Chapter 52. Bacterial Infections of the Central Nervous System

• More than 80% of adults with bacterial meningitis present clinically with fever, headache, meningismus, and signs of cerebral dysfunction; elderly patients, however, may present with insidious disease manifested only by lethargy or obtundation, variable signs of meningeal irritation, and no fever.
• Occasionally, a patient with acute bacterial meningitis has a low cerebrospinal fluid (CSF) white cell count despite high bacterial concentrations in CSF; therefore, a Gram stain and culture should be performed on every CSF specimen, even if the cell count is normal.
• Neuroimaging techniques have little role in the diagnosis of acute bacterial meningitis. However, computed tomography (CT) should be performed before lumbar puncture when a space-occupying lesion of the central nervous system (CNS) is suspected. Clinical features at baseline associated with an abnormal CT image (in patients with suspected meningitis) are age of at least 60 years, immunocompromise, a history of CNS disease, a history of seizure within 1 week before presentation, and specific neurologic abnormalities.
• Empirical antimicrobial therapy, based on the patient's age and underlying disease status, should be initiated as soon as possible in patients with presumed bacterial meningitis; therapy should never be delayed while diagnostic tests such as CT are awaited.
• Adjunctive dexamethasone therapy has been shown to decrease the morbidity rate in infants and children with acute Haemophilus influenzae type b meningitis and, if commenced with or before antimicrobial therapy, is also beneficial for pneumococcal meningitis in childhood. A recent study has associated adjunctive dexamethasone with decreased morbidity and mortality rates in adults with pneumococcal meningitis when administered before the first dose of antimicrobial therapy.
• Only about 50% of patients with brain abscess present with the classic triad of fever, headache, and focal neurologic deficit; the clinical presentation of brain abscess in immunosuppressed patients may be masked by the diminished inflammatory response.
• The diagnosis of brain abscess has been revolutionized by the development of CT; magnetic resonance imaging may offer advantages over CT in the early detection of cerebritis, cerebral edema, and satellite lesions.
• Aspiration of brain abscess under stereotaxic CT guidance is useful for microbiologic diagnosis, drainage, and relief of increased intracranial pressure.
• A short course of corticosteroids may be useful in patients with brain abscess who have deteriorating neurologic status and increased intracranial pressure.
• Cranial subdural empyema should be suspected in patients with headache, vomiting, fever, change in mental status, and rapid progression of focal neurologic signs.
• Spinal epidural abscess may develop acutely or chronically, with symptoms and signs of focal vertebral pain, nerve root pain, motor or sensory defects, and paralysis; the transition to paralysis may be rapid, indicating the need for emergent evaluation, diagnosis, and treatment.
• Surgical therapy is essential for the management of subdural empyema because antibiotics do not reliably sterilize these lesions.
• Rapid surgical decompression should be performed in patients with spinal epidural abscess who have increasing neurologic deficit, peristent severe pain, or increasing temperature or peripheral white blood cell count.
• Lateral gaze palsy may be an early clue to the diagnosis of cavernous sinus thrombosis because the abducens nerve is the only cranial nerve traversing the interior of the cavernous sinus.
• The noninvasive diagnostic procedure of choice for suppurative intracranial thrombophlebitis is magnetic resonance imaging, which can differentiate between thrombus and normally flowing blood.

Bacterial infections of the central nervous system (CNS) are frequently devastating. The brain possesses several defense mechanisms (e.g., intact cranium and blood-brain barrier) to prevent entry of bacterial species; but once microorganisms have gained entry to the CNS, host defense mechanisms are inadequate to control the infection. Antimicrobial therapy is limited by the poor penetration of many agents into the CNS and by the ability of antibiotics to induce inflammation in the CNS via their bacteriolytic action, thereby contributing to brain damage. We review meningitis, brain abscess, subdural empyema, epidural abscess, and intracranial thrombophlebitis, with an emphasis on recent developments in diagnosis and therapy as they pertain to the care of the critically ill patient.

Epidemiology and Etiology

The rates of morbidity and mortality from bacterial meningitis remain unacceptably high despite the availability of effective antimicrobial therapy. In a surveillance study of all cases of bacterial meningitis in 27 states of the United States from 1978 to 1982, the overall annual attack rate of bacterial meningitis was approximately 3.0 cases per 100,000 population, although there was variability according to geographic area, sex, and race;1 incidences for the various meningeal pathogens are listed in Table 52-1. Bacterial meningitis is also a significant problem in hospitalized patients. In a review of 493 episodes of bacterial meningitis in adults 16 years or older from the Massachusetts General Hospital from 1962 through 1988, 40% of cases were nosocomial in origin, and these episodes carried a high mortality rate (35% for single episodes of nosocomial meningitis).2 With the introduction of Haemophilus influenzae type b conjugate vaccines in the United States and elsewhere, dramatic declines in the incidence of invasive H. influenzae type b disease have been reported; these conjugate vaccines have been licensed for routine use in all children beginning at age 2 months.3 In a study that evaluated the epidemiology of bacterial meningitis in the United States during 1995 in laboratories serving all the acute care hospitals in 22 counties in four states (Georgia, Tennessee, Maryland, and California),4 the incidence of bacterial meningitis decreased dramatically as a result of the vaccine-related decline in meningitis caused by H. influenzae type b (see Table 52-1).

Before the development of effective vaccines against it, H. influenzae type b was isolated in almost half of all cases of bacterial meningitis in the United States, but this microorganism currently accounts for only 7% of cases. About 40% to 60% of cases were seen in children ages 2 months to 6 years; of these, 90% were due to capsular type b strains. Disease is most likely initiated after nasopharyngeal acquisition of a virulent organism with subsequent systemic invasion. Haemophilus influenzae is unusual after age 6 years; isolation of the organism in this older group should suggest the possible presence of certain predisposing factors, including sinusitis, otitis media, epiglottitis, pneumonia, head trauma with a cerebrospinal fluid (CSF) leak, diabetes mellitus, alcoholism, splenectomy or asplenic states, and immune deficiency (e.g., hypogammaglobulinemia).5

Meningitis due to Neisseria meningitidis is most often found in children and young adults and may occur in epidemics. Nasopharyngeal carriage of virulent organisms accounts for initiation of infection.6 The incidence of meningococcal serogroup C disease has been increasing in North America, with several recent outbreaks reported in the United States and Canada.7,8 Infection is more likely in persons who have deficiencies in the terminal complement components (C5, C6, C7, C8, and perhaps C9), the so-called membrane attack complex; the incidence of neisserial infections is more than 8000-fold greater in this group than among other persons.9

Pneumococcal meningitis is observed most frequently in adults (>30 years) and is often associated with distant foci of infection, such as pneumonia, otitis media, mastoiditis, sinusitis, and endocarditis; this organism currently accounts for 47% of cases of bacterial meningitis in the United States.4 Serious pneumococcal infections may be observed in persons with predisposing conditions, such as splenectomy or asplenic states, multiple myeloma, hypogammaglobulinemia, and alcoholism. Streptococcus pneumoniae is the most common meningeal isolate in head trauma patients who have basilar skull fracture with subsequent CSF leakage.10

Listeria monocytogenes accounts for only about 8% of all cases of bacterial meningitis but carries a high mortality rate.4 Infection with Listeria is more likely in neonates, the elderly, alcoholics, cancer patients, and immunosuppressed adults (e.g., renal transplant patients).11,12Listeria meningitis is found infrequently in patients with human immunodeficiency virus infection,13 despite its increased incidence in patients with deficiencies in cell-mediated immunity. However, up to 30% of adults and 54% of children and young adults with listeriosis have no apparent underlying condition. Listeriosis has been associated with several food-borne outbreaks involving contaminated cole slaw, milk, cheese, and processed meats.

Meningitis due to aerobic gram-negative bacilli is observed in specific clinical situations.14Escherichia coli is isolated in 30% to 50% of infants younger than 2 months with bacterial meningitis. Klebsiella species, E. coli, and Pseudomonas aeruginosa may be isolated in patients who have had head trauma or neurosurgical procedures, in the elderly, in immunosuppressed patients, and in patients with gram-negative septicemia. Despite the low frequency of meningitis due to this group of organisms, the mortality rates are very high (∼84% with P. aeruginosa, until recently).

Specific clinical situations also predispose to the development of meningitis due to staphylococcal species.15 Staphylococcus epidermidis is the most common cause of meningitis in persons with CSF shunts. Meningitis due to Staphylococcus aureus is frequently found (when compared with other pathogens) soon after neurosurgery. Underlying diseases among persons with no prior CNS disease who develop S. aureus meningitis include diabetes mellitus, alcoholism, chronic renal failure requiring hemodialysis, and malignancies. Conditions that increase S. aureus nasal carriage rates (e.g., injection drug abuse, insulin-requiring diabetes, and hemodialysis) may also predispose to staphylococcal infection of the CNS.

