviews we have obviously not attempted to produce a comprehensive review of the subject.

Our intention is that our selection of topics will appeal, not only to clinical neurologists and neurosurgeons, but also to general physicians, those involved primarily with infectious diseases, psychiatrists and microbiologists. Clearly, the future promises to hold many challenges for those concerned with investigating and treating neurological infections. We hope that this book will convey some of the excitement which many of us feel as we brace ourselves to face these challenges. Finally, we would like to thank our contributors for the rigour of their contributions.

2

Acute bacterial meningitis

J.S. Kroll and E.R. Moxon

Publisher Summary

This chapter reviews some aspects regarding the host and microbial determinants involved in bacterial meningitis. It also discusses current knowledge of its epidemiology, pathophysiology, diagnosis, and prevention. The determinants required for a bacterium to run the gauntlet of host defenses are those operative at five different stages in the pathogenesis: (1) survival in the nasopharynx, (2) invasion from the respiratory tract to the blood stream, (3) survival in the blood, (4) invasion of the blood-CNS barriers, and (5) survival in the CNS. Successful nasopharyngeal colonization may involve specific adhesions to epithelial cells. One bacterial component involved in this complex interaction is the pilus—a filamentous protein structure that extends from the bacterial outer surface. In adults and older children, meningitis usually presents with characteristic symptoms and signs. These include fever, headache, stiff neck, vomiting, and mental dysfunction ranging from lethargy to coma. Focal neurological signs are unusual; thrombophlebitis of major vessels may result in focal deficits and seizures, however, these are relatively uncommon early in the illness. In the management of the septic patient with meningitis, therapeutic maneuvers directed at sustaining cardiorespiratory function and adequate tissue perfusion take precedence over the administration of specific antimicrobial agents. Septic shock may be refractory to conventional volume replacement and pressor therapy.

INTRODUCTION

There have been substantial additions to our understanding of the biology of central nervous system (CNS) infections which are relevant to clinicians confronted by, and concerned with, the many problems inherent in their diagnosis and management.

Bacteria may cause acute infections of the CNS as a result of direct implantation, contiguous infection from a local septic process or an infected foreign body (e.g. a cerebrospinal fluid shunting device), or by haematogenous spread. CNS derangement may also occur by the action of neurotoxins produced at a distant focus of infection or as the result of the systemic effects of septicaemia.

The propensity of bacterial meningitis to cause death or permanent neurological sequelae underlies the critical importance of biomedical research into these problems.

In this chapter, some aspects of the present understanding of the host and microbial determinants involved in bacterial meningitis are reviewed, emphasizing current knowledge of its epidemiology, pathophysiology, diagnosis and prevention.

EPIDEMIOLOGY

National surveillance of the organisms responsible for bacterial meningitis has produced information of considerable practical importance and has proved to be a vital tool in defining the relative incidence of the major causes of meningitis (Figure 2.1). Such data as age-specific attack rates, antibiotic susceptibility, and the prevalence and geographical distribution of important phenotypic characteristics, e.g. capsular type, are critical for the implementation of sensible antibiotic policies and for planning and targeting preventive strategies such as immunoprophylaxis and chemoprophylaxis. Examples of the sort of information documented include the emergence since about 1973 of β-lactamase-producing Haemophilus influenzae, now accounting for about 20% of the type b strains causing meningitis in North America and about 14% of strains in the UK. Monitoring of chloramphenicol resistance shows this still to be rare in most Western countries, except Spain, where in the vicinity of Barcelona more than 50% of H. influenzae type b strains are chloramphenicol resistant (Campos, Garcia-Tornell and Sanfeliu, 1984). The importance of monitoring trends for an increase in chloramphenicol resistance is apparent since the drug is currently the mainstay of treatment for H. influenzae meningitis. Group B streptococci aand meningococci remain susceptible to penicillin, but occasional (about 1%) strains of pneumococci are relatively resistant to penicillin and therapeutic failures have been reported (Jackson et al., 1984). An outbreak of multiply resistant pneumococci causing several cases of meningitis in South Africa seems fortunately to have proved an exceptional occurrence (Editorial, 1977). The multiple antibiotic resistance patterns of enteric bacilli, especially Escherichia coli, which account for about one-half of the cases of neonatal meningitis and many instances of nosocomial meningitis in adults, poses a particularly difficult problem which is discussed later.

