From the cisterna magna, an organized flow of CSF occurs around the convexities of the brain to the arachnoid villi. There are multiple pathways of bidirectional flow around the spinal cord.

There are numerous potential and actual spaces among the layers of the meninges (Figure 134-2). Meningitis involves the actual space (i.e., the subarachnoid space), which consists of multiple interconnected compartments. The small size of the foramina of Luschka and Magendie allows unidirectional caudal flow toward the cisterna magna, where the CSF then moves either cephalad or into the spinal canal. This compartmentalization has implications for therapy, because the movement of medications and infectious agents depends on the rate and direction of CSF flow. A blockage at any of these levels may restrict entry of antibiotics into sites of ongoing infection.

Figure 134-2 This diagram of the potential and actual spaces between the layers of the meninges shows the relationship of blood vessels and nerve roots to the subarachnoid space.

Infectious agents can invade the CSF by at least three routes (Table 134-2). First, the vascular structures of the choroid plexus and pia and the vessels that traverse the subarachnoid space may serve as conduits during systemic bacteremia. A second less common route is direct invasion across the protective meninges. Physical disruption of the dura by trauma or surgery allows direct invasion of the subarachnoid space and should be considered in patients with a history of CSF leakage or rhinorrhea. Emissary veins provide another pathway for bacteria to spread from contiguous foci into the subarachnoid space. These veins traverse the skull and dura, directly connecting the soft tissues of the head and neck with the venous system of the brain and meninges, including the arachnoid villi. Although blood in the emissary veins usually flows away from the brain, the CNS veins and dural sinuses do not contain valves, and retrograde flow of bacteria is possible. Rarely, organisms may reach the ventricles or subarachnoid space from within the neural tissue; for example, rupture of a brain abscess into the ventricles may have disastrous effects.

TABLE 134-2 Routes by Which Bacteria May Enter the Subarachnoid Space

Vascular (Blood-Brain Barrier)

Mostly likely pathogens: pneumococci, meningococci, Listeria, Escherichia coli (neonates), group B streptococci (neonates), Haemophilus influenzae

Choroid plexus: may be common site of invasion for H. influenzae

Meningeal blood vessels: throughout the subarachnoid space; may be usual route for pneumococci

Arachnoid villi: possible route of invasion, located between the sagittal sinus and subarachnoid space

Transdural

Most likely pathogens: pneumococci, gram-negative enteric bacilli, staphylococci (including coagulase-negative), H. influenzae

Surgery: including ventriculoatrial or ventriculoperitoneal shunts

Trauma: especially when cribriform plate or petrous bone is fractured

Parameningeal infective focus: including sinusitis, mastoiditis, otitis, or osteomyelitis; emissary veins may serve as conduit

Congenital defects: including myelomeningocele and spinal dermal sinus

Transparenchymal

Mostly likely pathogens: anaerobic bacteria, enteric gram-negative bacilli

Occurs when brain abscess ruptures directly into ventricles or subarachnoid space

Pathophysiology

Neural damage occurs as a direct result of the host inflammatory response. The unique anatomy and composition of the CSF-filled compartments, combined with a paucity of host immunologic defenses, create a microenvironment that allows the persistence and proliferation of microorganisms.¹ Polymorphonuclear leukocytes are not normal inhabitants of the CSF, and mobilization of these phagocytic cells is delayed during the early stages of infection. Similarly, the concentration of immunoglobulin in CSF is significantly less than that in serum, limiting the effectiveness of humoral immunity. Most important, complement, which plays a critical role in chemotaxis, phagocytosis, and intracellular killing, is virtually absent from normal CSF. Once in the CSF, bacteria induce leukocyte migration into the subarachnoid space, resulting in occlusion of cortical blood vessels, damage to nerve roots that traverse the subarachnoid space (see Figure 134-2), and impaired CSF flow (see Figure 134-1). Clinically, this manifests as cranial or spinal nerve dysfunction and hydrocephalus. Activation of leukocytes leads to an inflammatory cascade, with the release of cytokines, oxidants, and proteolytic enzymes. At the cellular level, this chain of events produces disruption of the blood-brain barrier and impaired cerebrovascular autoregulation.⁴ Increased intracranial pressure may result in transtentorial herniation or tissue hypoxia due to decreased tissue perfusion.

Clinical Course

Acute Meningitis Syndrome

Early recognition and therapy of acute meningitis syndrome are essential to minimize morbidity and mortality. The initial manifestation of the illness may be subtle, with a low-grade headache or fever. However, once meningeal symptoms (vomiting, severe headache, stiff neck) develop, the clinical course is dramatic. Patients appear “toxic,” and higher integrative functions may deteriorate rapidly. The classic clinical triad associated with bacterial meningitis, fever, neck stiffness, and altered mental status is present in only 44% of cases.⁶ A rash is highly suggestive of meningococcal infections; however, skin lesions are noted in only 64% of meningitis cases due to this organism.⁷ Other common signs and symptoms include headache and nausea. In the elderly, recognition of acute bacterial meningitis may be delayed by the absence of suggestive clinical findings. Nuchal rigidity, vomiting, and headache are significantly less frequently noted in the elderly; in contrast, seizures are present in 26% of patients ≥65 years of age.¹⁰ In addition, the elderly have a higher incidence of noninfectious conditions that may mimic acute meningitis syndrome (e.g., subarachnoid bleeding and malignancies involving the CNS) complicating the initial evaluation.

