8 Practical Neurology

REVIEW

Pract Neurol 2008; 8: 823

Community-acquired bacterial meningitis in adults

Ewout S Schut, Jan de Gans, Diederik van de Beek

E S Schut
Neurology Resident

J de Gans
Neurologist

D van de Beek
Neurologist Department of Neurology, Centre of Infection and Immunity Amsterdam (CINIMA), Academic Medical Centre, Amsterdam, The Netherlands Correspondence to: Dr D van de Beek Department of Neurology, Academic Medical Centre, University of Amsterdam, PO Box 22660, 1100 DD Amsterdam, The Netherlands; D.vandeBeek@amc.uva.nl 10.1136/jnnp.2007.139725

Schut, de Gans, van de Beek 9

Despite the availability of effective antibiotics, vaccination programmes and skilled acute-care facilities, there is still a significant mortality and morbidity from bacterial meningitis. Neurologists are often called on to rule out bacterial meningitis, which can be difficult with the history and physical examination alone. In this review the authors will discuss the epidemiology, diagnosis and treatment of acute community-acquired bacterial meningitis in adults, focussing particularly on the management of patients with neurological complications, and stressing the importance of adjunctive dexamethasone.

ntil the early 20th century the prognosis for patients with acute bacterial meningitis was dismal.1 Since then, improvements in public health, the discovery of effective antimicrobial agents, the implementation of childhood vaccination programmes and the development of highly specialised acute-care facilities have had a dramatic impact on the mortality and morbidity associated with this disease. However, despite these advances, community-acquired bacterial meningitis continues to exact a heavy toll, even in developed countries. It is still therefore a neurological emergency and the patients require immediate evaluation and treatment.

and commonly occurs in patients with defective cell-mediated immunity. Since the early antibiotic era, the emergence of antimicrobial resistance has been a continuing problem.4, 5 Pneumococcal resistance to penicillin, due to changes in its penicillin binding proteins, started to appear in the 1960s and has since developed worldwide, often necessitating initial therapy with a combination of a third-generation cephalosporin with vancomycin, instead of monotherapy with penicillin. Another important change in epidemiology has been caused by the routine vaccination of children against Haemophilus influenzae type b and seven serotypes of S pneumoniae.6 As a result, bacterial meningitis now occurs more often in adults than in infants and young children. Also, in the UK, a campaign was launched seven years ago7 to immunise children with the serogroup C meningococcal polysaccharide-protein conjugate vaccines which resulted in a dramatic reduction in serogroup C invasive meningococcal disease, and this prompted other countries to introduce similar programmes. In the USA, the Advisory Committee on Immunization Practices has recently recommended quadrivalent conjugate vaccine, which offers protection against serogroups A, C, Y and W-135 for immunoprophylaxis of adolescents before high school entry. Although not all serotypes of meningococci are covered by this vaccine, this measure should further reduce the incidence of bacterial meningitis.

EPIDEMIOLOGY
The incidence of bacterial meningitis is about 5 cases per 100,000 adults per year in developed countries24 and may be 10 times higher in less developed countries. The predominant causative pathogens in adults are Streptococcus pneumoniae (pneumococcus) and Neisseria meningitidis (meningococcus) which are responsible for about 80% of all cases:

Pneumococcal meningitis most commonly occurs in patients with an antecedent illness such as pneumonia, acute otitis media, and acute sinusitis. Groups at increased risk include the elderly, the immunocompromised, smokers, diabetics, alcoholics and those who develop cerebrospinal fluid (CSF) rhinorrhoea after a basal skull fracture. The meningococcus most commonly causes meningitis and septicaemia in children and young adults, and is a major cause of epidemic bacterial meningitis worldwide. Listeria monocytogenes is the third most common cause of bacterial meningitis

CLINICAL PRESENTATION
Neurologists are often called on to rule out bacterial meningitis. In most cases the patient is febrile, confused and complaining of headache, and the question revolves around the need for a lumbar puncture.
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10 Practical Neurology occur in children). If there is no concern about the stability of the cervical spine, one should rotate the neck to determine whether the apparent rigidity in flexion is due to a mechanical problem. Brudzinskis sign is positive when passive flexion of the neck results in flexion of the hips and knees. To elicit Kernigs sign, the thigh is flexed on the abdomen, and with the knee flexed, the leg is then passively extended; with meningeal inflammation the patient resists leg extension. However, a prospective study8 of 297 adults found that none of these signs accurately identified patients with meningitis (of any cause), which was considered present if patients had >6 white blood cells per ml CSF; Kernigs and Brudzinskis signs had poor sensitivity (5%) but high specificity (95%), while neck stiffness had a sensitivity and specificity of 30% and 68% respectively. Deciding whether to do a lumbar puncture should not therefore rely solely on the absence or presence of these traditional meningeal signs. When suspicion of bacterial meningitis remains after a thorough history and physical examination, a diagnostic lumbar puncture should be carried out.

