Natural barriers act to prevent blood-borne invasion

Blood-borne invasion takes place across:

The blood–brain barrier consists of tightly joined endothelial cells surrounded by glial processes, while the brain–CSF barrier at the choroid plexus consists of endothelium with fenestrations, and tightly joined choroid plexus epithelial cells. Microbes can traverse these barriers by:

Examples of each route are seen in viral infections. Poliovirus, for instance, invades the central nervous system (CNS) across the blood–brain barrier. After oral ingestion of virus, a complex stepwise series of events leads to CNS invasion (Fig. 24.2). Poliovirus also invades the meninges after localizing in vascular endothelial cells, and can cross the blood–CSF barrier. Mumps virus behaves in the same way, as do circulating Haemophilus influenzae, meningococci or pneumococci. Once infection has reached the meninges and CSF, the brain substance can in turn be invaded if the infection crosses the pia. In poliomyelitis, for instance, a meningitic phase often precedes encephalitis and paralysis.

Figure 24.1 Structures of the blood–brain and blood–cerebrospinal fluid (CSF) barriers.

Figure 24.2 The mechanism of central nervous system (CNS) invasion by poliovirus. CSF, cerebrospinal fluid; GALT, gut-associated lymphoid tissue.

CNS invasion, however, is a rare event because most microorganisms fail to pass from blood to the CNS across the natural barriers. A large variety of viruses can grow and cause disease if introduced directly into the brain, but circulating viruses generally fail to invade, and CNS involvement by polio, mumps, rubella or measles viruses is seen in only a very small proportion of infected individuals. The factors that determine such CNS invasion are unknown.

Invasion of the CNS via peripheral nerves is a feature of herpes simplex, varicella-zoster and rabies virus infections

Herpes simplex virus (HSV) and varicella-zoster virus (VZV) present in skin or mucosal lesions (see Ch. 26), travel up axons using the normal retrograde transport mechanisms that can move virus particles (as well as foreign molecules such as tetanus toxin) at a rate of about 200    mm/day, to reach the dorsal root ganglia. Rabies virus, introduced into muscle or subcutaneous tissues by the bite of a rabid animal, infects muscle fibres and muscle spindles after the virus binds to the nicotinic acetylcholine receptor. It then enters peripheral nerves and travels to the CNS, to reach glial cells and neurones, where it multiplies.

CSF cell counts increase in response to infection

The response to invading viruses is reflected by an increase in lymphocytes, mostly T cells, and monocytes in the CSF (Table 24.1). A slight increase in protein also occurs, the CSF remaining clear. This condition is termed ‘aseptic’ meningitis. The response to pyogenic bacteria shows a more spectacular and more rapid increase in polymorphonuclear leukocytes and proteins (Fig. 24.3), so that the CSF becomes visibly turbid. This condition is termed ‘septic’ meningitis. Certain slower growing or less pyogenic microorganisms induce less dramatic changes, such as in tuberculous or listerial meningitis.

Table 24.1 Changes in cerebrospinal fluid (CSF) in response to invading microbes

Figure 24.3 Bacterial meningitis. Exudate of acute inflammatory cells in the subarachnoid space (H&E stain).

(Courtesy of P. Garen.)

The pathologic consequences of CNS infection depend upon the microorganism

In the CNS itself, viruses can infect neural cells, sometimes showing a marked preference. Polio and rabies viruses, for instance, invade neurones, whereas JC virus invades oligodendrocytes. Because there is very little extracellular space, spread is mostly direct from cell to cell along established nervous pathways. Invading bacteria and protozoa generally induce more dramatic inflammatory events, which limit local spread so that infection is soon localized to form abscesses.

Viruses induce perivascular infiltration of lymphocytes and monocytes, sometimes, as in the case of polio, with direct damage to infected cells. (The pathogenesis of viral encephalomyelitis is shown later, in Fig. 24.7.) Associated immune responses not only to viral, but also often to host CNS components, play a part in postvaccinial encephalitis. Infiltrating B cells produce antibody to the invading microorganism, and T cells react with microbial antigens to release cytokines that attract and activate other T cells and macrophages. The pathologic condition evolves over the course of several days and occasionally, when partly controlled by host defences, over the course of years, e.g. subacute sclerosing panencephalitis (SSPE) caused by measles, which has both a virological and immunological pathogenesis. Bacteria cause more rapidly evolving pathologic changes, with local responses to bacterial antigens and toxins playing an important part.

