GENERAL POINTS

Bacterial meningitis is an inflammatory response due to infection of the leptomeninges and subarachnoid space. This is characterised by the clinical syndrome of fever, headache, neck stiffness and CSF pleocytosis. Despite the existence of antibiotic therapy, patients continue to suffer significant morbidity and mortality.

The bacterial organisms are usually not confined to the brain and meninges and frequently cause systemic illness, for example, severe sepsis, shock, acute respiratory distress syndrome, and bleeding disorders such as disseminated intravascular coagulation.^1,2

A variety of other pathogens cause meningeal inflammation, resulting in very similar clinical presentations. Bacterial infections must be treated urgently and appropriately to limit ongoing central nervous system (CNS) damage. It is also important to treat the complications of meningitis such as seizures and raised intracranial pressure (ICP).

Where possible, spinal fluid examination following a lumbar puncture is required in order to confirm the diagnosis and establish the pathogenic organism responsible. A CSF examination may be contraindicated if there are signs of raised ICP, including:

These features raise the possibility of an undiagnosed cerebral mass lesion which, in turn, could cause cerebral herniation if lumbar puncture is performed. A computed tomography (CT) brain scan is required prior to CSF examination in order to explore this possibility and lessen but not obviate the risk of cerebral herniation. Even if the CT brain scan is normal, ICP may still be raised. The importance of performing a safe CSF examination must be balanced against the need to commence immediate treatment in each individual patient.^3,4

AETIOLOGY

The main causes of meningitis are spread by droplet infection or exchange of saliva. Meningitis may occur when pathogenic organisms colonise the nasopharynx and reach the blood–brain barrier. Meningitis can occur as a result of infection in the middle ear, sinus or teeth, leading to secondary meningeal infection. Most bacteria obtain entry into the CNS via the haematogenous route. As the organisms multiply, they release cell wall products and lipopolysaccharide, and generate a local inflammatory reaction which in itself also releases inflammatory mediators. The net result of the release of cytokines, tumour necrosis factor and other factors is associated with a significant inflammatory response. Vasculitis of CNS vessels, thrombosis, cell damage and exudative material all contribute to vasogenic and cytotoxic oedema, altered blood fiow and cerebral perfusion pressure. Later on infarction and raised ICP occur.⁵

The inflammatory events seen with infection are summarised in Figure 47.1.

Figure 47.1 Cascade of events in meningitis. IL-1, interleukin-1; TNF, tumour necrosis factor; PAF, platelet-activating factor; ICP, intracranial pressure; CPP, cerebral perfusion pressure.

ORGANISMS

Acute bacterial meningitis can be caused by many species of bacteria, although three organisms are commonly reported:

Until the advent of the meningitis vaccination programme, H. infiuenzae type B was the most common cause of bacterial meningitis. Recently S. pneumoniae and N. meningitidis have been considered the main causes, although one study suggested that Listeria monocytogenes is the second most common isolate in adult population. The occurrence of pneumococcal strains which are resistant to penicillin has also influenced the epidemiology of meningitis.⁶

NOSOCOMIAL INFECTIONS

Common systemic nosocomial pathogens such as Escherichia coli, Pseudomonas spp., Klebsiella and Acinetobacter spp. account for a high percentage of nosocomial infections of the meninges.

IMMUNOCOMPROMISED HOSTS

In the immunocompromised patient with meningitis (e.g. human immunodeficiency virus: HIV), fungal viral and cryptocococal meningitis should be considered.⁷

NEUROSURGERY AND TRAUMA

Infections following skull trauma are frequently caused by Staphylococcus aureus and S. epidermidis, which should be considered in those with shunts or other intracranial devices.

CLINICAL PRESENTATION

The history may reveal evidence of trauma or infection. Meningitis usually presents with an acute onset of:

However, in the immunocompromised, elderly or infant patient, non-specific features such as a low-grade fever or mild behavioural change may be all that is apparent. Many of the classic symptoms are late manifestations of meningitis: preceding trivial early symptoms such as leg pain or cold hands may not immediately suggest the more serious underlying diagnosis.

It is important to identify from the history reported about preceding trauma, upper respiratory tract infection or ear infection. Symptoms may develop over hours or days. Specific infections relate partly to an individual’s age.