Group B streptococcus (Streptococcus agalactiae) is a common cause of meningitis in neonates.16 The risk of transmission from the mother to her infant is increased when the inoculum of organisms and number of sites of maternal colonization are large; horizontal transmission has also been documented from the hands of nursery personnel to the infant. Risk factors for group B streptococcal meningitis in adults include age older than 60 years, diabetes mellitus, parturient status in women, cardiac disease, collagen vascular disease, malignancy, alcoholism, hepatic failure, renal failure, and corticosteroid therapy.17–19 No underlying illnesses were found in 43% of patients in one review.18

Clinical Presentation

The classic clinical presentation in adults with bacterial meningitis includes fever, headache, meningismus, and signs of cerebral dysfunction;20 these symptoms and signs are found in more than 80% of cases. Also seen are nausea, vomiting, rigors, profuse sweating, weakness, and myalgias. The meningismus may be subtle or marked or accompanied (rarely) by the Kernig and/or Brudzinski sign. The Kernig sign is elicited by flexing the thigh on the abdomen with the knee flexed; the leg is then passively extended, and, if there is meningeal inflammation, the patient resists leg extension. The Brudzinski sign is present when passive flexion of the neck leads to flexion of the hips and knees. However, these signs are elicited in fewer than 20% of cases of bacterial meningitis in adults. Cerebral dysfunction is manifested by confusion, delirium, or a declining level of consciousness ranging from lethargy to coma. Cranial nerve palsies (especially involving cranial nerves III, IV, VI, and VII) and focal cerebral signs are uncommon (10% to 20% of cases). Seizures occur in about 30% of all cases. Papilledema is rare (<5%) and should suggest an alternate diagnosis, such as an intracranial mass lesion. Late in the disease, patients may develop signs of increased intracranial pressure, including coma, hypertension, bradycardia, and third-nerve palsy; these findings are ominous prognostic signs.

Certain symptoms and signs may suggest an etiologic diagnosis in patients with bacterial meningitis.20 Persons with meningococcemia present with a prominent rash, principally on the extremities (∼50% of cases). Early in the disease course, the rash may be erythematous and macular, but it quickly evolves into a petechial phase, with further coalescence into a purpuric form. The rash often matures rapidly, with new petechial lesions appearing during the physical examination. A petechial, purpuric, or ecchymotic rash may also be seen in other forms of meningitis (i.e., those due to echovirus type 9, Acinetobacter species, S. aureus, and, rarely, S. pneumoniae or H. influenzae), in Rocky Mountain spotted fever or S. aureus endocarditis, and in overwhelming sepsis (due to S. pneumoniae or H. influenzae) in splenectomized patients. An additional suppurative focus of infection (e.g., otitis media, sinusitis, or pneumonia) is present in 30% of patients with pneumococcal or H. influenzae meningitis but is rarely found in meningococcal meningitis. Meningitis due to S. pneumoniae is relatively likely after head trauma in persons who have basilar skull fractures in which a dural fistula is produced between the subarachnoid space and the nasal cavity, paranasal sinuses, or middle ear.10 These persons commonly present with rhinorrhea or otorrhea due to a CSF leak; a persistent defect is a common explanation for recurrent bacterial meningitis.

Certain subgroups of patients may not manifest the classic signs and symptoms of bacterial meningitis. Usually in a neonate there is no meningismus or fever, and the only clinical clues to meningitis are listlessness, high-pitched crying, fretfulness, refusal to feed, or irritability. Elderly patients, especially those with underlying conditions such as diabetes mellitus or cardiopulmonary disease, may present with insidious disease manifested only by lethargy or obtundation, variable signs of meningeal irritation, and no fever. In this subgroup, altered mental status should not be ascribed to other causes until bacterial meningitis has been excluded by CSF examination. A patient after neurosurgery or a patient who has undergone head trauma also presents a unique clinical situation because these patients already have many of the symptoms and signs of meningitis from their underlying disease processes.10 One must have a low threshold for CSF examination in these patients should they develop any clinical deterioration.

Diagnosis

The diagnosis of bacterial meningitis rests on the CSF examination.20 The opening pressure is elevated in virtually all cases; values above 600 mm H2O suggest cerebral edema, the presence of intracranial suppurative foci, or communicating hydrocephalus. The fluid may be cloudy or turbid if the white blood cell count is elevated (>200/μL). If the lumbar puncture is traumatic, the CSF may appear bloody initially, but it should clear as flow continues. Xanthochromia, a pale-pink to yellow-orange color of the supernatant of centrifuged CSF, is found in patients with subarachnoid hemorrhage, usually within 2 hours after hemorrhage.

The CSF white cell count is usually elevated in untreated bacterial meningitis, ranging from 100 to at least 10,000 per microliter, with a predominance of neutrophils. About 10% of patients present with a lymphocytic predominance (>50%) in CSF. Some patients have a very low CSF white cell count (0 to 20/μL) despite high bacterial concentrations in CSF; these patients have a poor prognosis. Therefore, a Gram stain and culture should be performed on all CSF specimens, even those with a normal cell count. A CSF glucose concentration of less than 40 mg/dL is found in about 60% of patients with bacterial meningitis, and a CSF:serum glucose ratio of less than 0.31 is observed in 70% of cases. The CSF glucose level must always be compared with a simultaneous serum glucose concentration. The CSF protein concentration is elevated in virtually all cases of bacterial meningitis, presumably because of disruption of the blood-brain barrier.

CSF examination by Gram stain permits a rapid, accurate identification in 60% to 90% of cases of bacterial meningitis; the likelihood of detecting the organism by Gram stain correlates with the specific bacterial pathogen and the concentration of bacteria in CSF. False-positive findings may occur as a result of contamination in the collection of tubes or during staining. Cultures of CSF are positive in 70% to 80% of cases. These percentages may be lower in patients who have received prior antimicrobial therapy.

Several rapid diagnostic tests have been developed to aid in the diagnosis of bacterial meningitis.21 Tests using staphylococcal coagglutination or latex agglutination are rapid and sensitive, although many of the kits do not include tests for group B meningococcus, and other kits probably are poor detectors of this antigen because of the limited immunogenicity of group B meningococcal polysaccharide. Performance of one of these rapid diagnostic tests (preferably latex agglutination) should be considered on all CSF specimens from patients in whom bacterial meningitis is suspected when the Gram stain is negative. Recently, the routine use of CSF bacterial antigen tests for the etiologic diagnosis of bacterial meningitis has been questioned; positive results have not modified therapy and false-positive and false-negative results may occur. Measurement of serum C-reactive protein or pro-calcitonin may also be useful in discriminating between bacterial and viral meningitis because elevated serum concentrations of these proteins have been observed in patients with acute meningitis.22 In patients with acute meningitis in whom the CSF Gram stain is negative, serum concentrations of C-reactive protein or pro-calcitonin that are normal or below the limit of detection have a high negative predictive value in the diagnosis of bacterial meningitis. Polymerase chain reaction has been used to amplify DNA from patients with meningococcal meningitis; it showed a sensitivity and specificity of 91% in one study.23 Further refinements in polymerase chain reaction may render it useful in the diagnosis of bacterial meningitis when the CSF Gram stain and cultures are negative.

Neuroimaging techniques have little role in the diagnosis of acute bacterial meningitis, except to rule out the presence of other pathologic conditions or to identify a parameningeal source of infection. However, computed tomography (CT) or magnetic resonance imaging (MRI) may be useful in patients who have a persisting fever several days after initiation of antimicrobial therapy, prolonged obtundation or coma, new or recurrent seizure activity, signs of increased intracranial pressure, or focal neurologic deficits. MRI is better than CT for evaluation of subdural effusions, cortical infarctions, and cerebritis, although it is more difficult to obtain an MRI in a critically ill patient, which limits its usefulness in many patients with meningitis.

Treatment

Antimicrobial Therapy

The initial approach to the patient with suspected bacterial meningitis is to perform a lumbar puncture to determine whether the CSF findings are consistent with that diagnosis.20,24 Patients should receive empirical antimicrobial therapy based on their age and underlying disease status, if no etiologic agent is identified by Gram stain or rapid diagnostic tests. In patients with a focal neurologic examination, CT should be performed immediately to exclude an intracranial mass lesion because lumbar puncture is relatively contraindicated in that setting. However, obtaining a CT scan generally entails some delay, so empirical antimicrobial therapy should be started immediately, before the CT scan and lumbar puncture are done and after obtaining blood cultures, because of the high mortality rate in patients with bacterial meningitis in whom antimicrobial therapy is delayed. Although many clinicians routinely perform CT before lumbar puncture, this is probably not necessary in most patients. In a recent retrospective study of 301 adults with suspected meningitis,25 the clinical features at baseline that were associated with an abnormal finding on CT of the head were an age of at least 60 years, immunocompromise, a history of CNS disease, a history of seizure within 1 week before presentation, and the following neurologic abnormalities: an abnormal level of consciousness, an inability to answer two consecutive questions correctly or to follow two consecutive commands, gaze palsy, abnormal visual fields, facial palsy, arm drift, leg drift, and abnormal language. These results need to be validated but are a reasonable guide in determining which patients require CT before lumbar puncture.

