171 Meningitis, Encephalitis, and Brain Abscess
Key Points• There is significant overlap among the initial clinical presentations of meningitis, encephalitis, and brain abscess.
• The four most common bacteria responsible for adult bacterial meningitis are Streptococcus pneumoniae, Neisseria meningitides, Haemophilus influenzae type B, and Listeria monocytogenes. Group B Streptococcus remains the predominate cause of meningitis in infants less than 2 months of age.
• The classic constellation of fever, neck stiffness, headache, and change in mental status are seen in less than 50% of cases of acute bacterial meningitis.
• Cranial computed tomography (CT) scan, prior to lumbar puncture, is recommended in patients with a history of immunocompromised state, history of central nervous system (CNS) disease, new-onset seizure, abnormal neurologic examination, papilledema, altered mental status, or altered level of consciousness.
• Empiric therapy in patients with high clinical suspicion for CNS infection should not be delayed for neuroimaging or lumbar puncture.
• Although epidemiologic clues and assessment of risk factors should be sought in all patients with encephalitis, herpes simplex virus and arboviruses remain the most common causes of nonepidemic and epidemic outbreaks of encephalitis, respectively, in the United States.
• Acyclovir should be initiated in all patients with suspected encephalitis, pending the results of diagnostic studies.
• Risk factors for the development of intracranial abscess include inadequately treated subacute or chronic ear, nose, mastoid, and dental infection; endocarditis; congenital heart disease; and having undergone neurosurgical procedures.
• Patients with intracranial abscess often present with mild headache symptoms in the weeks to months prior the emergency department visit. The classic triad of fever, headache, and focal neurologic deficit is seen in less than 20% of patients with brain abscess.
Meningitis
Epidemiology
The combination of routine vaccination against Streptococcus pneumoniae, Haemophilus influenzae type B, and Neisseria meningitides, maternal screening for and intrapartum treatment of group B Streptococcus (Streptococcus agalactiae), and enhanced efforts to reduce the contamination of processed foods by Listeria monocytogenes have all led to a significant decrease in the incidence of acute bacterial meningitis (ABM). Data from the Emerging Infections Programs Network, established by the Centers for Disease Control and Prevention (CDC), have noted a decrease in the incidence of meningitis from 2.0 cases per 100,000 population in 1998 to 1999 to 1.38 cases per 100,000 population in 2006 to 2007.1 During this same time the case fatality rate decreased to 14.3%. Projecting these data on a national level reveals an estimated 4100 cases and 500 deaths from bacterial meningitis annually in the United States.1
Etiology
A 10-year review (1998 to 2007) of 3188 cases of bacterial meningitis noted that S. pneumoniae accounted for the greatest proportion of cases (58%), followed by group B. streptococcus (18.1%), N. meningitides (13.9%), H. influenzae (6.7%), and L. monocytogenes (3.4%).1 Among infants less than 3 months of age, group B Streptococcus and gram-negative rods account for most cases of ABM. After 3 months of age, S. pneumoniae and N. meningitidis become the predominant pathogens. L. monocytogenes is primarily seen in infants less than 1 month of age, in adults more than 50 years old, and in immunocompromised patients. Staphylococcus aureus is acquired mainly nosocomially and occurs predominantly after neurosurgical procedures or following penetrating head trauma. S. aureus may be acquired in the community setting, linked to predisposing conditions such as endocarditis, injection drug use, and compromised immune systems.
Pathophysiology
ABM develops after encapsulated bacteria, which have colonized the nasopharynx and/or oropharynx, penetrate the intravascular space and enter the subarachnoid space through vulnerable sites within the blood-brain barrier.2 Once the pathogens enter the central nervous system (CNS), they replicate rapidly, thus consuming glucose and liberating protein within the cerebrospinal fluid (CSF). The ensuing inflammatory reaction occurs in response to the liberation of bacterial cell wall and cell membrane components (e.g., lipopolysaccharide, peptidoglycan, lipoteichoic acid) and the induction of proinflammatory mediators. These events culminate in injury to the vascular endothelium that results in increased vascular permeability to the blood-brain barrier, meningeal inflammation, and cerebral vasculitis. The accompanying cerebral edema and increase in intracranial pressure (ICP) contribute to CNS hypoperfusion and cell death.
Presenting Signs and Symptoms
Patients with ABM typically appear ill and often present within 24 to 72 hours of symptom onset. Table 171.1 reviews the presenting signs and symptoms of adults with ABM.3 The cardinal symptoms of ABM (i.e., fever, neck stiffness, change in mental status, and headache) are seen in combination in less than half of all patients. Nearly 95% of patients will present with at least two of these cardinal symptoms, which provides the rationale for performing a lumbar puncture in patients who are lethargic or confused and develop a fever. The absence of these four findings typically excludes the diagnosis of ABM.