Figure 2.1 Relative incidence of aetiological agents causing bacterial meningitis. Total number of cases reported: 7605. (Reprinted with the kind permission of Dr N. Noah, Public Health Laboratory Service, Colindale, London, UK from Laboratory reports 1980–1984, England, Wales and Ireland)

In addition to standard reporting of the kind described above, a variety of laboratory techniques such as outer-membrane protein (Barenkamp, Granoff and Munson, 1981) and isoenzyme typing (Musser et al., 1985) are being applied in epidemiology. This has, for example, allowed the identification and tracking of a particular strain of meningococcus (group B, serotype 15:P1.16) of great concern in Europe. This strain has resulted in a prolonged epidemic in Norway and is currently the cause of substantial concern in the UK (Frasch, Zollinger and Poolman, 1985). The recognition that particular surface polypeptides are characteristic of this strain may be a prime consideration in developing a successful vaccine, since it belongs to serogroup B and immune responses to this capsular polysaccharide are particularly poor.

PATHOGENESIS

Any bacterium may cause meningitis, as evidenced by clinical experience and animal experiments, but in practice only a few do so consistently in humans. Although anatomical defects, congenital or as a result of head injury or neurosurgery, provide an obvious route for any organism to enter the CNS, most bacterial meningitis occurs in the absence of any such obvious breach. This suggests that such bacteria must possess special virulence factors which facilitate entry into the CNS, well protected as it is from infection by the blood–brain barrier.

The upper respiratory tract is the usual site for the initial acquisition of the bacteria most commonly implicated in causing meningitis. In animal experiments carried out to study the pathogenetic sequence of events following atraumatic nasopharyngeal colonization with such organisms, infant rats were inoculated intranasally with type b H. influenzae. Large numbers of organisms were seen on oral and nasopharyngeal mucosal surfaces and within minutes there was bacterial penetration of the submucosal epithelium (Ostrow et al., 1979).

Bacteraemia is an extremely common, although not invariable, accompaniment of the acute phase of pyogenic meningitis, consistent with the idea that bacteria spread from an initial site of mucosal or skin colonization to the meninges by haematogenous dissemination. On the other hand, the association of bacteraemia with meningitis could be as a secondary event, for once bacteria enter and proliferate in the subarachnoid space, secondary spread to the bloodstream is virtually inevitable. Experiments in animal models suggest that bacteraemia arises by both mechanisms, but that bacteria reach the CNS as a result of a primary bacteraemia rather than by contiguous spread of organisms from the nasopharynx, for example through the cribriform plate; in experiments on infant rats, bacteraemia preceded the detection of bacteria in the CNS by several hours (Ostrow et al., 1979).

Experimental and clinical evidence suggest that the choroid plexus is the favoured site of bacterial entry (Scheifele et al., 1980). The mechanisms by which bacteria breach the blood–brain barrier are poorly understood. Intercellular tight junctions normally act to exclude particles such as bacteria, but the observation that certain molecules, excluded in adults, enter the immature brain more easily has led to the suggestion that the blood–brain barrier in infants may be more susceptible to the passage of micro-organisms, and that this might underlie the increased incidence of bacterial meningitis in this age group. In fact, there is little evidence to support this contention – both functional assays and microscopic analysis indicate that the tight junctions are intact from a very early stage in development. However, it is interesting that the tight junctions of choroidal epithelium develop relatively late in gestation and this may be relevant to meningitis occurring in premature infants (Rapoport, 1976).

Rather than relative deficiencies in the blood–brain barrier, a crucial factor is more likely to be the substantially greater susceptibility of the young infant to bacteraemia. In experimental infection, a critical magnitude of bacteraemia (greater than 100 organisms/ml) is necessary, although not sufficient, for the occurrence of meningitis – the probability of meningeal infection correlates directly with the magnitude and duration of bacteraemia (Moxon and Ostrow, 1977). In neonates the insufficiency of host opsonophagocytic defences allows a critical bacteraemia to develop relatively easily. In older children and adults, the age-specific decline in incidence of meningitis correlates with acquisition of adequate humoral defences, and those cases that occur are, in general, caused by pathogens endowed with an ability to evade opsonophagocytosis.