When suspicion of bacterial meningitis remains after a thorough history and physical examination, a diagnostic lumbar puncture should be carried out
After the history and a thorough general physical and neurological examination, a diagnosis other than bacterial meningitis, such as delirium due to a urinary tract infection, or a headache accompanying an infectious syndrome other than meningitis, can often be established with reasonable certainty. However, when any alternative diagnosis is not so obvious and doubt remains about the possibility of bacterial meningitis, lumbar puncture is mandatory, as it is in almost every patient who clinically is thought to have bacterial meningitis (see below). Patients with bacterial meningitis usually complain of headache, nausea, vomiting and photophobia. In a nationwide prospective study2 of 696 adults with communityacquired bacterial meningitis, we found the following signs and symptoms at presentation: headache in 87% of cases, neck stiffness in 83%, fever (>38 C) in 77% and impairment of consciousness (,14 on the Glasgow Coma Scale) in 69% of cases. Although the classic triad of fever, neck stiffness and altered mental status was present in only 44% of patients, at least two of the four signs and symptoms (headache, fever, neck stiffness, and altered mental status) were present in 95%. The classic triad is more likely to occur with pneumococcal than meningococcal meningitis (58% vs 27%). Patients may also present with seizures or focal neurological deficits, such as aphasia and hemiparesis, or with cranial nerve palsies. A petechial skin rash has traditionally been considered the hallmark of meningococcal meningitis, but can also occur in viral meningitis. The classic signs of meningeal irritation are a stiff neck, and Brudzinskis and Kernigs signs. Neck stiffness is assessed by gentle forward flexion with the patient in the supine position. Disorders that may mimic meningism include posterior fossa tumours, disorders presenting with rigidity or stiffness (for example, druginduced dystonic reaction, neuroleptic malignant syndrome, tetanus), spontaneous CSF leaks, atlanto-axial subluxation and cervical lymphadenitis (the latter two disorders mainly
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DIFFERENTIAL DIAGNOSIS
The differential diagnosis of the triad of fever, headache and stiff neck is bacterial or viral meningitis, fungal meningitis, tuberculous meningitis, drug-induced aseptic meningitis, carcinomatous or lymphomatous meningitis, aseptic meningitis associated with inflammatory diseases (systemic lupus erythematosus, sarcoidosis, Behcets disease, Sjogrens syn drome, etc), and, when the temperature is normal or only moderately raised and the onset of headache is acute, subarachnoid haemorrhage. When impaired consciousness, focal neurological deficits or new-onset seizures are added to the classic triad, the differential diagnosis includes viral encephalitis, intracranial venous thrombosis, tickborne bacterial infections (depending on geography: Borrelia and Ehrlichia infections in North America and Europe, Rocky Mountain spotted fever in North America), brain abscess and subdural empyema. The differential diagnosis in HIV-infected patients who present with meningeal signs includes meningitis caused by Cryptococcus neoformans, Mycobacterium tuberculosis and

Schut, de Gans, van de Beek 11

Figure 1 Algorithm for the management of patients with suspected communityacquired bacterial meningitis. (This material was previously published as part of an online supplementary appendix to reference 4. Copyright 2006 Massachusetts Medical Society. All rights reserved.)

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12 Practical Neurology simultaneously in most cases (fig 1). The first step is to evaluate vital functions, obtain two sets of blood cultures, and blood tests which typically should not take more than one or two minutes. At the same time, the severity of the patients condition and the level of suspicion for the presence of bacterial meningitis should be determined. If the patient is in shock low doses of hydrocortisone (50 mg every six hours iv) and fludrocortisone (50 mg once daily through a nasogastric tube) should be administered.9 If the patient is not critically ill and there is no coagulopathy (due to anticoagulants or disseminated intravascular coagulation) a lumbar puncture should be carried out provided there are no contraindications (see below). Examination of the cerebrospinal fluid (CSF) is critically important in the diagnosis of bacterial meningitis because it:

TABLE 1 Indications for CT brain scanning before lumbar puncture

l l l l

Focal neurological deficit, not including cranial nerve palsies New-onset seizures Papilloedema Abnormal level of consciousness, interfering with proper neurological examination (Glasgow Coma Scale ,10) Severe immunocompromised state

Treponema pallidum. Focal brain lesions with mass effect and oedema are most commonly caused by Toxoplasma gondii and Mycobacterium tuberculosis. Patients with tuberculous meningitis tend to have a longer duration of illness (>6 days), frequently have an abnormal chest x ray, and often have a lymphocytic CSF with a low glucose. The search for acid-alcohol fast bacilli in the CSF remains the cornerstone of diagnosis, but requires diligence and time. In developed countries, when HIV-infected patients present with symptoms and signs of a mass lesion, Toxoplasma encephalitis is the most common aetiology, followed by primary central nervous system lymphoma.

N N N N

is required to confirm the diagnosis, identifies the causative organism, allows the testing of antibiotic sensitivities, and so helps to rationalise treatment.