Our choices for empirical antibiotic therapy in patients with presumed bacterial meningitis, based on age, are presented in Table 52-2.20,24 For neonates younger than 1 month, the most likely infecting organisms are E. coli, S. agalactiae, and L. monocytogenes; for those ages 1 to 23 months, infection may be due to S. pneumoniae, N. meningitidis, S. agalactiae, E. coli, or H. influenzae. From age 2 to 50 years, most cases of meningitis are due to N. meningitidis and S. pneumoniae. In older adults (≥50 years), the meningococcus and the pneumococcus are possible causes, as are L. monocytogenes and gram-negative bacilli. For all patients in whom S. pneumoniae is a possible causative pathogen, vancomycin should be added to empirical therapeutic regimens because highly penicillin- or cephalosporin-resistant strains of S. pneumoniae may be likely (see below). One other situation deserves comment: In patients after neurosurgery or patients with CSF shunts or foreign bodies, likely infecting organisms include staphylococci (S. epidermidis or S. aureus), diphtheroids, and gram-negative bacilli (including P. aeruginosa). Antimicrobial therapy in these situations should consist of vancomycin plus ceftazidime or cefepime pending culture results.

Once an infecting microorganism has been isolated, antimicrobial therapy can be modified for optimal treatment.20,24 Our antibiotics of choice are listed in Table 52-3. Dosages for adults are listed in Table 52-4. For bacterial meningitis due to S. pneumoniae or N. meningitidis, penicillin G and ampicillin are equally efficacious. However, although in past years pneumococci remained uniformly susceptible to penicillin (minimal inhibitory concentration ≤0.06 μg/mL), worldwide reports have now documented relatively and highly resistant strains of pneumococci, with minimal inhibitory concentrations of 0.1 to 1.0 μg/mL and at least 2 μg/mL, respectively. In view of these recent trends, and because sufficient CSF concentrations of penicillin are difficult to achieve with standard high parenteral doses (initial CSF concentrations of ∼1 μg/mL), penicillin can never be recommended as empirical antimicrobial therapy when S. pneumoniae is considered a likely infecting pathogen. Further, susceptibility testing must be performed on all CSF isolates. For relatively resistant strains, a third-generation cephalosporin (e.g., cefotaxime or ceftriaxone) should be used; for highly resistant strains, vancomycin in combination with a third-generation cephalosporin is the antimicrobial regimen of choice. Vancomycin used alone may not be optimal therapy for patients with pneumococcal meningitis. In one report of 11 consecutive patients with culture-proven pneumococcal meningitis caused by relatively penicillin-resistant strains,26 four patients experienced a therapeutic failure with vancomycin, necessitating a change in therapy. These data indicate the need for careful monitoring, perhaps even including measurement of CSF vancomycin concentrations, in adult patients who are receiving vancomycin alone for pneumococcal meningitis. We recommend the combination of vancomycin plus a third-generation cephalosporin (cefotaxime or ceftriaxone) for documented pneumococcal meningitis pending results of susceptibility testing. Some investigators have recommended the addition of rifampin (if the organism is susceptible) to vancomycin for the treatment of meningitis caused by highly resistant pneumococcal strains,27 although there are no firm data to support this. Meropenem, a carbapenem antimicrobial agent, yields microbiologic and clinical outcomes similar to those of cefotaxime or ceftriaxone in the treatment of patients with bacterial meningitis.28 The newer fluoroquinolones (e.g., moxifloxacin, gatifloxacin) have in vitro activity against resistant pneumococci and have shown activity in experimental animal models of resistant pneumococcal meningitis but should not be used as first-line therapy in patients with bacterial meningitis, pending results of ongoing clinical trials. Trovafloxacin was recently shown to be therapeutically equivalent to ceftriaxone with or without vancomycin for the treatment of pediatric bacterial meningitis,29 although this agent is no longer used because of concerns of liver toxicity.

Meningococcal strains that are relatively resistant to penicillin have also been reported from several areas (in particular Spain); however, most patients harboring these strains have recovered with standard penicillin therapy, so their clinical significance is unclear. In the United States, approximately 3% of meningococcal strains have shown intermediate resistance to penicillin.30 Some authorities would treat meningococcal meningitis with a third-generation cephalosporin (cefotaxime or ceftriaxone) pending results of in vitro susceptibility testing.

Treatment of H. influenzae type b meningitis has been hampered by the emergence of β-lactamase–producing strains of the organism, which accounted for approximately 25% to 33% of all isolates in the United States.1Chloramphenicol resistance also has been reported in the United States (<1% of isolates) and Spain (≥50% of isolates). In addition, a study found chloramphenicol to be bacteriologically and clinically inferior to certain β-lactam antibiotics (ampicillin, ceftriaxone, and cefotaxime) in childhood bacterial meningitis, and most of these cases were due to H. influenzae type b.20 From these findings and those of other studies, the third-generation cephalosporins (e.g., cefotaxime and ceftriaxone) seem to be at least as effective as ampicillin plus chloramphenicol for therapy of H. influenzae meningitis. Cefuroxime, a second-generation cephalosporin, has also been evaluated for therapy of H. influenzae meningitis. Although initial studies documented an efficacy for this drug similar to that of ampicillin plus chloramphenicol, recent case reports have documented delayed CSF sterilization and the development of epiglottitis in patients receiving cefuroxime for meningitis. In addition, a prospective randomized study of ceftriaxone versus cefuroxime for the treatment of childhood bacterial meningitis documented the superiority of ceftriaxone; patients receiving this drug had milder hearing impairment and more rapid CSF sterilization than did those receiving cefuroxime.31 We currently recommend a third-generation cephalosporin for empirical therapy when H. influenzae is considered a likely infecting pathogen.

The treatment of bacterial meningitis in adults that is caused by gram-negative enteric bacilli has been revolutionized by the third-generation cephalosporins,20 with cure rates of 78% to 94%. Ceftazidime or cefepime is also active against P. aeruginosa meningitis; ceftazidime, alone or in combination with an aminoglycoside, resulted in cure of 19 of 24 patients with Pseudomonas meningitis in one report. Intrathecal or intraventricular aminoglycoside therapy should be considered if there is no response to systemic therapy, although this therapy is now rarely needed. The fluoroquinolones (e.g., ciprofloxacin or pefloxacin) have been used in some patients with gram-negative bacillary meningitis, but at this time they can be considered only for patients with meningitis due to multidrug-resistant gram-negative bacilli or for patients in whom conventional therapy has failed.

The third-generation cephalosporins are inactive against meningitis caused by L. monocytogenes, an important meningeal pathogen; this is a major drawback of these agents. Therapy in this situation should consist of ampicillin or penicillin G; addition of an aminoglycoside should be considered in documented infection, at least for the first several days of treatment.12,20 Alternatively, trimethoprim-sulfamethoxazole can be used. Patients with S. aureus meningitis should be treated with nafcillin or oxacillin; vancomycin should be reserved for patients allergic to penicillin and patients with disease caused by methicillin-resistant organisms.15 Infection with S. epidermidis, the most likely isolate in a patient with a CSF shunt, should be treated with vancomycin, with rifampin added if the patient fails to improve. Shunt removal is often essential to optimize therapy.

The durations of therapy for bacterial meningitis should be 10 to 14 days for most causes of non-meningococcal meningitis and 3 weeks for meningitis due to gram-negative enteric bacilli.20,32 Seven days of therapy appear adequate for meningococcal meningitis; several reports have suggested that 7 days of therapy is effective also for H. influenzae meningitis. Patients with S. agalactiae meningitis should be treated for 14 to 21 days, and patients with meningitis caused by L. monocytogenes should be treated for at least 21 days. However, therapy must be individualized; on the basis of clinical response, some patients may require longer courses of treatment.