Neurological signs can be present with meningitis but signs such as nuchal rigidity, or a positive Kernig’s sign (pain and hamstring spasm resulting from attempts to straighten, the leg with the hip fiexed) are not universally found. A number of recent studies have shown that the classic signs were present in less than 50% of cases. Systemic signs may occur most often in meningococcal disease, where a haemorrhagic, petechial or purpuric rash may be observed. Digital gangrene or skin necrosis may occur. Some patients are severely septic, with acute respiratory distress syndrome and disseminated intravascular coagulation.

Approximately 25% of patients have a seizure during the course of the illness. Differential diagnosis may include subarachnoid haemorrhage, migraine, encephalitis and tumour.

INVESTIGATIONS

The patient with suspected bacterial meningitis requires immediate blood cultures and should be given empirical intravenous (IV) antibiotics if there is likely to be any delay in further assessment (Table 47.1).

CEREBROSPINAL FLUID FINDINGS

A CSF examination is a vitally important investigation which may definitively confirm the diagnosis of bacterial meningitis. In this regard its value should should not be dismissed. Concern about the risks of coning following lumbar puncture should be considered in the context of patients’ symptoms where the presence of seizures, focal neurological signs and papilloedema may suggest raised ICP. Neuroimaging may provide some level of reassurance that it is safe to proceed with a lumbar puncture; however, the clinican should be aware that all factors need to be taken into consideration.

Bacterial meningitis is suggested when there is:

An urgent Gram stain and microbiological culture are mandatory. The Gram stain is usually positive in approximately 50–60% of cases. A CSF examination shortly after empirical antibiotics does not necessarily decrease the diagnostic sensitivity of CSF culture. Polymerase chain reaction (PCR) techniques can be used to detect different organisms. A throat swab should be routinely taken. The clinical decision-making process that determines whether somebody does or does not have bacterial meningitis cannot be modelled easily and depends on multiple factors including clinical, laboratory findings and observation of the patient over time.

Blood cultures comprise an important investigation in patients with meningitis, as spread is haematogenous, and a number of sets of cultures should be sent. It is advisable to check routinely a full blood count clotting profile (to exclude disseminated intravascular coagulation) and biochemistry, including blood glucose level. A chest X-ray and blood gases should be performed to identify systemic involvement. Obviously, relevant areas such as infected sinuses or ears should be examined if there is an indication that they are implicated.

MANAGEMENT

Antibiotics should be started as early as possible and broad-spectum coverage is recommended until bacterial identifcation is made (Table 47.2). The selection of antibiotics is influenced by the clinical situation in conjunction with known allergies or local patterns of antibiotic resistance and the CSF findings. Delays in administering antibiotics are a significant risk factor for a poor prognosis. In the absence of a known organism, empirical choice for antibiotics has been complicated by the development of resistant strains. Penicillin G, ampicillin and third-generation cephalosporins are typical first-line agents. Until recently, ampicillin was appropriate for pneumococcal, meningococcal and Listeria infections. The emergence of resistant strains influences local antibiotic practice. If there is a history of recent head injury, a broad-spectrum cephalosporin may be indicated with vancomycin. Discussions with local microbiology services are recommended. If the CSF examination identifies the organism, then specific regimens can be prescribed (Table 47.3).

Table 47.2 Empiric antibiotics for meningitis

Table 47.3 General recommendation for known organisms*

* Always check local sensitiviity as resistance patterns are variable.

It is more difficult to select an appropriate empirical antibiotic in the immunocompromised patient. When the organism has been identified and sensitivity results are available, it may be necessary either to change the antibiotic or to rationalise those being given.⁸

In all cases, it is important to monitor the clinical response to therapy and, if necessary, antibiotics should be reviewed and appropriately altered once antibiotic sensitivities are known or a patient is not considered to be improving. A repeat CSF examination should be performed if there is concern about antibiotic sensitivity or selection. In those with penicillin-resistant pneumococcal meningitis, a CSF examination 48 hours after presentation is recommended to ensure bacteriological improvement. Antibiotics should be given for 10–14 days, although a shorter course may be adequate in some circumstances. Intrathecal antibiotics are not recommended.

STEROID ADMINISTRATION

The benefit of steroid administration in adult meningitis has been debated. Clear guidance is now available to support its routine use from the Cochrane Database, including 1800 adults and children, which demonstrated a reduction in mortality, hearing loss and neurological complications. Some concerns remain, including the possibility that dexamethasone may adversely affect CSF penetration or cause longer-term cognitive problems.⁹ A longer and more established literature exists for the use of steroids in bacterial meningitis in children. These studies confirm a benefit for those with Haemophilus infiuenzae type B infection and reduce the frequency of postmeningitis deafness.