MAKING THE DIAGNOSIS AND STARTING TREATMENT

Given the high mortality of acute bacterial meningitis, starting treatment and completing the diagnostic process should be carried out

INDICATION FOR COMPUTED TOMOGRAPHY BEFORE LUMBAR PUNCTURE

The advent of computed tomography (CT) in the 1970s has of course transformed neurological

TABLE 2 Recommendations for empirical antimicrobial therapy in suspected community-acquired bacterial meningitis (adapted from van de Beek et al4)
Predisposing factor Age 250 years .50 years Common bacterial pathogens Initial intravenous antibiotic therapy

With risk factor present{

N meningitidis, Vancomycin plus ceftriaxone or S pneumoniae cefotaxime* N meningitidis, {Vancomycin plus ceftriaxone or S pneumoniae, cefotaxime plus ampicillin L monocytogenes, aerobic gramnegative bacilli S pneumoniae, {Vancomycin plus ceftriaxone or L monocytogenes, cefotaxime plus ampicillin H influenzae

*In areas with very low penicillin-resistance rates monotherapy penicillin may be considered. {In areas with very low penicillin-resistance and cephalosporin-resistance rates combination therapy of amoxicillin and a third-generation cephalosporin may be considered. {Alcoholism, altered immune status.
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Schut, de Gans, van de Beek 13 practice, in this context allowing the differentiation of other types of pyogenic intracranial infections and the detection of brain swelling and mass lesions. The downside of its availability has been the concern among physicians about the possibility of an occult mass lesion leading to brain shift and herniation after lumbar puncture, started to routinely perform CT scans before lumbar punctureintroducing inevitable delay in antimicrobial therapy, sometimes for many hours, with catastrophic results. Numerous papers have tried to establish a clear link between lumbar puncture and subsequent herniation, but a causal relation has been difficult to prove. Many patients known to have raised intracranial pressure and papilloedema have in the past undergone lumbar puncture without adverse effects, and other patients have herniated even without a lumbar puncture. Clinicians must not use CT to rule out increased intracranial pressure (as intracranial pressure is almost always raised in acute bacterial meningitis) but instead, in selected patients, to detect brain shift either due to a focal space-occupying lesion or severe diffuse brain swelling. Consequently, a CT scan is not required before lumbar puncture in every patient and clinical features can be used10, 11 to select patients where an abnormal CT scan is likely (table 1). In patients with suspected bacterial meningitis who are CT scanned before lumbar puncture, initial therapy consisting of adjunctive dexamethasone (10 mg iv) and empirical antimicrobial therapy (table 2) should always be started without delay, even before sending the patient to the CT scanner. The yield of CSF Gram stain and culture may be diminished by antimicrobial therapy given for several hours prior to lumbar puncture, but antimicrobial therapy will not affect the CSF white blood cell count and glucose concentration so much that bacterial meningitis is not suspected.

A CT scan is not required before lumbar puncture in every patient and clinical features can be used
more than 40 cm water),2, 12 polymorphonuclear leukocytosis, decreased glucose concentration, and an increased protein concentration.2, 1215

N N

INTERPRETING THE LUMBAR PUNCTURE RESULTS

Frank turbidity of CSF instantly suggests bacterial meningitis. Microscopic examination of CSF for white cells, red cells and organisms; the measurement of glucose and protein; and culture, are important investigations in any case of possible meningitis. The CSF abnormalities of bacterial meningitis include raised opening pressure in almost all patients (40%

In immunocompetent patients with bacterial meningitis, the white blood cell count is typically greater than 1000 cells/ ml, while in viral meningitis it is less than 300 cells/ml, although there is considerable overlap (rarely, the count may be normal with ,6 cells/ml, all lymphocytes, but the CSF may still appear turbid because of the vast numbers of bacteria). The neutrophil count is typically raised in bacterial compared with viral meningitis. More than 90% of cases present with a CSF white cell count of more than 100/ml. In immunocompromised patients, CSF white blood cell counts tend to be lower, although an acellular CSF is probably rare, except in patients with tuberculous meningitis. The normal CSF glucose concentration is between 2.5 and 4.4 mmol/l with serum glucose of 3.96.7 mmol/l, or approximately 65% of the serum glucose. In bacterial meningitis the glucose concentration is usually less than 2.5 mmol/l, or less than 40% of a simultaneously measured serum glucose.2, 1215 The CSF protein in bacterial meningitis is usually raised (.50 mg/dl). Gram stain is positive in identifying the organism in 5090% of cases2, 15 and CSF culture is positive in 80% of untreated patients. Latex particle agglutination tests that detect antigens of N meningitidis, S pneumoniae, H influenzae and Streptococcus agalactiae can provide diagnostic confirmation, but they are not routinely available. Increasingly, laboratories are offering a broad range PCR that can detect small numbers of viable and non-viable organisms in CSF. When the broad-range PCR is positive, a PCR that uses specific bacterial primers to detect the nucleic acid of S pneumoniae, N meningitidis, E coli, L monocytogenes, H influenzae and S agalactiae should be done. However, although these tools are promising, further
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14 Practical Neurology refinements are needed before PCR can be routinely recommended.16, 17

TABLE 3 Specific antimicrobial therapy in community-acquired bacterial meningitis based on cerebrospinal fluid culture results and in vitro susceptibility testing
Microorganism, susceptibility