In all cases, a degree of inflammation and oedema that would be trivial in striated muscle, skin or liver may be life-threatening when it occurs in the vulnerable ‘closed box’ containing the leptomeninges, brain and spinal cord. It may be several weeks after clinical recovery before cellular infiltrations are removed and histologic appearances are restored to normal.

CNS invasion only rarely assists in the transmission of infection

From the point of view of a parasitic microorganism that needs to be transmitted to a fresh host, invasion of the CNS is generally foolish because it damages the host. The only occasions on which it makes sense are:

Acute bacterial meningitis is a life-threatening infection, needing urgent specific treatment

Bacterial meningitis is more severe, but less common, than viral meningitis and may be caused by a variety of agents (Table 24.2). Prior to the 1990s, Haemophilus influenzae type b (Hib) was responsible for most cases of bacterial meningitis. However, the introduction of the Hib vaccine into childhood immunization regimens has lowered overall Hib incidence in favour of Neisseria meningitidis and Streptococcus pneumoniae, which are now responsible for most bacterial meningitis. These three pathogens have several virulence factors in common (Table 24.3), including possession of a polysaccharide capsule (Table 24.4).

Table 24.2 The important causative agents of non-viral meningitis, their treatment and prevention

a Treatment should be initiated immediately and the susceptibility of the infecting isolate confirmed in the laboratory.

b If isolate is shown to be susceptible (10–20% of isolates are resistant because they produce a plasmid coded beta-lactamase).

c In areas of high prevalence of penicillin resistant pneumococci initial treatment with ceftriaxone may be advised until susceptibility of isolate is known. BCG, bacille Calmette–Guérin.

Table 24.3 Virulence factors in bacterial meningitis

Table 24.4 Polysaccharide capsules are important virulence factors in the pathogenesis of bacterial meningitis

Meningococcal meningitis

Clinical features of meningococcal meningitis include a haemorrhagic skin rash

After an incubation period of 1–3    days, the onset of meningococcal meningitis is sudden with a sore throat, headache, drowsiness and signs of meningitis which include fever, irritability, neck stiffness and photophobia. There is often a haemorrhagic skin rash with petechiae, reflecting the associated septicaemia (Fig. 24.4). In about 35% of patients, this septicaemia is fulminating, with complications due to disseminated intravascular coagulation, endotoxaemia and shock, and renal failure. In the most severe cases there is an acute Addisonian crisis, with bleeding into the brain and adrenal glands referred to as Waterhouse–Friedrichsen syndrome. Mortality from meningococcal meningitis reaches 100% if untreated, but remains around 10% even if treated. In addition, serious sequelae such as permanent hearing loss may occur in some survivors (Table 24.5).

Figure 24.4 Meningococcal septicaemia showing a mixed petechial and maculopapular rash on the extremities and exterior surfaces.

(Courtesy of W.E. Farrar.)

Table 24.5 Clinical features of bacterial meningitis

Type b H. influenzae causes meningitis in infants and young children

H. influenzae is a Gram-negative coccobacillus. ‘Haemophilus’ means ‘blood-loving’, and the name ‘influenzae’ was given because it was originally thought to be the cause of influenza, but is now known to be a common secondary invader in the lower respiratory tract. There are six types (a–f) of H. influenzae, distinguishable serologically by their capsular polysaccharides:

Maternal antibody protects the infant up to 3–4    months of age, but as it wanes, there is a ‘window of susceptibility’ until the child produces his/her own antibody. Anticapsular antibodies are good opsonins (see Ch. 14), which allow the bacteria to be phagocytosed and killed, but children do not generally produce them until 2–3    years of age, possibly because these antibodies are T independent. In addition to the capsule, H. influenzae has several other virulence factors, as shown in Table 24.3.