RECOMMENDATIONS IN ADULTS

Dexamethasone is an adjuvant treatment and should be given with the first dose of antibiotics and continued 6-hourly for 4 days (0.6 mg/kg daily).

GENERAL MANAGEMENT CONSIDERATIONS¹⁰

PROGNOSIS

Untreated, bacterial meningitis is usually fatal. Appropriate therapy significantly reduces the mortality rate; however, recent studies still show that the overall mortality is approximately 18%. Mortality is slightly higher in those who have seizures and when there have been delays introducing treatment, or if the patient is elderly or very young^12,13 (see Table 47.3).

CLINICAL PRESENTATION

Patients usually present with symptoms of meningeal irritation, fever, headache, neck stiffness, retrobulbar pain, photophobia, vertigo, nausea and vomiting which are less severe than those with bacterial meningitis. The presence of intellectual impairment, focal neurological symptoms or seizures suggests that the brain parenchyma is involved and, consequently, these are due to meningoencephalitis. True viral meningitis develops over hours to days but rarely lasts longer than 7–10 days. A variety of associated symptoms, such as nausea, vomiting and generalised malaise, may accompany this condition.¹⁴

INVESTIGATIONS

A CSF examination is important and usually shows:

Staining for microorganisms, including bacteria, Mycobacterium tuberculosis and cryptococcal meningitis, is necessary. Sites for culture include the mucous membranes, throat, skin and rectum.

MANAGEMENT

Acute viral meningitis is usually a self-limiting condition and only supportive therapy is required, with analgesia and bedrest. Viral meningitis caused by HSV 1 or 2 may require IV aciclovir. Acute HIV infection causing meningitis may respond to retroviral therapy.

CLINICAL PRESENTATION

The key clinical pointer of encephalitis is the presence of focal neurological symptoms, indicating involvement of the brain parenchyma. In particular, the presence of speech disturbance, seizures, altered cognition and disturbance of conscious level suggests this.

Diagnosis can be difficult.

Figure 47.2 Enhanced temporal lobe with herpes encephalitis.

TREATMENT

Specific treatment for HSV encephalitis requires IV aciclovir at a dose of 30 mg/kg per day for 14 days. Left untreated, the mortality of HSV encephalitis is approximately 70% but there is still a 25% mortality in patients treated with optimal therapy. Patients can be left with significant disability in terms of cognitive dysfunction or seizures. Most patients with significant cerebral oedema receive empirical steroids, although there are no clinical trials to support this therapy. Aciclovir can cause renal impairment and the patient should be hydrated intravenously and renal function monitored.¹⁶ Aggressive treatment of seizures is important.

Cytomegalovirus (CMV) infection requires antiviral therapy with ganciclovir or valganciclovir. CMV may cause a ganglionitis and polyradiculitis, which may suggest this diagnosis clinically in an immunocompromised patient.

Most CNS viruses cause neuronal damage but chronic JC virus infection in oligodendrocytes causes the syndrome of progressive multifocal leukoencephalopathy (PML). This condition presents with a subacute onset of confusion, weakness and visual symptoms, usually in an immunosuppressed individual. The MRI scan is usually suggestive but CSF examination with PCR amplification of the JC virus particles may be required. Currently, no specific therapy for PML exists. The survival of HIV patients with associated PML is poor, averaging 6 months in 90% of individuals.

Viral infection with HIV 1, measles and rubella can also cause chronic CNS infection, leading to chronic encephalitides.

A number of systemic neurological conditions (e.g. lymphoma, Lyme disease, sarcoidosis and vasculides such as Behçet’s disease) may present with aseptic meningitis. It is therefore important to consider these systemic conditions in those presenting with viral meningitis or encephalitis.

CLINICAL FEATURES

Tuberculous meningitis has a very varied clinical presentation. Often, it is heralded by a non-specific prodromal phase, frequently but not necessarily including headache, vomiting and fever. Of one case series which included those admitted to an intensive care unit, only 65% had fever, 52% had focal neurology and 88% had signs of meningism. A variety of cranial nerve palsies can occur but other presentations include those seen with stroke, hydrocephalus and tuberculoma.