Table 171.1 Findings in 696 Episodes of Bacterial Meningitis
| SIGN OR SYMPTOM | FREQUENCY (%) |
|---|---|
| Duration of symptoms ≤ 24 hr | 48 |
| Fever (temperature ≥ 38° C) | 77 |
| Headache | 87 |
| Nausea or vomiting | 74 |
| Neck stiffness | 83 |
| GCS ≤ 14 (AMS) | 69 |
| GCS ≤ 8 (coma) | 14 |
| Rash | 26 |
| Focal neurologic deficit | 33 |
| Seizures | 5 |
| Arthritis | 7 |
AMS, altered mental status; GCS, Glasgow Coma Scale.
From Van de Beek D, de Gans J, Spanjaard L, et al. Clinical features and prognostic factors in adults with bacterial meningitis. N Engl J Med 2004;351:1849-59.
The headache described by patients with ABM can be moderate to severe in intensity, generalized, often with an occipital or nuchal component, and unlike “normal” headaches. Photophobia is commonly present, as is nausea. Worsening of the headache while the examiner rapidly turns the patient’s head from side to side (at a rate of two to three times per second), the so-called jolt accentuation test, has been reported to be helpful in identifying patients with ABM,4 but a recent study questioned the utility of this finding.5
Although neck pain may be infrequently reported, the objective finding of neck stiffness is seen in more than 80% of patients. Examining the neck for rigidity, during gentle forward flexion, with the patient in the supine position best assesses neck stiffness, whereas difficulty in lateral motion of the neck is a less reliable finding. Patients with severe meningeal irritation may spontaneously assume the tripod position (also called the Amoss sign or the Hoyne sign) with the knees and hips flexed, the back arched lordotically, the neck extended, and the arms brought back to support the thorax.6 The Kernig sign is performed with the patient lying supine and the hip and knee flexed to 90 degrees. A positive sign is present when extension of the knee from this position elicits resistance or pain in the lower back or posterior thigh. The classic Brudzinski sign refers to spontaneous flexion of the knees and hips during attempted passive flexion of the neck. A separate sign described by Brudzinski, the contralateral reflex, is present if passive flexion of one hip and knee causes flexion of the contralateral leg. The presence or absence of Kernig or Brudzinski signs has been shown to have little positive or negative predictive value in the diagnosis of ABM, unless severe meningeal inflammation is present.7
Atypical presentations of ABM occur in infants, older adults, and immunocompromised patients. Infants with bacterial meningitis may present with fever or hypothermia, hypoglycemia, poor feeding, seizures, or irritability (excessive or abnormal crying). On examination, the findings of jaundice, ill appearance, a bulging fontanelle, meningeal irritation (including neck stiffness, the Kernig sign, and the Brudzinski sign), fever higher than 40° C, and increased general body tone predict bacterial meningitis.8
Older and immunocompromised patients may also present atypically. These populations are associated with a higher rate of misdiagnosis that contributes to an increase in the morbidity and mortality following an episode of acute meningitis. A lower proportion of fever, headache, and nausea or vomiting is present in these subgroups.9 Neck stiffness has a lower sensitivity and specificity for meningitis in older patients. Finally, these populations may present to the emergency department (ED) with altered mental status and/or altered level of consciousness but without a fever.
Differential Diagnosis
The differential diagnosis of patients presenting with fever, headache, and altered mental status includes other forms of meningitis (e.g., nosocomial meningitis, aseptic meningitis), encephalitis, and cerebral abscess. The diagnosis of meningitis is challenging in patients who present atypically. In a review of 156 cases of meningitis in patients who presented to a single tertiary care hospital, 66 cases were initially misdiagnosed in the ED as an alternative infection (i.e., sepsis of unclear origin, pneumonia, urinary tract infection), metabolic encephalopathy, or nonspecific conditions (e.g., weakness, malaise, degenerative state). Higher percentages of these patients were more than 65 years of age, and these patients were also noted to have lower proportions of fever, headache, nausea or vomiting, and neck stiffness.10
Aseptic meningitis refers to a disorder in which patients have clinical and laboratory evidence of meningeal irritation with negative results of routine bacterial cultures. Precise epidemiologic data on the incidence of aseptic meningitis are lacking, but aseptic meningitis is associated with an estimated 26,000 to 42,000 hospitalizations per year in the United States. The origin of aseptic meningitis is varied (Box 171.1). Enteroviruses, the leading causes of viral meningitis in adults and children, account for 50% to 75% of all cases of aseptic meningitis. Additional causes include other infections (mycobacteria, fungi, spirochetes), parameningeal infections, medications (especially nonsteroidal antiinflammatory drugs), and malignant disease. The signs and symptoms of bacterial meningitis significantly overlap with those of aseptic meningitis. This overlap led to the development of several decision rules to distinguish the two conditions. The most useful pediatric score appears to be the Bacterial Meningitis Score. This score classifies patients 1 month to 18 years old as being at very low risk of bacterial meningitis if they lack all the following criteria: positive CSF Gram stain, CSF absolute neutrophil count (ANC) of at least 1000 cells/mcL, CSF protein of at least 80 mg/dL, peripheral blood ANC of at least 10,000 cells/mcL, and a history of seizure before or at the time of presentation.11
Medical Decision Making
Routine Laboratory Tests
Routine testing of patients with suspected meningitis should include complete blood cell count (CBC), serum electrolytes, bicarbonate, serum urea nitrogen (BUN), creatinine, and glucose (Table 171.2). Serum lactate determinations and blood cultures are also indicated in patients with suspected meningitis.