Adjunctive Therapy

Despite the availability of effective antimicrobial therapy, the morbidity and mortality rates of bacterial meningitis remain unacceptably high. Recent studies have focused on the pathogenesis and pathophysiology of bacterial meningitis, in the hope of developing innovative strategies for adjunctive treatment.20,24 Recent work in experimental animal models of meningitis has suggested a potentially useful role for anti-inflammatory agents (e.g., corticosteroids and nonsteroidal anti-inflammatory agents) in decreasing the inflammatory response in the subarachnoid space, which may be responsible for the development of neurologic sequelae. Adjunctive dexamethasone therapy has been evaluated over the past decade in a number of published trials, mostly in infants and children with H. influenzae type b meningitis.20,24 A meta-analysis of clinical studies published from 1988 to 1996 confirmed the benefit of adjunctive dexamethasone (0.15 mg/kg every 6 hours for 2 to 4 days) in infants and children with H. influenzae type b meningitis and, if commenced with or before parenteral antimicrobial therapy, suggested benefit for pneumococcal meningitis in childhood.33 Administration of dexamethasone before or with initiation of antimicrobial therapy is recommended for optimal attenuation of the subarachnoid space inflammatory response; patients must be carefully monitored for the possibility of gastrointestinal hemorrhage. In a recently published prospective, randomized, double-blind trial in adults with bacterial meningitis, adjunctive treatment with dexamethasone was associated with a reduction in the proportion of patients who had unfavorable outcome and in the proportion of patients who died; the benefits were most striking in the subset of patients with pneumococcal meningitis.34 The use of adjunctive dexamethasone, however, is of particular concern in patients with pneumococcal meningitis caused by highly penicillin- or cephalosporin-resistant strains who are treated with vancomycin because a diminished inflammatory response may significantly decrease CSF vancomycin penetration and delay CSF sterilization, perhaps leading to a worse outcome. In the study cited above, only 72% of the 108 CSF cultures that were positive for S. pneumoniae were submitted for susceptibility testing, and all were susceptible to penicillin. However, based on the results of this trial and the apparent absence of serious adverse outcomes in the patients who received dexamethasone, routine use of adjunctive dexamethasone is warranted in most adults with pneumococcal meningitis.35 In patients with meningitis caused by pneumococcal strains resistant to penicillin and/or cephalosporins, careful observation and follow-up are critical to determine whether dexamethasone therapy is associated with an adverse outcome. When dexamethasone is used, the timing of administration is crucial. Administration of dexamethasone before or concomitant with the first dose of antimicrobial therapy is recommended for optimal attenuation of the subarachnoid space inflammatory response. Dexamethasone is not recommended in patients who have already received antimicrobial therapy. If the meningitis is found not to be caused by S. pneumoniae in adults, dexamethasone therapy should be discontinued.

Other adjunctive therapies may be useful in critically ill patients with bacterial meningitis.20 Patients who are stuporous or comatose (precluding assessment of worsening neurologic function) and who show signs of increased intracranial pressure (e.g., altered level of consciousness; dilated, poorly reactive or nonreactive pupils; and ocular movement disorders) may benefit from the insertion of an intracranial pressure monitoring device. Increased intracranial pressure can be lowered by elevating the head of the bed to 30 degrees to maximize venous drainage with minimal compromise of cerebral perfusion, by the use of hyperosmolar agents, and by hyperventilation. However, the routine use of hyperventilation (to maintain the partial arterial pressure of CO2 between 27 and 30 mm Hg) has been questioned in patients with bacterial meningitis. Infants and children with bacterial meningitis and normal initial CT scans can be treated with hyperventilation to decrease elevated intracranial pressure because it is unlikely that cerebral blood flow will be decreased to ischemic thresholds. However, in children in whom CT shows cerebral edema, cerebral blood flow is likely to be normal or decreased, so hyperventilation might decrease intracranial pressure at the expense of cerebral blood flow, possibly reducing flow to ischemic thresholds. The use of hyperosmolar agents (e.g., mannitol, glycerol) may be useful in reducing increased intracranial pressure in patients with bacterial meningitis. In one recent study in infants and children with bacterial meningitis, oral glycerol appeared to help prevent neurologic sequelae,36 although further studies are needed before adjunctive glycerol can be routinely recommended. A detailed discussion of the management of raised intracranial pressure is found in Chap. 65. Seizures must be treated promptly to avoid status epilepticus, which might lead to anoxic brain injury (see Chap. 64). Another important adjunctive measure in patients with bacterial meningitis is fluid restriction to combat hyponatremia caused by excess secretion of antidiuretic hormone, although this measure is not appropriate in the presence of shock or dehydration because hypotension may predispose the patient to cerebral ischemia. Many patients, particularly children, with bacterial meningitis are hyponatremic (serum sodium level <135 mEq/L) at presentation; the degree and duration of hyponatremia may contribute to neurologic sequelae. The management of hyponatremia is discussed in greater depth in Chap. 76.

Prevention

A final point concerns chemoprophylaxis of contacts of meningitis cases, which is indicated for contacts of patients with N. meningitidis or H. influenzae type b meningitis.20 For meningococcal meningitis, chemoprophylaxis usually is administered only to intimate contacts (e.g., household contacts, day-care contacts, nursery school contacts, contacts who eat or sleep in the same dwelling, and close contacts such as in a military barracks or boarding school); it is not indicated for other groups (e.g., office coworkers or classmates) unless there has been intimate contact. However, one study has suggested that school-aged children may be at increased risk of secondary infection when classrooms are crowded and/or when contact during lunch or recess is frequent. Prophylaxis is not necessary for medical personnel caring for cases unless there has been intimate contact (e.g., mouth-to-mouth resuscitation, or those who perform endotracheal intubation or endotracheal tube management). All contacts (children and adults) of a patient with H. influenzae meningitis should receive chemoprophylaxis if exposure has occurred in a household or day-care center containing children 4 years or younger (other than the index case), provided that the exposure to H. influenzae type b was in the week before presentation. The recommended drug of choice for chemoprophylaxis, for contacts of patients with either type of meningitis, is rifampin. For contacts of patients with H. influenzae meningitis, rifampin at a daily dose of 20 mg/kg (not exceeding 600 mg) for 4 consecutive days is most effective. For contacts of meningococcal cases, one rifampin dose of 10 mg/kg (not exceeding 600 mg) twice a day for 2 days is effective. One dose of ciprofloxacin (500 or 750 mg) may also be effective for eradicating nasopharyngeal carriage of meningococci; ciprofloxacin is not recommended in pregnant women or in persons younger than 18 years because of concerns of cartilage damage. Ciprofloxacin may well supplant rifampin for chemoprophylaxis in adults. On one study, ceftriaxone (250 mg intramuscularly in adults or 125 mg in children) was shown to eliminate the meningococcal serogroup A carrier state in 97% of patients for up to 2 weeks and is probably the safest alternative for meningococcal chemoprophylaxis in pregnant women. Azithromycin (500 mg orally once) was also shown to be as effective as a four-dose regimen of rifampin in the eradication of meningococci from the nasopharynx.37

Epidemiology and Etiology

Brain abscess is one of the most serious complications of head and neck infections. Even in the antibiotic era, mortality from brain abscess was not appreciably different from that in the era before antibiotics (about 40% to 60%) until the past decade, when mortality decreased to between 5% and 10%.38 This improvement is likely due to recent developments in diagnosis and treatment, which are discussed below. There is a large geographic variability in the incidence of brain abscess, with approximately 4 to 10 cases seen annually on active neurosurgical services in developed countries.

Bacteria can reach the brain by several different mechanisms. The factors predisposing to brain abscess and the etiologic agents in each circumstance are presented in Table 52-5.38–40 The most common pathogenic mechanism of brain abscess formation is spread from a contiguous focus of infection, most often in the middle ear, mastoid air cells, or paranasal sinuses. Early studies associated 40% of brain abscesses with otitis media, but this number has been decreasing in recent years. However, if antibiotic therapy of otitis is neglected, there is an increased risk of intracranial complications. Brain abscess secondary to otitis media is bimodally distributed, with peaks in children (acute otitis media) and in persons older than 40 years (chronic otitis media). Most cases of brain abscess due to otitis media occur in the temporal lobe and cerebellum. The etiologic agents in brain abscess secondary to otitis media include a broad range of bacterial species, including streptococci, Bacteroides fragilis, and members of the Enterobacteriaceae.

Paranasal sinusitis continues to be an important condition predisposing to brain abscess, most commonly in persons ages 10 to 30 years. The frontal lobe is the predominant abscess site; when brain abscess complicates sphenoid sinusitis, the temporal lobe or sella turcica is usually involved.38–40 Streptococci are the predominant bacterial species involved in brain abscess secondary to sinusitis, although anaerobes, S. aureus, and gram-negative bacilli have been isolated.

Dental infections are a less common source of brain abscess; infections of molar teeth seem most often to be the cause. The frontal lobe is usually involved, but temporal lobe extension has also been described.

A second mechanism of brain abscess formation is hematogenous dissemination to the brain from a distant focus of infection. These abscesses are usually multiple and multiloculated, and they have a higher mortality rate than do abscesses that arise secondary to contiguous foci of infection.38–40 The most common sources in adults are chronic pyogenic lung diseases, especially lung abscess, bronchiectasis, empyema, and cystic fibrosis. Anaerobes (Fusobacterium and Bacteroides species) and streptococci are likely infecting pathogens in this situation, as are Nocardia and Actinomyces species. Brain abscess may also occur hematogenously from wound and skin infections, osteomyelitis, pelvic infection, cholecystitis, and other intra-abdominal infections. Another predisposing factor leading to hematogenously acquired brain abscess is cyanotic congenital heart disease (accounting for 5% to 10% of all brain abscess cases, with higher percentages in some pediatric series), most commonly due to tetralogy of Fallot and transposition of the great vessels.41 Brain abscess is rare during bacterial endocarditis (<5% of cases in most series), despite the presence of persistent bacteremia.42 Hereditary hemorrhagic telangiectasia is a predisposing factor almost always observed in patients with coexisting pulmonary arteriovenous malformations; perhaps it allows septic emboli to cross the pulmonary circulation without capillary filtration. Brain abscesses have also developed after esophageal dilatation and sclerosing therapy for esophageal varices.