Acute H. influenzae meningitis is commonly complicated by severe neurologic sequelae

The incubation period of H. influenzae meningitis is 5–6    days, and the onset is often more insidious than that of meningococcal or pneumococcal meningitis (Table 24.5). The condition is less frequently fatal, but, as with meningococcal infection, serious sequelae such as hearing loss, delayed language development, and mental retardation and seizures may occur (Table 24.5).

General diagnostic features are the same as for meningococcal meningitis, as explained above. For laboratory diagnosis, see Chapter 32. It is important to note that the organisms may be difficult to see in Gram-stained smears of CSF, particularly if they are present in small numbers.

H. influenzae type b (Hib) vaccine is effective for children from 2 months of age

General features of treatment are referred to above under meningococcal meningitis; details are summarized in Table 24.2. An effective Hib vaccine, suitable for children 2    months of age and upwards, is available. Rifampicin prophylaxis is recommended for close contacts of patients with invasive Hib disease.

Streptococcus pneumoniae is a common cause of bacterial meningitis, particularly in children and the elderly

Strep. pneumoniae was first isolated more than 100    years ago but relatively little is known about its virulence attributes apart from its polysaccharide capsule (Tables 24.3, 24.4), and the pneumococcus remains a major cause of morbidity and mortality. (Pneumococcal respiratory tract infections are reviewed in Ch. 19.)

Strep. pneumoniae is a capsulate Gram-positive coccus carried in the throats of many healthy individuals. Invasion of the blood and meninges is a rare event, but is more common in the very young (<    2    years of age), in the elderly, in those with sickle cell disease, in debilitated or splenectomized patients and following head trauma. Susceptibility to infection is associated with low levels of antibodies to capsular polysaccharide antigens: antibody opsonizes the organism and promotes phagocytosis, thereby protecting the host from invasion. However, this protection is type specific and there are more than 85 different capsular types of Strep. pneumoniae.

The clinical features of pneumococcal meningitis are generally worse than with N. meningitidis and H. influenzae and are summarized in Table 24.5. The general diagnostic features are the same as for meningococcal meningitis described above. Details are referred to in Chapter 32.

Treatment and prevention of pneumococcal meningitis are summarized in Table 24.2. Since penicillin-resistant pneumococci have been observed worldwide, attention must be paid to the antibiotic susceptibility of the infecting strain, and empiric chemotherapy usually involves a combination of vancomycin and either cefotaxime or ceftriaxone.

An effective heptavalent protein-conjugate pneumococcal vaccine is available which the US Centers for Disease Control recommends for all children from 2 to 23    months of age (i.e. to be given with other recommended childhood vaccines) and for older children (24–59    months) who are at high risk (e.g. sickle cell disease, HIV infection, chronic illness or weakened immune systems) for serious pneumococcal infection. The older 23-valent polysaccharide vaccine remains available for children older than 5    years of age.

Listeria monocytogenes causes meningitis in immunocompromised adults

Listeria monocytogenes is a Gram-positive coccobacillus and an important cause of meningitis in immunocompromised adults, especially in renal transplant and cancer patients. It also causes intrauterine infections and infections of the newborn, as summarized in Chapter 23. L. monocytogenes is less susceptible than Strep. pneumoniae to penicillin, and the recommended treatment is a combination of penicillin or ampicillin with gentamicin.

Although mortality rates due to neonatal meningitis in resource-rich countries are declining, the problem is still serious

Neonatal meningitis can be caused by a wide range of bacteria, but the most frequent are group B haemolytic streptococci (GBS) and E. coli (Table 24.6; see also Ch. 23). This may occur by routes such as nosocomial infection. However, the infant may also be infected from the mother. For example, with women vaginally colonized by GBS, the infant may swallow maternal secretions such as infected amniotic fluid during delivery.

Table 24.6 Group B streptococci are a major cause of neonatal meningitis

Neonatal meningitis often leads to permanent neurologic sequelae such as cerebral or cranial nerve palsy, epilepsy, mental retardation or hydrocephalus. This is partly because the clinical diagnosis of meningitis in the neonate is difficult, perhaps with no more specific signs than fever, poor feeding, vomiting, respiratory distress or diarrhea. In addition, due to the possible range of aetiological agents, ‘blind’ antibiotic therapy in the absence of susceptibility tests may not be optimal, and adequate penetration of the antibiotic into the CSF is also an issue.