Meningitis: Bacterial, Viral, and Other

Pathology

On gross examination, purulent exudate in the subarachnoid space is most abundant in the cisterns at the base of the brain and over the convexities of the Rolandic and Sylvian sulci, which are expansions of the subarachnoid space. Although neither the infecting organism nor the inflammatory exudate directly invades cerebral tissue, the subjacent brain becomes congested and edematous. The pial barrier generally prevents bacterial meningitis from causing a cerebral abscess; when these two processes coexist, the sequence is usually that an initial abscess leaks its contents into the ventricular system or the subarachnoid space, where it produces secondary ventriculitis and/or meningitis.

The inflammatory exudate can extend around the perivascular spaces to adjacent structures, especially the arteries and veins that carry a layer of pia mater and arachnoid membrane as they enter the brain from the cortical surface. Cortical thrombophlebitis results from venous stasis and adjacent meningeal inflammation. Infarction of cerebral tissue may follow. Involvement of cortical and pial arteries by peripheral aneurysm formation and vascular occlusion or narrowing (related to spasm, arteritis, or both) of the supraclinoid portion of the internal carotid artery at the base of the brain occurs in approximately 15% of patients with meningitis. The anterior and middle cerebral arteries may also develop stenosis or spasm. In fulminating cases, particularly meningococcal meningitis, cerebral edema may be marked even though the pleocytosis is only moderate. Rarely, temporal lobe herniation through the tentorium develops in such patients and compresses the midbrain, thereby leading to ipsilateral third nerve palsy and contralateral hemiparesis; or cerebellar herniation through the foramen magnum with compression of the medulla, which results in apnea, hemodynamic instability, and coma. Damage to cranial nerves occurs in areas where dense exudate accumulates around the nerves; the third and sixth cranial nerves are also vulnerable to damage by increased intracranial pressure. Ventriculitis accompanies most cases of bacterial meningitis and may rarely progress to ventricular empyema . As the exudates accumulate, obstruction of the flow of CSF may result in hydrocephalus . Obstruction of the cerebral aqueduct or foramina of Magendie and Luschka at the base of the fourth ventricle results in noncommunicating or obstructive hydrocephalus, whereas obstruction at the level of the arachnoid granulations in the venous sinuses results in communicating hydrocephalus. Subdural effusions are sterile transudates that develop over the cerebral cortex and can be demonstrated readily by computed tomography (CT) as low-density areas about the cerebrum. On magnetic resonance imaging (MRI), they appear as high signal intensity lesions of T2 or fluid-attenuated inversion recovery (FLAIR) sequences. Rarely, such an effusion becomes an infected subdural empyema.

Pathogenesis

Bacteria may gain access to the meninges by several routes: (1) hematogenous spread from a distant site; (2) direct ingress from the upper respiratory tract or skin through an anatomic defect (e.g., skull fracture, meningocele, sequela of surgery); (3) passage intracranially through venules in the nasopharynx; or (4) spread from a contiguous focus of infection (infection of the paranasal sinuses, leakage of a brain abscess). Bacteremic spread of H. influenzae, N. meningitidis , and S. pneumoniae is probably the most frequent path of infection. Bacteremia is usually initiated by pharyngeal adhesion and colonization by an infecting strain. Adhesion of such strains, as well as of S. pneumoniae , to mucosal surfaces is abetted by their capacity to produce proteases that cleave immunoglobulin A, thus inactivating this local antibody defense. Adhesion of N. meningitidis to nasopharyngeal cells is affected by fimbriae or pili and promoted by previous damage to ciliated cells such as from smoking or viral infections. Meningococci invade the nasopharyngeal mucosal cells by means of endocytosis and are transported to the abluminal side in membrane-bound vacuoles. H. influenzae , in contrast, invades intercellularly by causing separation of the apical tight junctions between columnar epithelial cells. When these meningeal pathogens gain access to the blood stream, their intravascular survival is aided by the presence of polysaccharide capsules that inhibit phagocytosis and confer resistance to complement-mediated bactericidal activity.

Bacteria also may travel along nerve tracts to invade the brain. For example, L. monocytogenes invades the intestine, and animal models suggest that these bacteria can travel along the vagus nerve to the brain stem, from where they also may invade the meninges in the posterior fossa.

Bacteria can gain access to the subarachnoid spaces from blood cells, either by disruption of the blood-brain barrier or via the choroid plexus, also termed the blood-CSF barrier. Once established in any part of the meninges, infection quickly extends throughout the subarachnoid space. Bacterial replication proceeds relatively unhindered because the low CSF levels of immunoglobulin and complement early in meningeal inflammation result in minimal or no opsonic or bactericidal activity and because surface phagocytosis of unopsonized organisms is meager in such a fluid environment. During meningitis, the concentrations of immunoglobulins in CSF increase but still remain relatively low. Secondary bacteremia may follow meningeal infection and may itself contribute to continuing further inoculation of CSF.