Trauma is a third pathogenic mechanism in the development of brain abscess, whether secondary to an open cranial fracture with dural breach, to neurosurgery, or (especially in children) to a foreign body injury.38–40 The incidence of brain abscess formation after head trauma ranges from 3% to 17% in military populations, where it is usually secondary to retained bone fragments or contamination of initially “sterile” missile sites with bacteria from skin, clothes, and the environment. Predisposing traumatic conditions in the civilian population include compound depressed skull fractures, dog bites, rooster pecking, and, especially in children, injury from lawn darts and pencil tips. Likely infective microorganisms after trauma include staphylococci, streptococci, gram-negative bacilli, and anaerobes.

Brain abscess is cryptogenic in about 20% of patients. Many of these cases are secondary to unrecognized dental foci of infection. In this subgroup of patients, broad antimicrobial therapy is indicated pending culture results (see section on Treatment, below).

Overall, the most commonly isolated bacterial species in brain abscess are streptococci (aerobic, anaerobic, and microaerophilic), which are present in 60% to 70% of cases.38–40 These bacteria (especially the Streptococcus milleri group) normally reside in the oral cavity, appendix, and female genital tract and have a proclivity for abscess formation. Staphylococcus aureus, which was isolated in 25% to 30% of cases in the era before antibiotics, currently accounts for 10% to 15% of isolates, although the frequency of isolation of S. aureus is increased in certain clinical situations (e.g., cranial trauma and endocarditis). Attention to proper culture techniques has increased the rate of isolation of anaerobes, with Bacteroides species isolated in 20% to 40% of cases, often in mixed culture. Enteric gram-negative bacilli (Proteus species, E. coli,Klebsiella species, and Pseudomonas species) are isolated in 23% to 33% of patients. Other bacterial species occur less commonly (<1% of cases) and include H. influenzae, S. pneumoniae, L. monocytogenes, and Nocardia asteroides (Nocardia is more often isolated in patients with T-lymphocyte or mononuclear phagocyte defects). Nocardial brain abscesses have increased in incidence with the increasing numbers of immunosuppressed patients, although up to 48% of patients with nocardiosis have no underlying conditions. Brain abscesses due to Actinomyces species are commonly associated with pulmonary and odontogenic infections.

Clinical Presentation

The clinical course of brain abscess may be indolent or fulminant; 75% of patients have symptoms for less than 2 weeks. Most of the clinical manifestations are due to the presence of space-occupying lesions within the brain.38–40 The most common symptom is headache, present in more than 70% of patients. The headache is usually moderate to severe and hemicranial, but it may be generalized. Other findings include nausea and vomiting (∼50% of cases), nuchal rigidity (∼25%), and papilledema (∼25%). Mental status changes ranging from lethargy to coma occur in the majority of cases. Seizures, usually generalized, occur in 25% to 35% of patients. Fever appears in only 45% to 50% of cases; afebrile patients tend to be older and to have a longer duration of illness and a higher mortality rate. Only about 50% of patients present with the classic triad of fever, headache, and focal neurologic deficit. Patients with frontal lobe abscess often present with headache, drowsiness, inattention, and deterioration in mental status; the most common focal neurologic signs are hemiparesis, with unilateral motor signs, and a motor speech disorder. The clinical presentation of cerebellar abscess may include ataxia, nystagmus, vomiting, and dysmetria. Persons with abscess of the temporal lobe may present with ipsilateral headache and aphasia, if the lesion is in the dominant hemisphere. A visual field defect (e.g., an upper homonymous quadrantanopia) may be the only presenting sign of a temporal lobe abscess. Persons with brain stem abscesses usually present with facial weakness, fever, headache, hemiparesis, dysphagia, and vomiting. Clues to the site of origin of the infection should also be sought; these include otorrhea, orbital cellulitis, purulent nasal discharge, dental sepsis, and postoperative or posttraumatic cranial infection; such findings occur in about 60% of cases. It is important to note that the clinical presentation of brain abscess in immunosuppressed patients may be masked by the diminished inflammatory response.

Diagnosis

The diagnosis of brain abscess has been revolutionized by CT, which not only is an excellent means to examine the brain parenchyma but also is superior to standard radiologic procedures for examination of the paranasal sinuses, mastoid cells, and middle ear.38–40 The sensitivity of CT is 95% to 99% for brain abscess; it also yields information concerning the extent of surrounding edema, the presence or absence of a midline shift, the presence of hydrocephalus, and the possibility of imminent ventricular rupture. The characteristic appearance of brain abscess on CT is a hypodense center with a uniform peripheral ring enhancement after the injection of contrast material; this is surrounded by a variable hypodense area of brain edema. A similar appearance is seen with neoplasms, granulomas, cerebral infarction, or resolving hematoma. Contrast enhancement of the ependymal lining suggests ventriculitis. Other CT findings include nodular enhancement and areas of low attenuation without enhancement; the latter finding is observed during the early stage of cerebritis, before abscess formation; as the abscess progresses, contrast enhancement is observed. In later stages, as the abscess becomes encapsulated, contrast no longer differentiates the lucent center, and the CT appearance is similar to that in the early stage of cerebritis. The use of delayed films may be helpful because the presence of contrast material in the center of the lesion suggests cerebritis. The absence of contrast material likely indicates a well-encapsulated lesion. This difference is important therapeutically because cerebritis may respond to medical therapy alone, whereas most encapsulated lesions require surgical intervention. CT is also useful for following the course of brain abscess, although, after aspiration, improvement in the CT appearance may not be seen for up to 5 weeks or longer. Complete resolution may take 4 to 5 months.

Scintigraphy with 111In-labeled leukocytes has also been evaluated in the diagnosis of brain abscess.43 Radiolabeled leukocytes migrate to, and accumulate in, an area of active inflammation, thereby differentiating brain abscess from other cerebral mass lesions, although false-positive scans can be observed in necrotic tumors and false-negative scans in patients receiving corticosteroids. This modality is most useful as a complement to CT.

MRI has an important role in the diagnosis of brain abscess, for which it has several advantages over CT.38 MRI is more effective for the early detection of cerebritis. Also, in cases of cerebral edema, MRI shows a stronger contrast between an edematous and a normal brain and more clearly shows the spread of inflammation into the ventricles and subarachnoid space. MRI also permits earlier detection of satellite lesions. T1-weighted images characteristically demonstrate a peripheral zone of mild hypointensity (representative of edema formation) related to adjacent brain, which surrounds a central zone of more marked hypointensity (indicative of the necrotic center of the abscess); these two regions are separated by a capsule that appears as a discrete rim, which is isointense to mildly hyperintense. On T2-weighted images, there is an area of marked hyperintensity in the zone of edema when compared with adjacent brain, whereas the central core is isointense to hyperintense compared with gray matter; the capsule appears as a well-defined hypointense rim at the margin of the abscess. Contrast-enhanced MRI, using the paramagnetic agent gadolinium diethylenetriamine penta-acetic acid, has the advantage of clearly differentiating the central abscess, the surrounding contrast-enhancing rim, and the cerebral edema surrounding the abscess. MRI is the current diagnostic procedure of choice for detection of brain abscess, although it is not always feasible in critically ill patients.

A major advance in the use of CT is the availability of stereotaxic CT-guided aspiration of the abscess to facilitate bacteriologic diagnosis. However, aspiration during the early cerebritis stage may be complicated by hemorrhage. At the time of aspiration, a specimen should be sent for Gram stain (and other special stains, e.g., Ziehl-Nielsen, modified acid-fast, and silver stains, when appropriate), routine culture, and anaerobic culture. The use of this modality in the treatment of brain abscess is discussed under Surgical Therapy in the section on Treatment.

Lumbar puncture is contraindicated in patients with suspected or proven brain abscess because of the risk of life-threatening cerebral herniation after removal of CSF. When lumbar puncture is performed, the CSF profile is nonspecific, with a predominantly mononuclear pleocytosis and an elevated protein concentration. Hypoglycorrhachia is present in only 25% of cases, and fewer than 10% of CSF cultures are positive. Microorganisms usually are not demonstrated on Gram stain, unless the abscess has ruptured into the subarachnoid space or there is accompanying meningitis.