BLOOD TESTS
Standard therapy Alternative therapies

Streptococcus pneumoniae Penicillin minimal inhibitory concentration (MIC) Penicillin G or ampicillin Cefotaxime or ceftriaxone, ,0.1 mg/l chloramphenicol Cefotaxime or Cefepime, meropenem 0.11.0 mg/l ceftriaxone Fluoroquinolone{ Vancomycin plus >2.0 mg/l cefotaxime or ceftriaxone* Cefotaxime or ceftriaxone MIC Fluoroquinolone{ Vancomycin plus >1.0 mg/l cefotaxime or ceftriaxone{ Neisseria meningitidis Penicillin MIC Penicillin G or ampicillin Cefotaxime or ceftriaxone, ,0.1 mg/l chloramphenicol Cefotaxime or Chloramphenicol, fluoroquinolone, 0.11.0 mg/l ceftriaxone meropenem Penicillin G or ampicillin"Trimethoprim-sulfamethoxazole, Listeria meropenem, monocytogenes Penicillin G or ampicillin"Cefotaxime or ceftriaxone Group B streptococcus Aztreonam," fluoroquinolone, Escherichia coli and Cefotaxime or ceftriaxone" meropenem," trimethoprimother sulfamethoxazole, ampicillin" enterobacteriaceae Ceftazidime" or Aztreonam," ciprofloxacin," Pseudomonas cefepime" meropenem" aeruginosa Haemophilus influenzae Ampicillin Cefotaxime or ceftriaxone, b-Lactamase cefepime, chloramphenicol, negative fluoroquinolone Cefotaxime or Cefepime, chloramphenicol, b-Lactamase ceftriaxone fluoroquinolone positive Chemoprophylaxis1 Neisseria meningitidis Rifampicin (rifampin), ceftriaxone, ciprofloxacin, azithromycin This material was previously published as part of an online supplementary appendix to van de Beek et al.4 Copyright 2006 Massachusetts Medical Society. All rights reserved. *Consider addition of rifampicin (rifampin) if dexamethasone is given. {Gatifloxacin or moxifloxacin; no clinical data in patients with bacterial meningitis. {Consider addition of rifampicin (rifampin) if the MIC of ceftriaxone is >2 mg/l. "Consider addition of an aminoglycoside. 1Prophylaxis is indicated for close contacts, defined as those with intimate contact, which covers those eating and sleeping in the same dwelling as well as those having close social and kissing contacts; or healthcare workers who perform mouth-to-mouth resuscitation, endotracheal intubation or endotracheal tube management. Patients with meningococcal meningitis who are treated with monotherapy of penicillin or amoxicillin (ampicillin) should also receive chemoprophylaxis, because carriage is not reliably eradicated by these drugs.1 4

When bacterial meningitis is suspected, blood cultures should be drawn first, followed by leukocyte count with differential cell count, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), sodium, potassium, urea, creatinine, glucose, haemoglobin, haematocrit, platelets, activated partial thromboplastin time (APTT), prothrombin time (PT) and serum lactate. In most cases, and especially when pneumonia or an impaired level of consciousness are present, arterial blood gases are also required.

Measurement of CRP may be helpful in distinguishing viral from bacterial meningitis, with sensitivities from 6999% and specificities from 2899%.1820 Procalcitonin might also be helpful; it increases during severe infection, and high levels have been reported in children and adults with severe bacterial infection. More readily available, a leukocytosis with left shift in the differential cell count is also a marker for bacterial infection and helps distinguish bacterial from viral meningitis. Several prediction rules combining serum and CSF markers to exclude bacterial meningitis have been published, especially for children, but their use for clinical decisions in individual patients is discouraged by the bacterial meningitis guideline of the Infectious Disease Society of America.18 Disorders of sodium homeostasis frequently accompany bacterial meningitis and will be discussed later. Monitoring kidney function is important, especially in patients who develop septic shock, and those with pre-existing renal disease. Hyperglycaemia and insulin resistance occur frequently in patients with sepsis.21 High serum glucose concentrations are associated with lower scores on the Glasgow Coma Scale on admission and with unfavourable outcome (van de Beek D, unpublished data).2 Although randomised trials should be carried out to demonstrate a beneficial effect of intensive insulin therapy in patients with bacterial meningitis and hyperglycaemia,

N N

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Schut, de Gans, van de Beek 15

maintaining normoglycaemia seems prudent for now.

TABLE 4 General recommendations for intravenous empirical antibiotic treatment

Treatment Penicillin Amoxicillin or ampicillin Vancomycin Third generation cephalosporins ceftriaxone cefotaxime cefepime ceftazidime Meropenem Chloramphenicol Fluoroquinolones gatifloxacin moxifloxacin Trimethoprim-sulfamethoxazole Aztreonam Ciprofloxacin Rifampicin (rifampin) Aminoglycoside gentamicin Dose 2 million units every 4 h 2 g every 4 h 15 mg/kg every 8 h 2 g every 12 h 2 g every 46 h 2 g every 8 h 2 g every 8 h 2 g every 8 h 11.5 g every 6 h 400 mg every 24 h 400 mg every 24 h 5 mg/kg every 612 h 2 g every 68 h 400 mg every 812 h 600 mg every 1224 h 1.7 mg/kg every 8 h

Coagulation tests and platelet count are important, especially in patients with known coagulation disorders, before a lumbar puncture is carried out, and in patients suspected of developing disseminated intravascular coagulation as a systemic complication of bacterial meningitis; however, these laboratory investigations should not delay a lumbar puncture if there are no clinical signs of coagulopathy. In patients receiving anticoagulants who are suspected of having bacterial meningitis, empirical treatment should be started and anticoagulation should temporarily be reversed in order to safely perform a lumbar puncture.