Acute meningitis syndrome represents an infectious disease emergency. Baseline predictors of adverse outcome in adults include advanced age, tachycardia (heart rate >120 beats/min), low Glasgow Coma Scale score, cranial nerve palsies, CSF WBC count less than 1000/mm³, and presence of gram-positive cocci on CSF Gram stain.⁸ This latter variable reflects the higher mortality associated with pneumococcal meningitis. Despite the availability of antibiotics active against all common causes of acute bacterial meningitis, in adults the overall mortality remains approximately 20%.⁶ A delay in antibiotic therapy increases the risk of an adverse outcome, particularly when progressive neurologic impairment occurs before receiving therapy.⁹ For this reason, recently published guidelines recommend the administration of empirical antibiotics to patients with a presumptive diagnosis of bacterial meningitis as soon as possible after presentation (Figure 134-3).⁵

Figure 134-3 Algorithm for management of adult patients with acute meningitis syndrome. *For severe cephalosporin allergy, consider meropenem or moxifloxacin. ^†Ampicillin is indicated if there is a history of alcoholism, organ transplant, malignancy, pregnancy, or age older than 50 years. For penicillin-allergic patients, an alternative is trimethoprim-sulfamethoxazole. ^‡Consider magnetic resonance imaging (MRI) if the patient is known or suspected to have human immunodeficiency virus (HIV), if it can be obtained rapidly. CNS, central nervous system; CSF, cerebrospinal fluid; CT, computed tomography; H&P, history and physical examination; PMN, polymorphonuclear leukocyte; WBC, white blood cell.

Coupled with the need for urgent treatment is the need for urgent diagnosis. Identification of a pathogen allows the clinician to tailor the antibiotic regimen based on susceptibility patterns, and has prognostic and therapeutic implications. However, situations arise when lumbar puncture is unavoidably delayed. This may be due to anatomic factors that make lumbar puncture technically difficult or the need to perform neuroimaging studies to exclude a contraindication to lumbar puncture. If a significant delay in obtaining CSF is anticipated, antibiotics should be given immediately after peripheral blood cultures are obtained. The yield of CSF culture decreases within as little as 15 minutes following administration of antibiotics.¹¹ Nevertheless, the risk of delaying treatment outweighs the need to make a microbiological diagnosis. Despite the inhibitory effect of prior antibiotics on bacterial culture and Gram stain, the absolute neutrophil count and neutrophilic pleocytosis remain suggestive of bacterial meningitis,^12,¹³ and a full course of empirical therapy should be completed if CSF parameters are consistent with this diagnosis.

Historically, the perceived risk (and legal consequences) of uncal herniation following lumbar puncture in the presence of an intracranial mass lesion led to the ubiquitous use of neuroimaging. More recently, studies have challenged this practice, citing the potential deleterious effect of computed tomography (CT) scan–related delays in the initiation of therapy or the compromising effect of premature sterilization of CSF cultures.^9,^11,¹⁶ Even among patients with an abnormal CT scan, only a minority of cases have radiographic findings precluding lumbar puncture.¹⁴ For this reason, guidelines suggest that neuroimaging prior to lumbar puncture should be reserved for patients with compromised immune systems (e.g., human immunodeficiency virus [HIV] infection, use of immunosuppressive medications, or organ transplantation), history of an intracranial mass lesion, abnormal level of consciousness, papilledema, or focal neurologic deficit.⁵ In the absence of one of these features, the recommendation is to proceed directly to lumbar puncture, followed by immediate administration of empirical antibiotics.⁵

Subacute Central Nervous System Infection Syndrome

Febrile illness associated with a somewhat more gradual progression of signs and symptoms of CNS involvement represents the subacute meningitis syndrome. Headache can be mild to severe, and neck stiffness can be minimum or marked. However, patients with this syndrome are typically oriented and clinically stable at the onset of illness, with a gradual progression of neurologic symptoms (>24-48 hours). Although bacterial infection may rarely cause subacute meningitis, most cases are due to other pathogens or noninfectious factors.

Herpes simplex encephalitis, brain abscess, and meningitis due to fungi, mycobacteria, fastidious bacteria (e.g., Rickettsia rickettsii, Treponema pallidum), or viruses all produce fever, worsening headache, and progressive impairment of higher integrative functions. On occasion, carcinomatous meningitis, brain tumor, and subarachnoid bleeding cause similar findings (see Table 134-1). To avoid inappropriate therapy and unnecessary hospitalization, the decision to institute antimicrobial therapy should be carefully weighed. However, if pyogenic meningitis is still a possibility, empirical antimicrobial therapy should be begun, as outlined in the previous section.