Treatment

Antimicrobial Therapy

Perhaps related to the alteration of the blood-brain barrier in the area of the brain abscess, there is increased penetration of normally excluded antibiotics into the brain. However, this increased penetration into the brain does not predict penetration into cerebral abscesses. Brain abscess concentrations of antibiotics have been measured, and several generalizations can be made:38 (a) metronidazole can be expected to achieve inhibitory levels for sensitive anaerobic microorganisms; (b) chloramphenicol concentrations in the brain are likely to be high relative to serum; and (c) concentrations of various penicillins and cephalosporins in brain tissue and abscess are usually poor, although when given in large parenteral doses, these agents achieve therapeutic concentrations for sensitive microorganisms.

When a diagnosis of brain abscess is made, whether presumptively on the basis of radiologic studies or through aspiration of the abscess, antimicrobial therapy should be initiated. Aspiration may provide an etiologic diagnosis on Gram stain examination, but when aspiration is impractical or delayed, we recommend empirical therapy based on the likely etiologic agent, if a predisposing condition can be identified (Table 52-6).38 Because of the high rate of isolation of streptococci (particularly the S. milleri group) from brain abscesses of various etiologies (see Table 52-5), high-dose penicillin G (20 to 24 million U/day) or another drug that is active against this organism (e.g., a third-generation cephalosporin, either cefotaxime or ceftriaxone) should be included in the initial therapeutic regimen. Penicillin is also active against most anaerobic species, with the notable exception of B. fragilis, which is isolated in a high percentage (20% to 40%) of brain abscess cases. When B. fragilis is suspected, we recommend the addition of metronidazole (7.5 mg/kg every 6 hours). The advantages of metronidazole over other agents include its bactericidal activity against B. fragilis (the others are frequently bacteriostatic for this organism) and the high concentrations it attains in brain abscess pus, even with concomitant corticosteroid administration. In addition, one retrospective review has suggested that metronidazole may improve mortality rates in patients with brain abscess.44 In cases in which S. aureus is a likely infecting pathogen (e.g., cranial trauma or prior neurosurgery), nafcillin should be used. Vancomycin, which penetrates into brain abscess fluid,45 is reserved for patients who are allergic to penicillin or in whom methicillin-resistant organisms are likely or have been isolated. The penetration of clindamycin, erythromycin, and the first-generation cephalosporins into brain abscesses is usually inadequate to achieve therapeutic concentrations, thus precluding their use in this setting. For empirical therapy when members of the Enterobacteriaceae are suspected (e.g., in cases of abscess of otitic origin), a third-generation cephalosporin or trimethoprim-sulfamethoxazole should be used.

One regimen that has theoretical advantages and covers a broad range of possible infecting bacterial pathogens is metronidazole, vancomycin, and a third-generation cephalosporin (cefotaxime or ceftriaxone; see Table 52-6). In addition to activity against gram-negative bacilli, these third-generation cephalosporins have excellent antistreptococcal activity and possess antistaphylococcal action. However, it is important to note that there are no clinical trials comparing this regimen with traditional penicillin-containing formulas. If P. aeruginosa is a likely infecting pathogen, ceftazidime or cefepime is the agent of choice. However, if ceftazidime is the third-generation cephalosporin used in empirical therapy of brain abscess, the regimen must also include penicillin G to treat a possible streptococcal infection because ceftazidime has unreliable activity against gram-positive organisms.

Once an infecting pathogen is isolated, antimicrobial therapy can be modified (Table 52-7).38 Antimicrobial therapy with large-dose intravenous antibiotics should be continued for 6 to 8 weeks and is often followed by oral antibiotic therapy for 2 to 6 months, if an appropriate agent is available. A shorter course (3 to 4 weeks) may be adequate for patients undergoing excision of the abscess. Surgical therapy (see below) is often required for treatment of brain abscess, although certain subgroups of patients can be managed without surgery.46,47 These include patients with medical conditions that increase the risks from surgery, patients with multiple abscesses or an abscess in a deep or dominant location, patients with coexisting meningitis or ependymitis, patients in whom antimicrobial therapy results in early abscess reduction and clinical improvement, and patients with an abscess smaller than approximately 3 cm.

Surgical Therapy

Most patients require surgical management for optimal treatment of brain abscess. The two procedures judged equivalent by outcome are aspiration of the abscess after burr hole placement and complete excision after craniotomy.38,48,49 Drainage and marsupialization are rarely used. The choice of procedure must be individualized for each patient. Aspiration may be performed using stereotaxic CT guidance, which affords the surgeon rapid, accurate, and safe access to virtually any intracranial point. Aspiration can also be used for swift relief of increased intracranial pressure. Incomplete drainage of multiloculated lesions is a major disadvantage of aspiration; these lesions frequently require excision. Other risks of aspiration are that it may allow the abscess to rupture into the ventricle, and that pus may leak into the subarachnoid space, resulting in ventriculitis or meningitis.

Complete excision after craniotomy is most often employed in patients in a stable neurologic condition. Surgery is also indicated for abscesses exhibiting gas on radiologic evaluation and for posterior fossa abscesses. In patients with worsening neurologic deficits, including deteriorating consciousness or signs of increased intracranial pressure, surgery should be performed emergently. Excision is contraindicated in the early stages, before a capsule is formed. All brain abscesses larger than 2.5 cm in diameter should be aspirated or excised for optimal management.50

Adjunctive Therapy

Intracranial pressure monitoring has become important in the intensive care management of brain abscess patients who have cerebral edema (see Chap. 65). The use of these monitoring devices has diminished the likelihood of transtentorial herniation, brain stem compression, and further injury from cerebral ischemia.

Corticosteroids have been used as one method to manage increased intracranial pressure, although their use remains controversial.38 These agents may retard the encapsulation process, reduce antibiotic entry into the CNS, increase necrosis, and alter the appearance of ring enhancement on CT as inflammation subsides, thereby obscuring information from sequential studies. Steroids (at a dexamethasone dose for adults of 4 to 6 mg every 6 hours) are most useful in the patient with deteriorating neurologic status and increased intracranial pressure, for whom steroids may prove lifesaving. When used to treat cerebral edema, steroids should be used for the shortest time possible and withdrawn when the mass effect no longer poses a significant danger to the patient. The management of increased intracranial pressure is discussed in Chap. 65.

Epidemiology and Etiology

The term subdural empyema refers to a collection of pus in the space between the dura and arachnoid. This process accounts for about 20% of all localized intracranial infections.51–53 The disease was essentially lethal before the advent of antimicrobial therapy; with current methods of diagnosis and treatment, mortality rates are 10% to 20%. The most common predisposing conditions are otorhinologic infections, especially infection of the paranasal sinuses, which are affected in 50% to 80% of cases.51,52,54 The pathogenesis involves spread of infection to the subdural space through valveless emissary veins in association with thrombophlebitis or by extension of an osteomyelitis of the skull with accompanying epidural abscess. The mastoid cells and middle ear are the source in 10% to 20% of patients, especially in geographic areas where many cases of otitis media are not treated promptly with antibiotics. Other predisposing conditions include skull trauma, neurosurgical procedures, and infection of a pre-existing subdural hematoma. The infection is metastatic in a minority of cases (∼5%), principally from the pulmonary system. In infants, meningitis is an important predisposing condition for the development of subdural empyema, which occurs in about 2% of infants with bacterial meningitis. Different bacterial species have been isolated from cranial subdural empyemas53–55 (Table 52-8), including streptococci (35% to 40% of cases), staphylococci (∼15%), aerobic gram-negative bacilli (∼3%), and anaerobes (33% to 100%, when careful culturing is performed); these organisms constitute the microbial flora that are frequently isolated from patients with chronic sinusitis and cranial abscesses.

Spinal subdural empyema is a rare condition occurring secondary to metastatic infection from a distant site.56Staphylococcus aureus is the most frequent isolate, whereas streptococci are found less frequently.

The term epidural abscess refers to a localized infection between the dura mater and the overlying skull or vertebral column. Cranial epidural abscess can cross the cranial dura along emissary veins, so subdural empyema often is also present. Therefore, the etiology, pathogenesis, and bacteriology of intracranial epidural abscess are usually identical to those described for subdural empyema (see above), with the initial focus of infection in the middle ear, paranasal sinuses, or mastoid cells.

In contrast, spinal epidural abscess usually follows hematogenous dissemination from foci elsewhere in the body to the epidural space or, by extension, from vertebral osteomyelitis.57,58 Hematogenous spread occurs in 25% to 50% of cases, secondary to infections of the skin (furuncles, cellulitis, or infected acne), urinary tract infections, periodontal abscesses, pharyngitis, pneumonia, or mastoiditis. Mild blunt spinal trauma may provide a devitalized site susceptible to transient bacteremia. Infection of the epidural space has also been reported after penetrating injuries, extension of decubitus ulcers or paraspinal abscesses, back surgery, lumbar puncture, and epidural anesthesia. Bacteremia may be an important predisposing factor because the incidence of spinal epidural abscess is increased in patients who use injection drugs59 or have intravenous catheters. The infecting microorganism in the vast majority of cases is S. aureus (50% to 95% in various series; see Table 52-8). Other isolates include aerobic and anaerobic streptococci (∼8% of cases) and gram-negative aerobic bacilli (∼18%), especially E. coli and P. aeruginosa.