ANTIMICROBIAL TREATMENT
The choice of antibiotic for empirical therapy (that is, before the organism is known) is based on the possibility that a penicillin- and cephalosporin-resistant strain of S pneumoniae is the causative organism, and on the patients age and any associated conditions that may have predisposed to meningitis (table 2). For adults up to 50 years old from countries with high rates of pneumococcal penicillin- or cephalosporin-resistance, this should be a combination of either a third- or fourth-generation cephalosporin plus vancomycin.4, 18 In countries with very low rates of pneumococcal penicillin-resistance (such as The Netherlands), penicillin can still be used safely as a first-line agent.22 In the UK, the addition of vancomycin is also not considered necessary and is not recommended unless the patient presents from one of the geographic regions associated with high-level ceftriaxone resistance, such as Spain, Southern Africa, and certain parts of the USA. In adults older than 50 years, and in the immunocompromised patient, ampicillin should be added to this combination because of possible Listeria meningitis. Once the bacterial pathogen is isolated and the sensitivity of the organism to the antibiotic is confirmed by in vitro testing, antimicrobial therapy should be modified accordingly. Recommendations for antibiotic therapy in bacterial meningitis are summarised in tables 35 and some important tips are:

TABLE 5 General recommendations for chemoprophylaxis

Treatment Rifampicin (rifampin) Ceftriaxone Ciprofloxacin Azithromycin Dose 600 mg oral twice daily for two days One dose 250 mg intramuscularly One dose, 500 mg orally One dose, 500 mg orally

N N

Bacterial meningitis due to S pneumoniae, H influenzae and group B streptococci is usually treated with intravenous antibiotics for 1014 days. Meningitis due to N meningitidis is treated for 57 days. Patients with clinically suspected meningococcal meningitis who are treated with penicillin must be isolated for the first 24 h after initiation of antibiotic therapy and also treated with rifampin 600 mg orally every 12 h for 2 days to eradicate nasopharyngeal colonisation (penicillin does not eradicate the organisms in the nasopharynx). Meningitis due to L monocytogenes and Enterobacteriaceae is treated for 3 4 weeks.
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16 Practical Neurology

Figure 2 Neurological complications of bacterial meningitis. (A) T2-weighted MR brain scan showing hyperintense signal in the cerebral hemispheres (arrows) indicating cerebral oedema. (B) Unenhanced brain CT showing complete effacement of the basal cisterns (arrow) indicating impending herniation. (C) Unenhanced brain CT showing communicating hydrocephalus with dilatation of the lateral and third ventricles. (D) Contrast-enhanced brain CT showing a hypodense subdural collection (arrow) over the anterior convexity of the left cerebral hemisphere, with an enhancing rim, indicating a subdural empyema.

Gentamicin is added to ampicillin in critically ill patients with L monocytogenes meningitis.

ADJUNCTIVE DEXAMETHASONE
After being argued about for decades it is now clear from the results of a large randomised trial that dexamethasone (10 mg iv 1520 min before or with the first dose of antibiotic and given every 6 h for 4 days) is beneficial in adults with acute bacterial meningitis;23 unfavourable outcome was reduced from 25% to 15%, and mortality from 15% to 7%. The benefits were most striking in patients with
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pneumococcal meningitis. Furthermore, patients on dexamethasone were less likely to have impaired consciousness, seizures and cardiorespiratory failure. At present, the benefits of adjunctive dexamethasone treatment are unclear when dexamethasone is started several hours or days after initiation of antibiotics, highlighting the importance of prompt treatment. Dexamethasone should preferably be given with the first dose of parenteral antibiotics, but we would use dexamethasone within a timeframe of a few hours after the initiation of parenteral antibioticsalthough this is not

Schut, de Gans, van de Beek 17

Figure 3 Arterial cerebral infarction complicating acute bacterial meningitis. (A) Axial T2weighted MR brain scan showing a hyperintense signal in the cerebellar vermis (arrow). (B) Axial diffusionweighted imaging (DWI) shows increased signal in the same area. (C) This bright DWI signal was confirmed to represent an area of restricted diffusion on the apparent diffusion coefficient map. (D) Macroscopic postmortem sagittal view of the cerebellum of the same patient showing necrosis of part of the vermis (arrow). (E) Areas of confluent necrosis with loss of staining for haematoxylin and eosin. (F) Microscopic view of the affected part of the vermis shows vacuolisation of white matter (arrow) and loss of Purkinje cells.

supported by systematic evidence. For some adults with suspected meningitis, the beneficial effect of adjunctive dexamethasone is less certain, or may even be harmful. We do not recommend steroids in patients with postneurosurgical meningitis or those with a severe immunocompromised state (HIV infection), nor in those who are hypersensitive to steroids.

patients in whom septic shock is suspected and the platelet count and coagulation tests are important in those in whom disseminated intravascular coagulation is suspected. Core body temperatures exceeding 40 C should be treated with antipyretic agents and cooling blankets if necessary to avoid excessive fluid loss.