Table 171.2 Suggested Laboratory Testing in Suspected Meningitis
| BLOOD TEST | COMMENT |
|---|---|
| Complete blood count | WBC typically elevated with left shift, although normal or low values in infants and immunosuppressed patients |
| Electrolytes | Hyponatremia (Na < 135 mmol/L) seen in 30% of cases of ABM |
| Bicarbonate | Alkalosis seen with excessive vomiting, acidosis seen with poor tissue perfusion |
| BUN, creatinine | Renal function tests essential for antibiotic dosing and timing |
| Glucose | Useful in calculating the CSF/serum glucose ratio and in the initial evaluation of altered mental status or altered level of consciousness |
| Lactate | Has prognostic information (i.e., correlates with mortality) and used to identify candidates for early goal-directed therapy |
| Blood cultures | Positive results in 50% to 75% of patients with ABM when obtained before antibiotic administration |
ABM, Acute bacterial meningitis; BUN, blood urea nitrogen; CSF, cerebrospinal fluid; Na, sodium; WBC, white blood cell count.
Several newer tests have shown potential in distinguishing bacterial meningitis from nonbacterial meningitis. These tests include serum procalcitonin,12 serum C-reactive protein,13 CSF cortisol,14 and CSF lactate.15 Additional tests employing common biochemical laboratory techniques (e.g., latex agglutination, enzyme-linked immunosorbent assay, polymerase chain reaction [PCR] assay, microarrays) have shown significant promise in identifying the specific pathogen responsible for infection.
Neuroimaging Before Lumbar Puncture
Selected patients with meningitis may warrant a computed tomography (CT) scan of the head, to identify patients with lesions that place them at risk for herniation from LP and to diagnose conditions that would make LP unnecessary if the patient’s work-up was limited to the LP (e.g., tumor, cerebral abscess). Unfortunately, cranial CT has inadequate sensitivity for identifying patients at risk for brain herniation. A systematic review on this subject found only a handful of cases of brain herniation that occurred following a normal cranial CT scan.16 Despite this limitation, generally accepted criteria for obtaining a cranial CT scan before LP are listed in Box 171.2. For maximal sensitivity in those patients with suspected or confirmed human immunodeficiency virus infection, contrast-enhanced cranial CT should be performed at the same time as the nonenhanced cranial CT.
Box 171.2
General Recommendations for Computed Tomography Before Lumbar Puncture17
History of immunocompromised state
History of central nervous system disease (e.g., mass lesion, stroke, focal infection)
New-onset seizure (or new-onset seizure within 1 week of presentation)
Papilledema on funduscopic examination (or elevated optic nerve sheath diameter on ultrasound)
Hasbun R, Abrahams J, Jekel J, et al. Computed tomography of the head before lumbar puncture in adults with suspected meningitis. N Engl J Med 2001;345:1727-33.
Lumbar Puncture and Cerebrospinal Fluid Analysis
Although the diagnosis of bacterial meningitis rests on CSF examination, CSF analysis alone cannot reliably distinguish bacterial and aseptic meningitis.13 In addition to measuring the opening pressure, the examiner should obtain four tubes of CSF, each containing 1 to 2 mL of fluid, and send them for analysis. Typically tube 1 (and/or tube 4) is sent for cell count and differential, tube 2 for protein and glucose, tube 3 for Gram stain and culture, and tube 4 for special testing or additional cultures.
The appearance of the CSF can range from clear to cloudy, depending on the presence of significant concentrations of cells, bacteria, and protein. The CSF white blood cell (WBC) count can be significantly elevated, usually in the range of 1000 to 5000 cells/mm3, although this range can be quite broad (<100 to >10,000 cells/mm3). Up to 20% of adults with bacterial meningitis have a CSF WBC count lower than 1000 cells/mm3, and one third of these adults have a CSF WBC count of less than 100 cells/mm3.18 Classically, a CSF neutrophil predominance is present (seen in 80% to 95% of cases). In 10% of cases, such as in neonatal meningitis or patients infected with L. monocytogenes, a CSF lymphocyte predominance can be seen.18 In resource-depleted environments, a urinary reagent strip to determine the presence of leukocyte esterase can be used as a marker for the presence of WBCs in the CSF and a point of care glucose device can be used to rapidly obtain a CSF glucose concentration.
Despite the classic teachings on CSF findings (Table 171.3), the absence of one or more typical findings is commonly seen in patients with confirmed ABM. For example, in a review of 296 episodes of ABM, 50% of patients had a CSF glucose concentration of approximately 40 mg/dL, 44% had a CSF protein level lower than 200 mg/dL, and 13% had a CSF WBC count lower than 100 cells/mm3.19 In another series of 696 episodes of ABM, 12% had none of the characteristic CSF findings of ABM.3