Clinical Presentation

Persons with subdural empyema can present in a rapidly progressive, life-threatening clinical condition.51–53 Symptoms and signs relate to the presence of increased intracranial pressure, meningeal irritation, or focal cortical inflammation. In addition, 60% to 90% of patients have evidence of the antecedent infection (e.g., sinusitis or otitis). Headache, initially localized to the infected sinus or ear is a prominent complaint and can become generalized as the infection progresses. Vomiting is common as intracranial pressure increases. Early in the infection, about 50% of patients have altered mental status, which can progress to obtundation if the patient is not treated. Fever with a temperature above 39°C is present in most cases. Focal neurologic signs appear in 24 to 48 hours and progress rapidly, with eventual involvement of the entire cerebral hemisphere. Hemiparesis and hemiplegia are the most common focal signs, although ocular palsies, dysphasia, homonymous hemianopsia, dilated pupils, and cerebellar signs have been observed. Seizures (focal or generalized) are observed in more than 50% of cases. Signs of meningeal irritation (e.g., meningismus) are found in approximately 80% of patients, although fewer have Kernig or Brudzinski sign. If the patient remains untreated, neurologic deterioration occurs rapidly, with signs of increased intracranial pressure and cerebral herniation. Papilledema develops in fewer than 50% of patients. This fulminant picture may not be seen in patients with subdural empyema after cranial surgery or trauma, in patients who have received prior antimicrobial therapy, in patients with infected subdural hematomas, or in patients with infections metastatic to the subdural space.

Spinal subdural empyema usually manifests as radicular pain and symptoms of spinal cord compression, which may occur at multiple levels.56 Clinically, this lesion is difficult to distinguish from a spinal epidural abscess (see the section on Diagnosis, below).

The onset of symptoms in cranial epidural abscess may be insidious and overshadowed by the primary focus of infection (e.g., sinusitis or otitis media).51 Headache is a usual complaint, but the patient may otherwise feel well unless the clinical course is complicated (e.g., by development of subdural empyema or involvement of deeper intracranial structures). Because the dura is closely opposed to the inner surface of the cranium, the abscess usually enlarges too slowly to produce sudden major neurologic deficits (in contrast to subdural empyema) unless there is deeper intracranial extension. However, there may eventually be development of focal neurologic signs and focal or generalized seizures. In the absence of treatment, papilledema and other signs of increased intracranial pressure develop as the abscess enlarges. An epidural abscess near the petrous bone may present as Gradenigo syndrome, characterized by involvement of cranial nerves V and VI, with unilateral facial pain and weakness of the lateral rectus muscle.50

Spinal epidural abscess may develop within hours to days (after hematogenous seeding) or may grow slowly over months (associated more often with vertebral osteomyelitis).57–61 Most abscesses pass through the following stages: focal vertebral pain; root pain; defects of motor, sensory, or sphincter function; and paralysis. Pain is the most consistent symptom and is accompanied by local tenderness at the affected level in more than 90% of cases. Subsequently, radicular pain develops; it is followed by progression to weakness and paralysis. Fever occurs in most patients during the course of the illness. Headache and neck stiffness may also occur. Respiratory function may be impaired if the cervical spinal cord is involved. The usually irreversible manifestations of cord involvement include muscle weakness, sensory deficits, and disturbances of sphincter control. At this juncture there may be rapid transition to paralysis (usually within 24 hours from onset of weakness), indicating the need for emergent evaluation, diagnosis, and treatment.

Diagnosis

Subdural empyema should be suspected in any patient with meningeal signs and a focal neurologic deficit. Lumbar puncture is contraindicated in this setting because of the risk of cerebral herniation. When lumbar puncture is performed, CSF findings are nonspecific and include elevated opening pressure, moderate neutrophilic pleocytosis, and an increased protein concentration. Unless the course is complicated by bacterial meningitis, CSF Gram stain and cultures are negative. Skull radiographs may demonstrate evidence of concurrent sinusitis or osteomyelitis.

The diagnostic procedures are CT with contrast enhancement or MRI.51,62 The typical CT appearance is a crescentic or elliptical area of hypodensity below the cranial vault or adjacent to the falx cerebri. Loculations may also be seen. Depending on the extent of disease, there is often an associated mass effect with displacement of midline structures. After the administration of contrast material, a fine, intense line of enhancement can be seen between the subdural collection and the cerebral cortex. However, false-negative CT scans do occur. MRI provides greater clarity of morphologic detail and may detect empyema not clearly seen on CT; it is of particular value in identifying subdural empyemas located at the base of the brain, along the falx cerebri, or in the posterior fossa. On the basis of signal intensity, MRI can differentiate extra-axial empyemas from most sterile effusions and chronic hematomas. Based on these findings, MRI is considered the modality of choice for the diagnosis of subdural empyema. CT and MRI are also useful for demonstrating sinusitis and otitis, although CT is better than MRI at imaging bone and should be used in cases of penetrating injury or osteomyelitis. MRI is the diagnostic procedure of choice for spinal subdural empyema because it more accurately defines the extent of the lesion than does CT.60,61

CT and MRI are also the diagnostic procedures of choice for cranial epidural abscess because both demonstrate a superficial, circumscribed area of diminished density.51 The possibility of adjacent subdural empyema or other intracranial involvement can also be assessed. MRI or CT should be performed in cases of suspected spinal epidural abscess. MRI is recommended as the diagnostic procedure of choice because it can visualize the spinal cord and epidural space in sagittal and transverse sections and can identify accompanying osteomyelitis, intramedullary spinal cord lesions, and joint space infection; the response to therapy also can be assessed readily with this technique.

Treatment

The therapy of subdural empyema and epidural abscess optimally requires a combined medical and surgical approach. Surgical therapy is essential for three reasons: because antibiotics do not reliably sterilize these lesions without concurrent drainage; because cultures of purulent material guide antimicrobial therapy; and because surgical decompression is useful in controlling increased intracranial pressure.

Antimicrobial Therapy

Once purulent material is aspirated, antimicrobial therapy should be initiated; it should be based on a Gram stain and on the site of primary infection51,63 (Table 52-9). For suspected S. aureus,nafcillin (1.5 to 2.0 g every 4 hours) should be used, with vancomycin (1.0 g every 12 hours) reserved for patients allergic to penicillin and for cases where methicillin-resistant organisms are suspected. Metronidazole (15 mg/kg loading dose and then 7.5 mg/kg every 6 to 8 hours) is used when anaerobes (e.g., B. fragilis) are suspected. For aerobic gram-negative bacilli, a third-generation cephalosporin (cefotaxime or ceftriaxone) should be used, with ceftazidime or cefepime reserved for cases in which P. aeruginosa is likely. Parenteral antibiotics should be continued for 3 to 6 weeks, depending on the patient's clinical response. Longer periods of intravenous therapy (and perhaps oral therapy) may be required if an associated osteomyelitis is present.

Presumptive antimicrobial therapy for spinal epidural abscess must include a first-line antistaphylococcal agent (nafcillin or vancomycin); coverage for gram-negative organisms should be included for any patient with a history of a spinal procedure or of injection drug abuse.58,60 In addition, pending culture results, empirical antimicrobial therapy in patients who have undergone a spinal procedure should include vancomycin for presumed involvement by S. epidermidis.

Surgical Therapy

The optimal surgical approach for subdural empyema is controversial, and there are several unanswered questions with regard to management.51 First, should drainage be performed by craniotomy or via burr holes? Previous studies have documented a lower mortality rate in patients undergoing craniotomy, although it may be that a larger percentage of gravely ill patients were treated with burr holes because of the greater surgical risk. Burr hole therapy may be more efficacious in the early stages of subdural empyema, when the pus is liquid, because thickening occurs as the disease progresses, making aspiration more difficult. If burr holes are to be placed, they should be multiple to allow extensive irrigation. However, craniotomy may be essential for posterior fossa subdural empyema, and it is also needed in 10% to 20% of patients initially treated with trephination. Thus, burr hole drainage, even with catheter irrigation, may not adequately drain the empyema. When craniotomy is performed, wide exposure should be afforded to allow adequate exploration of all areas where subdural pus is suspected. Second, should antibiotics be instilled locally to irrigate the subdural space? Although antibiotic irrigation has become common, there are no data on the potential benefits of this practice. Third, should drains, or catheters, be left in the subdural space? This decision is best made by the neurosurgeon intraoperatively; however, with drains in place, the risk of nosocomial superinfection must be kept in mind. Further, surgical correction of the antecedent otorhinologic infection may also be necessary. In patients with spinal epidural abscess, laminectomy with decompression and drainage may need to be performed as a surgical emergency to minimize the likelihood of permanent neurologic sequelae. However, in a literature review of 38 patients with spinal epidural abscess treated with antimicrobial therapy alone, 23 recovered, two died, one worsened, and the rest remained the same or improved.64 However, there have been no prospective, randomized trials comparing the efficacy of antimicrobial agents plus surgery with antimicrobial therapy alone. Rapid surgical decompression should be performed in patients with increasing neurologic deficit, persistent severe pain, or increasing temperature or peripheral white blood cell count.65

Adjunctive Therapy

Patients may also require various adjunctive measures to control increased intracranial pressure. Preoperative use of mannitol, hyperventilation, and/or dexamethasone may be effective in controlling intracranial pressure before surgical decompression. However, corticosteroids should be tapered rapidly after surgical therapy because of the increased risk of secondary infection. We believe a short course of corticosteroids is appropriate in cases in which surgical intervention is delayed or contraindicated. Anticonvulsants should be used in patients with seizures.