Bacterial meningitis following head trauma occurs because of a dural fistula from the nasal cavity, paranasal sinuses, or middle ear to the subarachnoid space. The most frequent site is at the cribriform plate, where the bone is thin and the dura is tightly adherent to the bone. Leakage of CSF results in CSF rhinorrhea and loss of smell.

Cerebral blood flow, which depends on mean arterial pressure, is increased in the early stages of meningitis, but it subsequently decreases, substantially in some patients, which may cause ischemic neurologic injury. Localized regions of marked hypoperfusion, attributable to focal vascular inflammation or thrombosis, can occur in patients with normal blood flow. Impairment of cerebral blood flow autoregulation, as measured by transcranial Doppler ultrasonography of the middle cerebral artery, occurs early in acute bacterial meningitis and causes cerebral blood flow to correspond directly to mean arterial blood pressure, with attendant hyperperfusion or hypoperfusion of the brain. On recovery, the ability of the cerebral vasculature to maintain a constant level of perfusion despite variations in mean arterial pressure is restored.

Genetics

Patients with defects in cell-mediated immunity are susceptible to the development of CNS infections with intracellular organisms such as L. monocytogenes . Patients with defective humoral immunity and an inadequate antibody response are particularly vulnerable to meningitis with S. pneumoniae and H. influenzae . For example, deficiencies in the complement system predispose patients to meningitis, and 50 to 60% of adults with pneumococcal meningitis may have C2 deficiency. Mutation in the intron of UBE2U, which is involved in antigen presentation, is also linked to severity of pneumococcal meningitis. Meningococcal meningitis is associated with polymorphisms in CD32, CD16, mannose-binding lectin, toll-like receptor 4 (TLR4), and the B-2 adrenoceptor gene. Patients with neutropenia are at higher risk for meningitis with Pseudomonas aeruginosa and members of the Enterobacteriaceae family.

History

Acute-onset fever, generalized headache, vomiting, and stiff neck are common to many types of meningitis ( Table 381-1 ). Most patients with community-acquired pyogenic meningitis have had an antecedent or accompanying upper respiratory tract infection or nonspecific febrile illness, acute otitis (or mastoiditis), or pneumonia. Myalgia, particularly in patients with meningococcal disease, backache, and generalized weakness are common symptoms. The illness usually progresses rapidly, with the development of confusion, obtundation, and loss of consciousness. Occasionally, the onset may be less acute, with meningeal signs being present for several days to a week.

General Physical Findings

Evidence of meningeal irritation is usually present, as evidenced by a stiff neck, Kernig sign (inability to straighten the leg when the hip is flexed to 90 degrees), and Brudzinski sign (involuntary flexion of the hip and knee when the neck is passively flexed). Neck stiffness, Kernig sign, and Brudzinski sign each have sensitivities of approximately 30% or lower for diagnosing acute bacterial meningitis in adults. Although the classic triad of fever, stiff neck, and change in mental status is initially present in only about 45% of episodes, a combination of two of four symptoms (headache, fever, stiff neck, and altered mental status) is found in 95% of patients. The findings of meningitis may be easily overlooked in infants, obtunded patients, elderly patients with heart failure or pneumonia, or immunosuppressed individuals, who may have meningitis without prominent meningeal signs; in such patients, lethargy should be investigated carefully, meningeal signs should be sought, and examination of CSF is indicated if any doubt exists. In elderly patients, neck stiffness may be difficult to evaluate because of osteoarthritis in the neck or stiffness of neck muscles secondary to basal ganglia disorders. When neck stiffness is caused by meningitis, the neck resists flexion but can be rotated passively from side to side; with cervical spine disease, however, resistance is present in all directions of neck movement. Neck stiffness disappears during coma.

The presence of a petechial or ecchymotic rash (see Fig. 274-2 in Chapter 274 ) in a patient with meningeal findings almost always indicates meningococcal infection and requires prompt treatment because of the rapidity with which this infection can progress ( Chapter 274 ). Rarely, extensive petechial and ecchymotic lesions occur in meningitis caused by S. pneumoniae, H. influenzae , or echovirus type 9. Very rarely, skin lesions almost indistinguishable from those of meningococcal bacteremia occur in patients who have acute S. aureus endocarditis (see Fig. 61-1 in Chapter 61 ) and who also have meningeal signs and pleocytosis (secondary to either staphylococcal meningitis or embolic cerebral infarction). Usually, one or two of the lesions in such a patient represent purulent purpura; aspiration of material reveals staphylococci on Gram staining. In the summer, viral aseptic meningitis may produce meningeal signs, macular and petechial skin lesions, and a pleocytosis of several hundred cells, sometimes with neutrophils predominating initially.