It has been proposed, in summary, that in the context of a substantial bacteraemia, microbial factors, acting directly and also via the triggering of inflammatory mediators, bring about an alteration in tight-junctional integrity, so facilitating the entry of bacteria (Scheid, 1985). Once bacteria penetrate the CNS, the meagre amounts of opsonins and the paucity of neutrophils – typically absent in CSF samples taken early in a case of meningitis – provide a permissive environment for microbial proliferation. Neutrophils do not appear to exert any substantial rein on bacterial growth in the CSF, but may be important in limiting secondary bacteraemia. Removal of bacteria depends, in part, upon removal of CSF by bulk flow at arachnoid granulations, but this clearance mechanism becomes impaired in established meningitis since smooth arachnoid cells and their villi become covered by a diffuse coagulum of fibrin strands and inflammatory cells. The resulting picture is one of bacterial proliferation in blood and CSF, the latter also acting as a source of secondary bacteraemia. Indeed, death from overwhelming sepsis may abrogate the most strenuous therapeutic efforts and render the treatment of the meningitis and cerebral involvement an essentially academic exercise. However, in most cases, affected individuals survive the potentially fatal consequences of bacteraemia and the physician must consider the management of an encephalopathic illness of varying severity whose pathophysiological basis is complex.

DETERMINANTS OF VIRULENCE

The scheme depicted in Figure 2.2 indicates the sequential stages involved in the pathogenesis of haematogenous meningitis. The determinants required for a bacterium to run the gauntlet of host defences are those operative at five different stages in the pathogenesis. These are: survival in the nasopharynx, invasion from the respiratory tract to the blood stream, survival in the blood, invasion of the blood–CNS barriers and survival in the CNS.

Figure 2.2 Pathogenesis of H. influenzae meningitis. The scheme indicates sequential, but potentially independent, stages in the evolution of meningitis. At each stage, either host or bacterium may prevail, resulting in termination or progression of infection. Outcome at each stage may be affected by the interaction of several host and bacterial determinants. (Reproduced from article by Moxon, E. R., 1984, Antigen expression influencing tissue invasion of Haemophilus influenzae type b, in The Pathogenesis of Bacterial Infections, edited by G. G. Jackson and H. Thomas, by courtesy of Springer-Verlag)

Successful nasopharyngeal colonization may involve specific adhesins to epithelial cells. One bacterial component involved in this complex interaction is the pilus – a filamentous protein structure that extends from the bacterial outer surface. Structural differences in pili appear to determine the type of cells to which bacteria attach and, as a consequence, which host cells may be targets. Stephens and McGee (1981) examined both the distribution of receptors for the meningococcus and the effect of pili on meningococcal attachment. Meningococci which lack pili attach only in low numbers to cells from a variety of mucosal surfaces. In contrast, piliated meningococci attach in large numbers to cells of the nasopharynx and posterior pharynx, but attach only in low numbers to cells from bladder and anterior nares. These findings suggest that the distribution of receptors for meningococcal pili may be a major factor in determining the selective colonization of the nasopharynx by meningococci which in turn may be a permissive step in the pathogenetic sequence.

In addition to bacterial surface structures, there is evidence that the elaboration of other molecules, such as toxins and enzymes, may be important virulence factors. Haemophilus influenzae, Neisseria meningitidis and Streptococcus pneumoniae share the facility to secrete IgAl proteases, enzymes which selectively cleave one of the polymorphic variants of the major secretory immunoglobulin at its hinge region (Plaut, 1983). Although the biological relevance of IgAl protease production by the meningeal pathogens is not well understood, the circumstantial evidence of their importance is strong. The production of substances by H. influenzae, which interfere with the clearance mechanisms of the respiratory tract, affords a further example of virulence factors which may enhance bacterial survival and proliferation (Wilson, Roberts and Cole, 1985).

The mechanisms by which the meningeal pathogens enter the blood are poorly understood. Nonetheless, capsular polysaccharides have been shown to enhance survival by increasing resistance to opsonophagocytosis by neutrophils, macro phages and reticuloendothelial cells (Robbins and Hill, 1977). Thus, these pathogens are well suited to extracellular survival unless the host has adequate concentrations of type-specific anticapsular antibodies which, acting in concert with complement components, effect their clearance. Although capsular polysaccharide is probably the major bacterial cell surface component facilitating intravascular survival, the cooperative or independent role of other cell wall antigens (e.g. lipopolysaccharide, outer-membrane proteins) is currently of much interest. A genetically engineered strain of H. influenzae which possesses wild- type amounts of capsule, but which has a modified lipopolysaccharide, is a good illustration of the modulating effect of alterations in non-capsular surface structures, since this laboratory strain is virtually devoid of any virulence potential (Zwahlen et al., 1985). Molecular analysis of the bacterial factors responsible for the induction of inflammation during pneumococcal meningitis has been investigated using whole bacteria and isolated cell-wall components. Capsular polysaccharide produced little response whereas cell-wall material evoked an inflammatory response similar to that of whole bacterial cells (Tuomanen, et al., 1985).