MONITORING OF THE PATIENT AFTER ADMISSION AND COMPLICATIONS

Patients who are diagnosed with acute bacterial meningitis are at risk of various neurological and systemic complications, and to detect them patients should be admitted to a highdependency unit where the following should be monitored: vital signs (blood pressure, heart rate, respiratory rate, temperature), oxygen saturation, level of consciousness (using the Glasgow Coma Scale), presence or absence of focal neurological signs or symptoms, pupillary diameter, and certain laboratory parameters, like CRP, leukocyte count, electrolytes, urea and creatinine. Analysis of arterial blood gases and measurement of serum lactate are important in

SYSTEMIC COMPLICATIONS Hypotension, septic shock and adult respiratory distress syndrome
Septic shock is an important predictor of poor outcome2, 24 and may manifest in several ways: hypotension (systolic BP (90 mm Hg or a reduction of >40 mm Hg from baseline) despite adequate fluid resuscitation, tachycardia (.100/min), tachypnoea (.20/min), core body temperature .38 C or ,36 C, drowsiness and oliguria. Dyspnoea, laboured breathing, agitation, followed by progressive drowsiness, tachycardia, scattered crackles on pulmonary auscultation and hypoxaemia (as documented by arterial blood gas analysis) point to the diagnosis of adult respiratory
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18 Practical Neurology
distress syndrome (ARDS). The chest x ray usually reveals characteristic diffuse alveolarinterstitial infiltrates in all lung fields. Both septic shock and ARDS require management in an intensive care unit, and specific recommendations can be found elsewhere.25, 26 with a higher heart rate, lower CSF protein and lower CSF glucose levels. Overall, patients with hypernatraemia are admitted with more severe disease, reflected by lower levels of consciousness, and hypernatraemia is independently predictive of unfavourable outcome and mortality; however, it is unclear whether this is because it reflects severe disease or directly contributes to the poor outcome. Severe brain injury can lead to reductions in antidiuretic hormone secretion resulting in diabetes insipidus, but diabetes insipidus has been described only sporadically in bacterial meningitis. Physicians should be aware of the potential importance of hypernatraemia in patients presenting with bacterial meningitis and care should be taken in their fluid management. Whether this improves prognosis is still uncertain.

Hyponatraemia
Hyponatraemia (serum sodium ,135 mmol/l) on admission to hospital is found in 30% of patients with culture-proven acute bacterial meningitis.27 Most episodes of hyponatraemia resolve within a few days without specific treatment, and hyponatraemia does not influence outcome. Severe hyponatraemia (,130 mmol/l) is present in 6% of patients. An exceptionally high frequency of hyponatraemia is seen in meningitis due to L monocytogenes (73%) and S pyogenes. (58%).28 The cause of hyponatraemia is unclear29 but may be from cerebral salt wasting, the syndrome of inappropriate antidiuretic hormone secretion (SIADH), or from too aggressive fluid resuscitation. Differentiation between cerebral salt wasting and SIADH requires measurement of extracellular fluid volume.30 Unfortunately, the clinical assessment of extracellular fluid volume has a notoriously low sensitivity and specificity,31 and invasive measurement is cumbersome. Patients with bacterial meningitis who develop hyponatraemia should not automatically be assumed to have SIADH and be fluid restricted. Instead, the goal of fluid management should be to maintain a normovolaemic state and in patients with severe hyponatraemia we would rather use fluid maintenance therapy then fluid restriction, although there is no clear evidence supporting this approach.

Arthritis
The coexistence of bacterial meningitis and arthritis has been described in several studies;24, 3335 it occurs in 7% of patients overall,36 more in meningococcal meningitis (12%). It is caused either by haematogenous bacterial seeding of joints (septic arthritis) or by immune-complex deposition in joints (immunomediated arthritis). Non-gonococcal bacterial arthritis often presents with the abrupt onset of a single hot, swollen and very painful jointthe knee being the site of infection in half the cases, but any joint may be involved. Culture of synovial fluid yields bacteria in only 26% of patients. A patient with immunomediated arthritis during meningococcal infection typically develops symptoms from day 5 of the illness or during recovery from the infection, generally involving the large joints. Although history and physical examination may provide important clues, it is often difficult to discriminate between infectious and noninfectious causes. The differential diagnosis in patients further includes gout and pseudogout, which commonly flare up during stress and acute medical illness. A definitive diagnosis of septic arthritis requires identification of bacteria in the synovial fluid by Gram stain or culture. The treatment of acute bacterial arthritis requires antibiotics and joint drainage. Although some limitation in the range of movement was found in 23% of our patients

Hypernatraemia
While hyponatraemia is relatively frequent and usually benign, the same cannot be said of hypernatraemia (serum sodium .143 mmol/l) which is found on admission in 7% of patients with culture-proven bacterial meningitis.32 Patients with sodium levels >146 mmol/l (2% of patients) are more likely to have seizures before admission compared to those with lower levels. Sodium levels of >143 mmol/l are associated
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Schut, de Gans, van de Beek 19 with meningitis and arthritis, functional outcome was good in most of them.
outcome in patients with advanced stages of cerebral oedema, we only recommend an intracranial pressure monitoring device in young (,50 years) patients without comorbidity, and as a last resort.