DIAGNOSIS

An investigation of the differential diagnosis of tuberculous meningitis is important. PCR amplification of mycobacterial DNA has not been fully evaluated in this technique which, in the case of tuberculous meningitis, usually requires a lumbar puncture examination. Those who are immunosuppressed may have atypical CSF appearance, including normal CSF examinations in occasional HIV individuals. Tuberculosis culture from CSF is required but may take up to 6 weeks before a positive culture result is available. Imaging studies may show a basal meningitis and hydrocephalus but these features are non-specific.¹⁸

Current advice suggests that the first 2 months of treatment should comprise quadruple therapy:

Streptomycin is used rarely. The toxicity of the agents must be monitored in terms of renal and liver function and the effect on other organs such as the eye.

There is increasing multidrug-resistant tuberculous meningitis, especially in the HIV-positive population, and so sensitivity is important. Some clinical trials suggest that steroids have a beneficial effect in some groups of patients.¹⁹ Patients may require neurosurgical intervention for the treatment of hydrocephalus.

DIAGNOSIS

CT and MRI are both effective in demonstrating a fluid collection.

Surgical intervention, drainage and appropriate antibiotic regimes are required. Both Gram-positive Staphylococcus and Streptococcus and Gram-negative organisms may be implicated. Initial broad-spectrum cover should be narrowed to targeted treatment when the organism or organisms are known.

PROGNOSIS

If left untreated, this condition is invariably fatal. With treatment, mortality is in the order of 20% and neurological sequelae are common.

PRESENTATION

Epidural infection commonly presents on the back, and may be generalised to the area of the back involved. There may be local tenderness over the site associated with redness of the catheter insertion site. Fever is common. Initially mild neurological deficit may rapidly progress, leading to para/quadriparesis.

Blood cultures may be positive and may indicate the organism.

DIAGNOSIS

CT and MRI are both effective in diagnosis.

Spinal decompression and drainage are urgently required. This is usually a nosocomial infection and therefore resistant organisms are commonly found. Antibiotics should be specific for the organisms involved and may need to be continued for prolonged periods, often weeks, to eradicate the infection.

Where there have been neurological symptoms and signs prior to surgery, residual deficit is common. In one series, the recovery rate for patients with paresis/plegia after lumbar epidural abscess was 50%, while no patients with paresis/plegia following a thoracic abscess recovered. The majority of long-term survivors had severe neurological deficits.

TREATMENT

AETIOLOGY

A brain abscess may spread directly from bone or dura or spread may be haematogenous. Predisposition includes cranial trauma, neurosurgery, chronic ear or sinus disease, suppurative lung disease, congenital heart disease and recurrent sepsis. Immunological compromise may predispose to more exotic organisms: more common organisms include Staphylococcus spp. associated with trauma, and Streptococcus, Bacteroides and Gram-negative bacteria, which are common with lung disease or recurrent sepsis.

PRESENTATION

The presentation is severe headache, vomiting, obtundation, seizures and focal neurological signs. Neck stiffness is often absent. Clinical sepsis may not be obvious.

DIAGNOSIS (Figure 47.4)

Figure 47.4 Abscess: (a) precontrast and (b) postcontrast.

INVESTIGATIONS

TREATMENT

Indications for surgery include large single lesions, relief of raised ICP and the need for tissue diagnosis.

Antibiotics are the mainstay of therapy. If the organism is known, then the treatment should be specific. In the absence of a definitive organism, penicillin plus chloramphenicol (as for meningitis) and metronidazole 500 mg IV 8-hourly or 500 mg rectally 12-hourly should be empirical therapy. Cefotaxime 1–2 g can be given IV 6–8-hourly and metronidazole 500 mg IV 8-hourly. If there is a recent history of trauma or neurosurgery, then a regimen that will cover Staphylococcus should he used. Antibiotics should be continued for 3–6 weeks.

Supportive therapy limits morbidity, which is nevertheless high. Mortality from cerebral abscesses is still 10–20%.0²¹

INVESTIGATIONS

TREATMENT

β-lactam antibacterials, such as penicillin V, amoxicillin and cefuroxime, are effective first-line treatment. The optimal duration of treatment is not known, but 10–21 days is recommended.^23,24 Practice parameters for the treatment of nervous system Lyme disease state that nervous system infection responds favourably to penicillin, ceftriaxone, cefotaxime and doxycycline. Prolonged treatment with antibiotic appears to have no benefit in preventing post-Lyme syndrome.