The first priority when managing subacute CNS syndrome is rapid diagnosis (as opposed to the rapid-therapy approach to acute meningitis syndrome). With this syndrome, the physician has time to carefully evaluate the patient and relevant laboratory data (Figure 134-4). Peripheral blood granulocytosis (>10,000/mm³), CSF cell counts over 1000/mm³, CSF protein concentration over 100 mg/dL, and CSF glucose concentrations below 40 mg/dL favor a bacterial cause, and these patients should be given empirical antibiotics for acute meningitis syndrome until a specific diagnosis is made or bacterial cultures return negative.

Figure 134-4 Algorithm for the management of patients with subacute central nervous system (CNS) infection syndrome. CSF, cerebrospinal fluid; CT, computed tomography; EEG, electroencephalogram; HSV, herpes simplex virus; LP, lumbar puncture; MRI, magnetic resonance imaging; PCR, polymerase chain reaction; WBC, white blood cell.

If history and physical examination suggest a space-occupying lesion, lumbar puncture and even antimicrobial therapy can be safely delayed pending results of emergent head CT or magnetic resonance imaging (MRI). However, if significant delays are likely, empirical therapy should be given. Other causes of subacute CNS infection syndrome are discussed later (see Brain Abscess and Viral Infections of the Central Nervous System).

Additional diagnostic studies may be indicated for subacute infections. Serologic testing for HIV should be performed, because the spectrum of infectious agents is much broader among HIV-infected individuals. Testing for enteroviruses (CSF polymerase chain reaction [PCR] or viral culture), Cryptococcus (cryptococcal antigen), neurosyphilis (VDRL), mycobacterial infection (culture or PCR of CSF), herpes simplex virus (CSF PCR), tickborne infections (Ehrlichia, Rickettsia, Lyme disease), and arboviral encephalitides (West Nile virus) should be individualized based on patient characteristics, severity of illness, knowledge of local pathogens, and season. Despite intensive diagnostic testing, a pathogen is identified in only two-thirds of patients with subacute meningitis syndrome.¹⁷

Epidemiology

The epidemiology of bacterial meningitis has evolved in the last twenty years. The incidence of bacterial meningitis in the pediatric population has decreased markedly in the United States following the widespread use of conjugate vaccines active against Haemophilus influenzae type B, Neisseria meningitidis, and Streptococcus pneumoniae.¹⁸Conversely, the incidence of nosocomial bacterial meningitis caused by resistant strains of Enterobacteriaceae, Pseudomonas aeruginosa, and Staphylococcus aureus is increasing following surgery or instrumentation of the CNS.²

Therapy

Antibiotics

The choice of empirical antibiotics is based on knowledge of the likely causative agents, which vary based on host characteristics (e.g., age, immunocompromise), site of acquisition (nosocomial versus community acquired), and local resistance patterns. Recommendations for empirical therapy are listed in Table 134-3, with dosages commonly used for the treatment of CNS infections listed in Table 134-4.^3,⁵ Pneumococci and meningococci remain the most common causes of community-acquired meningitis in immunocompetent adults younger than 50 years.³ In the last decade, pneumococci that are intermediately (minimum inhibitory concentration [MIC] >0.12 to 1 µg/mL) or highly (MIC >2 µg/mL) resistant to penicillin have emerged as important pathogens. Penicillin-resistant pneumococci are typically multidrug resistant; however, many isolates remain sensitive to third-generation cephalosporins, and all are susceptible to vancomycin.

TABLE 134-3 Empirical Antimicrobial Therapy for Adult Patients with Presumed Bacterial Meningitis

TABLE 134-4 Antimicrobial Dosages for Central Nervous System Infections

Drug	Dosage (by Total Body Weight)	Usual Dosage (for 70-kg Adult)
Acyclovir	10 mg/kg IV q 8 h	700 mg IV q 8 h
Ampicillin	30 mg/kg IV q 4 h	2 g IV q 4 h
Cefotaxime	30 mg/kg IV q 6 h	2 g IV q 6 h
Ceftazidime	30 mg/kg IV q 8 h	2 g IV q 8 h
Cefepime	30 mg/kg IV q 8 h	2 g IV q 8 h
Ceftriaxone	30 mg/kg IV q 12 h	2 g IV q 12 h
Meropenem	40 mg/kg IV q 8 h*	2 g IV q 8 h
Metronidazole	7.5 mg/kg IV q 6 h	500 mg IV q 6 h
Nafcillin	30 mg/kg IV q 4 h	2 g IV q 4 h
Penicillin G	60,000-70,000 units/kg IV q 4 h	4 million units IV q 4 h
Tobramycin or gentamicin^†	2 mg/kg IV load, then 1.7 mg/kg q 8 h^‡	140 mg IV load, then 120 mg IV q 8 h^‡
Intrathecal	0.1 mg/kg/d	5-10 mg/d
Intraventricular	0.1 mg/kg/d	5-10 mg/d
Trimethoprim-sulfamethoxazole	5 mg/kg IV q 6 h	350 mg IV q 6 h^§
Vancomycin	15 mg/kg IV q 6 h	500 mg IV q 6 h^‡ or 1 g IV q 12 h