APPROACH TO THE PATIENT WITH A FALLING CONSCIOUSNESS LEVEL

Patients with bacterial meningitis often present with impairment of consciousness, the cause of which is not completely understood.15, 37 The release of proinflammatory cytokines in the subarachnoid space leads to an inflammatory response in the CNS that contributes to increased permeability of the blood-brain barrier, resulting in vasogenic oedema and the formation of proteinaceous exudates in the subarachnoid space. These proteinaceous exudates cause obstruction to outflow and resorption of CSF, leading to interstitial oedema. The migration of polymorphonuclear cells into the CSF leads to their degranulation and release of toxic metabolites, resulting in cortical inflammation and cytotoxic oedema. The net result is cerebral oedema and an increase in intracranial pressure. Loss of cerebral autoregulation, thought to be caused by inflammation and thrombosis of small cerebral arteries, results in impairment of cerebral blood flow, further compromising normal cortical function. The development of coma in bacterial meningitis portends a poor prognosis2, 24 and the patients should be rapidly evaluated for the most common causes: cerebral oedema, hydrocephalus, seizure activity or infarction of brain tissue due to inflammatory occlusion of basal vessels or septic intracranial venous thrombosis (figs 2 and 3). Some of these complicationsfor example, cerebral oedema and cerebral infarctionare difficult to treat, others howeverfor example, hydrocephalus or seizurescan often be treated effectively. To distinguish between these possibilities, brain CT or MRI is critical.

Hydrocephalus
Cerebrospinal fluid is formed by the choroid plexus in the lateral ventricles, from where it flows via the third and fourth ventricles through the foramina of Luschka and Magendie to the subarachnoid space. It is absorbed through the arachnoid villi in the intracranial venous sinuses. In bacterial meningitis a purulent exudate forms over the cerebral hemispheres where it interferes with CSF absorption by the arachnoid villi, resulting in communicating hydrocephalus (fig 2C). When the inflammatory exudate involves the basal cisterns and surrounds the cranial nerves at the base of the brain (basilar meningitis), it may block CSF flow at the foramina of Luschka and Magendie, resulting in obstructive hydrocephalus. Obstructive hydrocephalus may also complicate infratentorial subdural empyema. In patients with communicating hydrocephalus, we recommend repeated lumbar punctures (with measurement of CSF pressure) or the temporary insertion of a lumbar drain. In patients with mild enlargement of the ventricular system without clinical deterioration, spontaneous resolution may occur and watchful waiting may be justified. Acute obstructive hydrocephalus requires ventricular drainage.39

Cerebral infarction
Cerebral infarction (fig 3) due to arterial occlusion complicates bacterial meningitis in 1015% of patients,2, 4 venous infarction due to septic venous thrombosis occurs in 35%. Infarction of paramedian thalamic or brain stem nuclei due to septic arteriitis of basal vessels or septic venous thrombosis may rarely cause coma and we have seen patients who developed this devastating complication late (approximately 10 days) in the course of their treatment. Arteritis of small and medium-sized arteries and inflammatory involvement of veins is probably caused by tissuedestructive agents, such as oxidants and proteolytic enzymes, released by activated
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Cerebral oedema
A CT scan is necessary to make the diagnosis of cerebral oedema; early signs are effacement of the perisylvian fissures, narrowing of ventricular size, effacement of cerebral sulci, and obliteration of the basal cisterns (fig 2B). Although mannitol and hyperventilation are often tried,38 there are no randomised trials to support their use. Given the invariably poor

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Figure 4 Prediction rule for risk of unfavourable outcome in adults with bacterial meningitis. Tachycardia is defined as a heart rate greater than 120 beats/min, low cerebrospinal fluid (CSF) leukocyte count as ,1000 cells/mm3. Result of CSF Gram stain: G2, gram-negative cocci; No, no bacteria; Other, other bacterial species; G+, gram-positive cocci. Locate the age of the patient on the top axis and determine how many points the patient receives. Repeat this for the remaining five axes. Sum the points for all six predictors and locate the total sum on the total point axis. Draw a line straight down to the axis labeled % unfavourable outcome to find the estimated probability of an unfavorable outcome for this patient. (This material was previously published as part of reference 57. Copyright 2007 John Wiley & Sons, Inc. All rights reserved.)

leukocytes. Treatment is mainly supportive and these patients have a poor outcome.

with renal insufficiency, and when there are no other obvious causes of seizures.

Seizures
Seizures occur in about 20% of patients with bacterial meningitis.2, 4 These patients tend to be older, are more likely to have focal abnormalities on brain CT and to have S pneumoniae as the causative micro-organism, and they have a higher mortality.40 If a patient with a falling conscious level has a normal brain CT and normal serum electrolytes, then an EEG should be performed to look for seizure activity. The high mortality warrants a low threshold for starting antiepileptic therapy in those with clinical suspicion of seizures. A rare cause of seizures, asterixis and encephalopathy is the neurotoxic effect of certain antimicrobial agents (cefuroxime, penicillin, imipenem)41, 42 which should be suspected in a patient with prior stroke or Parkinsons disease and in those

APPROACH TO THE PATIENT WHO DEVELOPS FOCAL NEUROLOGICAL SIGNS

In patients who develop focal neurological signs (hemiparesis, monoparesis, aphasia) the following should be sought: cerebral infarction (due to inflammatory occlusion of cerebral arteries, septic venous thrombosis), seizures, subdural empyema or a combination of these causes.2, 4, 24, 43, 44 Again, an unenhanced brain CT scan is needed to rule out many of these causes.