Epidemiology and Etiology

Septic intracranial thrombophlebitis involves venous thrombosis and suppuration. It may begin within veins and venous sinuses or may follow infection of the paranasal sinuses, middle ear, mastoid, face, or oropharynx, and it may involve additional vessels by propagation or discontinuous spread. Septic thrombophlebitis may also occur in association with epidural abscess, subdural empyema, or bacterial meningitis. Occasionally, there is metastatic spread from distant sites of infection. Conditions that increase blood viscosity or coagulability, such as dehydration, polycythemia, pregnancy, oral contraceptive use, sickle cell disease, malignancy, and trauma, increase the likelihood of thrombosis.

The antecedent conditions that predispose to the development of intracranial venous sinus thrombosis depend on the close proximity of various structures to the dural venous sinuses66,67 (Fig. 52-1). The usual predisposing conditions for cavernous sinus thrombosis are paranasal sinusitis (especially frontal, ethmoidal, or sphenoidal) and infection of the face or mouth. Likely infecting bacterial pathogens depend on the initial source: staphylococci, streptococci, gram-negative bacilli, and anaerobes, if the antecedent condition is sinusitis, and predominantly S. aureus in the case of facial infections. Otitis media and mastoiditis are infections associated with lateral sinus thrombosis and infection of the superior and inferior petrosal sinuses. Infections of the face, scalp, subdural space, and epidural space and meningitis are associated with suppurative thrombophlebitis of the superior sagittal sinus. The likely infecting microorganisms depend on the associated primary condition (see Table 52-5).

In cavernous sinus thrombosis, S. aureus is the most important infecting microorganism, having been isolated in more than 66% of cases. This relates to the importance of this organism in infections of the face and scalp and in acute sphenoid sinusitis. Less common isolates include streptococci (isolated in about 17% of cases), pneumococci and gram-negative bacilli (5% each), and Bacteroides species (2%).

Clinical Presentation

The clinical manifestations of suppurative cortical thrombophlebitis depend on the location of involvement. With involvement of the cortical venous system, the appearance of neurologic deficits depends on the adequacy of collateral venous drainage.68 Persons with inadequate collateral flow present with impairment of consciousness, focal or generalized seizures, symptoms of increased intracranial pressure, and focal neurologic signs (e.g., hemiparesis). Aphasia is common if the dominant cerebral hemisphere is involved.

The findings in dural venous sinus thrombosis also depend on location.66,67 In cavernous sinus thrombosis, the most common complaints are periorbital swelling (73% of cases) and headache (52%). Headache is more common if the antecedent condition is sinusitis rather than a facial infection. Other symptoms include drowsiness, diplopia, eye tearing, photophobia, and ptosis. Fever is present in more than 90% of patients. Other common signs are proptosis, chemosis, periorbital edema, and weakness of the extraocular muscles (due to involvement of cranial nerves III, IV, and VI). Because the abducens nerve is the only cranial nerve traversing the interior of the cavernous sinus, lateral gaze palsy may be an early neurologic finding. Papilledema or venous engorgement and a change in mental status are observed in 65% and 55% of patients, respectively. Meningismus is present in about 40% of cases, usually secondary to retrograde spread of the thrombophlebitis. About 25% of patients have dilated or sluggishly reactive pupils, decreased visual acuity (frequently progressing to blindness), and dysfunction of cranial nerve V. As the infection spreads to the opposite cavernous sinus through the intercavernous sinuses, findings are duplicated in the opposite eye. Persons with septic cavernous sinus thrombosis may present with acute or chronic illness.67 In the acute presentation (generally secondary to facial infection), the time between primary infection and cavernous sinus thrombosis is short (<1 week), and the patient presents in a significantly toxic state, with rapid development of the symptoms and signs described above; there is also rapid progression to bilateral eye signs. In contrast, there is a more indolent form of cavernous sinus thrombosis, usually secondary to dental infection, otitis media, or paranasal sinusitis. In these patients, the orbital manifestations are often unimpressive, and involvement of the contralateral eye is a late and inconsistent finding.

Patients with septic lateral sinus thrombosis complain predominantly of headache (>80% of cases); earache, vomiting, and vertigo also may occur because otitis media is a common predisposing condition.66,68 Fever and abnormal ear findings are observed in most patients (79% and 98%, respectively), and there may be seventh nerve palsy, facial pain and altered facial sensation, papilledema, and mild nuchal rigidity. Thrombosis of the superior sagittal sinus produces an abnormal mental status, motor deficits, nuchal rigidity, and papilledema. Seizures occur in more than 50% of these patients. Patients with sinusitis as a predisposing condition tend to have a subacute onset of symptoms. Involvement of the inferior petrosal sinus may produce ipsilateral facial pain and lateral rectus muscle weakness (Gradenigo syndrome).

Diagnosis

The noninvasive diagnostic procedure of choice for suppurative intracranial thrombophlebitis is MRI.69 This technique visualizes blood vessels and differentiates between thrombus and normally flowing blood. It can also demonstrate the evolution and resolution of the entire veno-occlusive process. CT, with and without use of intravenous contrast material, also permits diagnosis of venous sinus thrombosis,67 although it is considerably less sensitive and reliable than MRI. CT usually visualizes unilateral or bilateral multiple irregular filling defects in the enhancing cavernous sinus, with or without orbital inflammatory change. An additional benefit of MRI and CT is the ability to fully evaluate the paranasal sinuses and to provide information concerning subdural and epidural infection, cerebral infarction, cerebritis, hemorrhage, and cerebral edema.

Other laboratory studies are usually nonspecific.66,67 Lumbar puncture demonstrates a mild pleocytosis (mononuclear, neutrophilic, or mixed) and an elevated protein concentration (consistent with a parameningeal focus of infection), although, in septic thrombosis of the superior sagittal sinus, there may be findings consistent with frank meningitis; often the causative organism is isolated on CSF culture. Blood cultures may be positive, especially in patients with a rapidly progressive course. Chest radiographs may show evidence of septic pulmonary emboli after propagation of thrombus into the inferior petrosal sinus and jugular vein. Sinus radiographs may document involvement of the paranasal sinuses, although conventional radiographs are inferior to MRI and CT in the detection of sphenoid sinusitis.

Treatment

Antimicrobial Therapy

Appropriate antimicrobial therapy of septic intracranial thrombophlebitis depends on the antecedent clinical condition. The likely organisms are similar to those observed in cranial subdural empyema and epidural abscess; empirical antibiotic therapy should be directed toward those organisms68 (see Table 52-9). If the antecedent condition is paranasal sinusitis, empirical therapy should be directed toward gram-positive organisms (staphylococci and streptococci), aerobic gram-negative bacilli, and anaerobes. In cavernous sinus thrombosis, an antistaphylococcal agent should always be included (because of the high incidence of S. aureus isolates) in the empirical therapeutic regimen pending culture results. Nafcillin should be used, with vancomycin reserved for penicillin-allergic patients and cases in which methicillin-resistant organisms are suspected.

Surgical Therapy

Surgical intervention may be required for optimal therapy. Surgical drainage of infected sinuses is necessary when antimicrobial therapy alone is ineffective. This is especially important in patients with cavernous sinus thrombosis secondary to sphenoid sinusitis; some investigators have recommended operative intervention for patients who develop cavernous venous thrombosis as a complication of sinusitis. Internal jugular vein ligation has been used for lateral sinus vein thrombosis, and thrombectomy has also been used in some situations, but the efficacy of these procedures is poorly defined. Surgical therapy may also be required for other infections (e.g., dental abscess).

Adjunctive Therapy

The use of anticoagulants (e.g., heparin) is controversial, although there is literature to support their use in prevention of the spread of thrombus from the cavernous sinus to other dural venous sinuses and cerebral veins.66 Recent evidence has indicated that anticoagulation (in combination with antibiotics) decreases mortality rate and is most beneficial early in the treatment of cavernous sinus thrombosis to reduce the morbidity rate among survivors.70 However, the hazards of intracranial hemorrhage (bleeding from sites of cortical venous infarction or from sites on the intracavernous walls of the carotid artery) must be recognized. In the absence of specific contraindications, anticoagulation is most likely to be useful early in the course of cavernous sinus thrombosis.