The mechanisms which determine the capacity of the meningeal pathogens to breach the blood–brain barrier are equally ill understood. The use of genetically defined strains in suitable animal models together with the use of systems in vitro, such as cerebral microvessel preparations (Scheid, 1985) offer a promising avenue for future research.

PATHOPHYSIOLOGY AND CLINICAL CORRELATES

In adults and older children, meningitis usually presents with characteristic symptoms and signs. These include fever, headache, stiff neck, vomiting and mental dysfunction ranging from lethargy to coma. Focal neurological signs are unusual; thrombophlebitis of major vessels may result in focal deficits and seizures, but these are relatively uncommon early in the illness.

The presenting features in young infants, especially neonates, are typically very different. The classic signs of meningitis may be lacking; instead there is a prominence of the non-specific signs of sepsis – poor perfusion of extremities, defective central respiratory control leading to tachypnoea or apnoeic episodes, lethargy, temperature instability, jaundice and poor feeding. In contrast to the situation in older patients, seizures are common at the time of presentation, reflecting perhaps differences in the less mature brain, and the greater likelihood of delay in diagnosis.

Irrespective of the age at which meningitis occurs, the presenting clinical features result from both the direct toxic actions of bacteria and from the triggering of host inflammatory responses, especially the latter. Thus, fever occurs as the result of the release of interleukins; meningeal irritation, which gives rise to positive Kernig and Brudzinsky signs and a stiff neck, is the result of an inflammatory reaction around the spinal nerve roots and nerves, giving rise to pain and reflex muscular spasm on stretching. Where the inflammatory response is inadequate and/or delayed, as in early infancy, fever, neck rigidity etc. may be absent.

The disturbances in cerebral function are multifactorial in origin. Although bacteria may exert a direct cytopathic effect on neurones and glia because of the diffusion of toxic factors into the brain, it should be emphasized that direct invasion of brain tissue does not occur other than in exceptional circumstances, such as in neonates, where an intense vasculitis and infarction may lead to brain abscess. Neutrophils, however, are locally toxic; they infiltrate the superficial layers of cortex and track along the Virchow–Robin spaces early in meningitis. Indeed, the accumulation of inflammatory cells and exudate is the quintessential histopathological feature of meningitis and neutrophils presumably play a pivotal role in causing the encephalopathy. The principal lesion is vasculitic. Inflammatory infiltration of small vessels occurs, leading to luminal narrowing or thrombus formation with major changes in local cerebral blood flow and vascular resistance; this may result in infarction of brain, but recanalization and resolution of the changes will occur if the patient survives. Cerebral angiography performed in children with bacterial meningitis shows leakage of contrast material due to this vascular involvement, although these changes revert rapidly to normal following successful treatment. The resulting altered and often inadequate perfusion of cerebral tissues, together with mechanical damage consequent upon brain swelling, are important determinants of the acute encephalopathy.

For its functional integrity to be maintained, the brain must be adequately supplied with oxygen and suitable nutrients – glucose or in some circumstances ketone bodies. In meningitis, both increased metabolic demands and reduced cerebral blood flow may lead to inadequate tissue perfusion.

Metabolic demand may be increased by toxin-induced changes in neurones or glia or by cerebral hypoxia, resulting in a switch to anaerobic metabolism and so curtailing the generation of high-energy phosphates. When they occur, seizures may markedly increase the energy requirements of cerebral tissues.