Fulminant meningococcal septicemia may cause hemorrhages within the adrenal glands and result in Waterhouse-Friderichsen syndrome ( Chapter 208 ), a condition characterized by the sudden onset of a febrile illness, large petechial hemorrhages in the mucous membranes and skin, cardiovascular collapse, and disseminated intravascular coagulation. In contrast, hyponatremia and the syndrome of inappropriate secretion of antidiuretic hormone may develop in patients with meningitis attributable to H. influenzae . A concurrent respiratory tract infection or acute otitis media may be present with either H. influenzae or S. pneumoniae .

In patients with a basilar skull fracture, the potential for development of a dural fistula and bacterial meningitis is indicated by the presence of CSF rhinorrhea, periorbital ecchymoses, bruising behind the ear (Battle sign), hemotympanum, or blood in the external auditory canal. Meningitis complicating neurosurgical procedures may be insidious in onset and difficult to distinguish from the altered consciousness and signs of meningeal irritation that are expected in the postoperative period. However, fever or prolonged obtundation is an indication for evaluation of CSF.

Neurologic Findings and Complications

Neurologic abnormalities in patients with inadequately treated bacterial meningitis can be severe and disabling. Cranial nerve abnormalities, involving principally the third, fourth, sixth, or seventh nerve, occur in 5 to 10% of adults with community-acquired meningitis and usually disappear shortly after recovery. The most likely sites of involvement in patients with persistent sensorineural deafness appear to be the inner ear (infection or toxic products possibly spreading from the subarachnoid space along the cochlear aqueduct) and the acoustic nerve.

Seizures (focal or generalized; Chapter 372 ) occur in 20 to 30% of patients and may result from reversible causes (high fever or hypoglycemia in infants, penicillin neurotoxicity when large doses are administered intravenously [IV] to patients with renal failure) or, more commonly, from focal cerebral injury related to arterial hypoperfusion and infarction, cortical venous thrombosis, or focal edema and cerebritis. Seizures can occur during the first few days or can appear with associated focal neurologic deficits caused by vascular inflammation some days after onset of the meningitis. In adults with seizures accompanying meningitis, S. pneumoniae is more commonly the cause, but alcohol withdrawal is a confounding factor.

Increased CSF pressure, which can be caused by brain swelling or hydrocephalus, is associated with seizures, vomiting, sixth and third nerve dysfunction, abnormal reflexes, reduced consciousness or coma, dilated and poorly reactive pupils, and the Cushing response of decerebrate posturing, hypertension, bradycardia, and irregular respirations. In approximately a fourth of fatal cases of community-acquired meningitis in adults, cerebral edema accompanied by temporal lobe herniation is observed at autopsy.

Papilledema (see Fig. 391-25 in Chapter 391 ) occurs in less than 1% of patients with bacterial meningitis, even with high CSF pressure, probably because the patient is seen early in the process before changes in the nerve head have occurred. The presence of this sign should indicate the possibility of another associated or independent suppurative intracranial process, such as subdural empyema or brain abscess or a more chronic process such as fungal or tuberculous meningitis. Marked central hyperpnea sometimes occurs in patients with severe bacterial meningitis; CSF acidosis, which is principally due to increased lactic acid levels, provides much of the respiratory stimulus.

Focal cerebral signs (principally hemiparesis, dysphasia, visual field defects, and gaze preference) occur in approximately a third of adults with community-acquired bacterial meningitis. These signs may develop because of arterial or venous occlusion or concurrent development of brain abscess ( Chapter 382 ), subdural empyema or cerebral edema. In addition, cerebral blood flow velocity may be decreased in patients with increased intracranial pressure and may lead to temporary or lasting neurologic dysfunction. It is important to distinguish these vascular effects from postictal changes (Todd paralysis), which usually persist for less than a day. Meningitis may cause the syndrome of inappropriate secretion of antidiuretic hormone.