The high mortality warrants a low threshold for starting antiepileptic therapy in those with clinical suspicion of seizures
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The possibility of septic intracranial venous thrombosis should be considered in patients with an impaired level of consciousness, seizures, fluctuating focal signs and stroke in non-arterial distributions when MR venography can help confirm the diagnosis.44 Subdural empyema should be suspected in patients who have concomitant sinusitis or mastoiditis, or who have recently undergone surgery for either of these disorders.45 In most cases contrast-enhanced brain CT will reveal the hypodense subdural

Schut, de Gans, van de Beek 21

collections (fig 2D). Brain MRI is more sensitive than CT in detecting subdural empyema along the convexity, and especially for infratentorial subdural empyema because CT is bedevilled by scanning artefacts in the posterior fossa. 4 6 Currently, MRI with diffusion-weighted images (DWI) and apparent diffusion coefficient mapping (ADC) remains the preferred imaging modality for detecting subdural empyema, especially infratentorial subdural empyema, because of its multiplanar capabilities, improved soft tissue imaging, and the lack of scanning artefacts at the skull base. Subdural empyema should be surgically drained by craniotomy but the outcome is poor if the patient is unconscious.

PRACTICE POINTS
l

WHEN TO REPEAT THE LUMBAR PUNCTURE

A repeat analysis of the cerebrospinal fluid should only be carried out in patients whose condition has not responded clinically after 48 hours of appropriate antimicrobial and adjunctive dexamethasone treatment. It is essential when pneumococcal meningitis caused by penicillin-resistant or cephalosporin-resistant strains is suspected. Gram staining and culture of the cerebrospinal fluid should be negative after 24 hours of appropriate antimicrobial therapy.

The most common causes of community-acquired bacterial meningitis in adults are Streptococcus pneumoniae and Neisseria meningitidis. The absence of neck rigidity, Kernigs sign and Brudzinskis sign does not rule out acute bacterial meningitis. The first step in the management of acute bacterial meningitis is to obtain blood cultures and start adjunctive dexamethasone and antimicrobial therapy; timing is critical, dexamethasone should be administered either before or with the first dose of antibiotic. Empirical antimicrobial therapy is based on the possibility that a penicillinand cephalosporin-resistant strain of S pneumoniae is the causative organism, geography, patient age and any associated conditions. It is reasonably safe to do a lumbar puncture without a brain CT scan if there are no signs of a space-occupying lesion (papilloedema or focal neurological signs, not including cranial nerve palsy), new-onset seizure, moderate-to-severe impairment of consciousness, or an immunocompromised state. Patients with clinically suspected meningococcal meningitis must be isolated for the first 24 hours after initiation of antibiotic therapy.

OUTCOME
Acute bacterial meningitis caused by S pneumoniae has a high mortality, from 1937%.2, 4, 24, 50 The mortality of meningococcal meningitis is lower, from 313%. In up to a third of survivors, long-term neurological sequelae develop, including hearing loss (14%) and focal neurological deficits (hemiparesis, monoparesis, aphasia). Cognitive impairment occurs in up to one third of patients,51 more so in those who have had pneumococcal rather than meningococcal meningitis. Over the years, patients tend to report fewer complaints, but the cognitive impairment does not seem to improve. The strongest risk factors for poor outcome are systemic compromise (shock, adult respiratory distress syndrome, pneumonia), impairment of consciousness, low white cell count (less than 100/ml) in the CSF, and infection with S pneumoniae.2 Recently, we have constructed and validated a simple model for predicting outcome, using six variables that are routinely available within one hour of admission (age, heart rate, score on the Glasgow Coma Scale, presence or absence of cranial nerve palsies, a CSF leukocyte count ,1000/ml, and the presence of Gram positive cocci on CSF Gram stain). This helps to identify high-risk individuals and provides important information for patients and their relatives (fig 4).52
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RECURRENT BACTERIAL MENINGITIS

Recurrent bacterial meningitis occurs in 5% of community-acquired bacterial meningitis cases, and most patients have a predisposing condition, particularly head injury and CSF leak, only occasionally impairment of humoral immunity.47 In patients with no apparent cause of recurrent meningitis or known history of head trauma, the high prevalence of remote head injury and CSF leakage justifies an active search for anatomical defects and CSF leakage. Detection of b-2 transferrine in nasal discharge is a sensitive and specific method to confirm a CSF leak,48 and thin-slice CT of the skull base is best to detect small bone defects. It should be borne in mind however that the detection of a small bone defect does not prove CSF leakage. Surgical repair has a high chance of success with low mortality and morbidity.49

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ACKNOWLEDGEMENT
This article was reviewed by Guy Thwaites, London, UK.

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