Cerebral blood flow is a function of the cerebral perfusion pressure, which is in turn determined by the difference between systolic blood pressure and intracranial pressure, both of which may change for the worse in meningitis. Even where mean cerebral blood flow is maintained, important regional derangement may occur. Hypotension occurring secondary to generalized sepsis may compromise cerebral perfusion, but vascular changes confined to the CNS are more usually a problem, and raised intracranial pressure a frequent and often intractable complication. One of the earliest pathophysiological changes in meningitis, described above, is altered permeability of the blood–brain barrier through disruption of the integrity of tight junctions in cerebral microvessels (Scheid, 1985). An immediate consequence is so-called vasogenic cerebral oedema, leading to raised intracranial pressure. Other mechanisms often contribute: substances released from neutrophils may diffuse into the brain leading to cytotoxic oedema, while the inflammation of arachnoid villi results in impaired reabsorption of CSF and, by back pressure, interstitial oedema. With the ventriculitis that is also to some extent an inevitable occurrence, blockage of normal CSF flow by fibrinous exudate at various foramina or the aqueduct of Silvius may lead to acute, life-threatening pressure rise. Finally, inappropriate antidiuretic hormone secretion and water overload may further exacerbate the oedema, as may the hydrostatic effect of increased end-capillary pressure occurring in hypercapnia, or secondary to thrombosis of cortical veins or through loss of cerebral perfusion autoregulation.

CLINICAL CORRELATES AND PROGNOSIS

Although it is worth noting that during epidemics of meningococcal meningitis, as reported in the early part of the century, spontaneous recovery without neurological sequelae was well documented (Hirsch, 1886), most individuals who contract bacterial meningitis die unless treated. With treatment, mortality from meningitis is less than 10% (Figure 2.3), but it should be noted that these figures would be unreasonably optimistic for neonates or the elderly.

Figure 2.3 Deaths from bacterial meningitis in England, Wales and Ireland – case fatality ratios, 1983 (laboratory data). (Reprinted with the kind permission of Dr N. Noah, Public Health Laboratory Service, Colindale, London, UK)

Several reports have documented the gross and microscopic findings found at autopsy in cases of bacterial meningitis. Although the immediate cause of death may be apparent – signs suggesting overwhelming sepsis, or evidence of temporal lobe or cerebellar herniation leading to brainstem compression and so cardiorespiratory arrest – in general little that might have been of prognostic value other than directly before death can be discerned. An exception might be the finding of a substantial accumulation of purulent exudate in the ventricles, noted repeatedly in fatal cases (Adams, Kubik and Bonner, 1948), and now detectable by computerized tomographic (CT) scan during life, which attests to the severity of the inflammatory involvement and likely poor outcome.

The extent of the encephalopathy at the time of admission, as judged clinically by the degree of impairment of consciousness, is an important variable correlating with prognosis. Intuitively, it seems reasonable to expect that those patients merely irritable or lethargic on presentation would do better both acutely and long term than those who present in a somnolent condition or in coma, and in at least one study the association has been examined prospectively and validated (Kaplan and Feigin, 1985). The age of the patient has also been found to correlate with outcome (Swartz and Dodge, 1965). Children aged less than one year (especially neonates), as well as persons older than 40 years, have been found to have a worse prognosis.

An issue of potential great importance for prognostic purposes, once the diagnosis of meningitis has been established, is to know when during the illness bacterial invasion of the meninges first occurred. Since this information can never be pin-pointed with certainty, it is therefore unsurprising that there is no convincing evidence to suggest that duration of illness prior to the recognition of meningitis correlates with outcome. In one prospective study in which the mean durations of illness and fever were 3.3 and 2.5 days, respectively, the duration of neither of these parameters bore a significant relationship to acute or longer term neurological abnormalities (Kaplan and Feigin, 1985).

Seizures are common in children with meningitis, occurring in up to 30% either prior to diagnosis or within 2 days of starting treatment. Generalized seizures, especially in the context of fever, are not associated as such with a worse outcome in childhood. The occurrence of focal seizures or other focal neurological signs such as hemiparesis, cranial nerve palsies or visual field defects, suggests the possible presence of arterial or venous thrombosis. These occur in approximately 15% of patients with meningitis and are associated with an increased likelihood of later neurological abnormalities (Feigin, 1981). There is an association between the occurrence of focal seizures and later hearing deficits (Feigin et al., 1976). Papilledema is an uncommon finding during the acute phase of meningitis, but if found should prompt a rigorous evaluation in search of venous sinus thrombosis, subdural effusions or brain abscess.

The following laboratory findings should also be of concern as regards the likelihood of lasting damage; delayed sterilization of CSF, a CSF protein concentration greater than 10 g/l and CSF glucose less than 100 mg/l. Serial measurement of C-reactive protein may also aid in the identification of patients with complications (Peltola, Luhtala and Valmari, 1984).

In the paediatric context, meningitis ranks as one of the most important causes of postnatal acquired neurological damage. The maximal incidence of meningitis in the first 2 years of life coincides with that time in postnatal brain development identified by Dobbing as the ‘vulnerable period’ (Dobbing, 1981). Exposure of the brain in infancy to a variety of insults may affect neuronal and glial growth. In the infant, as in the adult, destruction of neurones is irremediable, but proliferation of dendrites, formation of synaptic connections and myelination of brain tracts continue through the first 2 years of life. The observations of Purpura (1974) suggest that dendritic dysgenesis may be the neuroanatomical basis of some developmental retardation, and such changes have been found in experimental meningitis. Averill, Moxon and Smith (1976) have investigated the effect of H. influenzae meningitis in infant rats on neuronal growth and synaptogenesis and found reduced cortical dendritic complexity and interconnections. As can be seen from Figure 2.3, antibiotic treatment prevents a fatal outcome in the majority, but some studies suggest that up to 50% of survivors face the prospect of apparently permanent CNS sequelae (Sell et al., 1972; Feigin et al., 1976). The occurrence of sensorineural deafness is sufficiently common that hearing tests should be performed in all patients. However, deafness occurring during the acute phase of meningitis often resolves spontaneously, so testing should be deferred for several weeks. A prospective study (Ferry et al., 1982) of 50 infants followed after H. influenzae meningitis found 50% to be entirely normal, 9% normal except for behavioural problems and 28% with significant handicaps. These included hearing deficits (10%), language disorders or delayed development of language (15%), impaired vision (2%), mental retardation (10%), motor abnormalities (5%) and seizure disorders (5%). The mean intelligence of postmeningitic children tested by the Wechsler Intelligence Scale was significantly less (86 versus 97 for controls). Such individuals are an accumulating registry within our society whose problems, quite apart from the humanitarian aspects, represent a substantial economic burden.

Despite the substantial data which attest to the occurrence of lasting CNS sequelae following childhood bacterial meningitis, it is important to emphasize the possibility that even major neurological deficits may resolve over a period of years of careful follow-up. This is an important point when discussing the long-term prognosis with relatives.

LUMBAR PUNCTURE AND MENINGITIS

Although a diagnosis of meningitis may, based on clinical findings, be obvious, its confirmation must be, wherever possible, confirmed by examination of CSF. However, as has been intimated already, the signs of meningitis may be subtle in the very young and the physician is faced with the difficult problem of identifying the occasional child with meningitis among the many with episodes of fever which occur so frequently, most of which are due to self-limiting viral illnesses. Indeed, this proposition has been extended to include a substantial literature which discusses the recognition of children with unsuspected bacteraemia who are at risk of developing meningitis, since childhood bacteraemia is usually caused by the same three encapsulated bacterial species which are the aetiological agents of meningitis. In a recent study, the relative risks of meningitis associated with bacteraemia were pneumococcus 1.0, if. influenzae type b 12.0 and meningococcus 85.6 (Shapiro et al., 1986). Since the penalties of missing or delaying the diagnosis of meningitis are so potentially catastrophic, paediatricians are prone to perform lumbar punctures readily. As a result, the number of normal lumbar punctures greatly outnumber those that result in the diagnosis of meningitis. However, since lumbar puncture is a relatively safe procedure resulting in very few complications, this practice is both acceptable and advisable. There are nonetheless certain circumstances when lumbar puncture should not be carried out or its performance should be delayed. These include cases where there are clinical signs of raised intracranial pressure – such as retinal changes, altered pupillary responses, increase in blood pressure with slow pulse rate, focal or lateralizing neurological signs – and those where there is a particular risk of bleeding such as may occur with thrombocytopenia. Administration of platelets or the correction of a coagulation disorder may be required before a lumbar puncture can be undertaken with safety. Infection in the skin or soft tissues through which the needle must pass to obtain CSF is a further contraindication. Under these and other rare circumstances where a decision is made to defer a lumbar puncture, cultures of blood should be obtained and antimicrobial therapy commenced without delay. In untreated meningitis, blood cultures will yield the offending pathogen in the majority of cases and the diagnosis of meningitis, as opposed to the specific aetiology, can be verified by lumbar puncture performed hours or days after starting specific therapy. Furthermore, bacterial antigens (see later) can be detected in CSF samples several days into the acute illness, thus further minimizing the potential deficiency in data to guide