Laboratory Findings

Radiologic Studies

Because of the frequency with which pyogenic meningitis is associated with primary foci of infection in the chest, nasal sinuses, or mastoid, radiographs of these areas should be taken when clinically indicated at the appropriate time after antimicrobial therapy is begun. Initial head CT or MRI is not indicated in most patients with bacterial meningitis. For example, in patients who undergo head CT or MRI before lumbar puncture for suspected meningitis, only approximately 5% have a mass effect identified on CT. Baseline clinical features associated with abnormal findings on CT include age older than 60 years, history of CNS disease, seizure within the previous week, abnormal level of consciousness, abnormal visual fields, limb drift, and aphasia. In patients without any of these clinical findings, only approximately 1% have a mass effect identified on CT or MRI that would raise concern regarding lumbar puncture.

Specific changes that may be observed on CT or MRI during meningitis include cerebral edema and enlargement of the subarachnoid spaces, contrast enhancement of the leptomeninges and the ependyma, or patchy areas of diminished density as a result of associated cerebritis and necrosis. In patients with meningitis whose clinical status deteriorates or fails to improve, CT or MRI may help demonstrate suspected complications—that is, sterile subdural collections or empyema; ventricular enlargement secondary to communicating or obstructive hydrocephalus; prominent persisting basilar meningitis; extensive areas of cerebral infarction resulting from occlusion of major cerebral arteries, veins, or venous sinuses; or marked ventricular wall enhancement suggesting ventriculitis or ventricular empyema. MRI is superior to CT for visualizing these abnormalities. Rarely, cerebral hemorrhage identifiable on CT may complicate acute bacterial meningitis in adults. In approximately 10% of adults with bacterial meningitis, findings on cranial CT (mastoid or sinus wall defect, eroding retrobulbar mass, pneumocephalus) are indicative of disruption of the dural barrier.

Rarely, paraparesis or tetraparesis resulting from myelitis may complicate bacterial meningitis. In this situation, T2-weighted or short tau inversion recovery (STIR) sequences on MRI can be helpful to exclude spinal cord compression by an extramedullary mass.

Differential Diagnosis

Headache, fever, stiff neck, confusion, vomiting, and pleocytosis are features of meningeal inflammation and are common to many types of meningitis (e.g., bacterial, fungal, viral, chemical) and also some parameningeal processes. The CSF findings are most helpful in distinguishing among these processes ( Chapters 382 and 383 ), and PCR can usually provide a rapid diagnosis.

In most modern studies of adults, viral meningitis or encephalitis is about four times more common than bacterial meningitis ( Table 381-3 ). Although a lymphocyte-predominant pleocytosis without hypoglycorrhachia is characteristic of viral (usually enteroviral or herpes simplex virus type 2 [HSV-2]) meningitis or meningoencephalitis (HSV-1), the initial CSF finding may be a polymorphonuclear response (of ≤60%) that quickly becomes mononuclear. HSV-1 encephalitis is suggested by neurologic findings (dysphasia, hemiparesis, olfactory hallucinations, other temporal lobe signs, seizures), abnormalities in the orbitofrontal and medial temporal lobes on MRI, and distinctive electroencephalographic changes in the temporal lobe or lobes.

The rash, fever, and headache of Rocky Mountain spotted fever ( Chapter 302 ) may suggest meningococcal infection, but the geographic and seasonal predilections of the former can provide clues. Approximately 10% of patients hospitalized with Rocky Mountain spotted fever have CSF cell counts higher than 100/µL (>70% polymorphonuclear), and thus the condition initially may be confused with bacterial meningitis. The rash associated with enteroviral infections typically consists of erythematous macules and papules on the face, neck, and trunk.

Acute subarachnoid hemorrhage ( Chapter 377 ) may be confused with bacterial meningitis because of headache, stiff neck, and vomiting. However, subarachnoid hemorrhage usually has a more abrupt onset without a prodromal fever but with evidence of subarachnoid blood on CT or CSF examination. In patients with neuroleptic malignant syndrome ( Chapters 379 and 386 ), fever, generalized rigidity, and a fluctuating level of consciousness with autonomic instability and leukocytosis may develop. The most specific laboratory abnormality in these patients is a markedly elevated creatine kinase level.

In patients who have meningitis but whose CSF does not reveal the etiologic agent on a Gram-stained smear or PCR test, particularly when the CSF glucose level is normal and the polymorphonuclear pleocytosis is atypical, certain treatable processes that can mimic bacterial meningitis should be considered in the differential diagnosis:

• 1.

  Parameningeal infections . The presence of infections (chronic ear or nasal accessory sinus infections, lung abscess) predisposing to brain abscess ( Chapter 382 ), epidural (cerebral or spinal) abscess, subdural empyema, or pyogenic venous sinus phlebitis should be considered ( Chapter 382 ). Neurologic symptoms may appear in the course of primary bacterial meningitis, but their presence may indicate the presence of a space-occupying infectious process in the CNS. Neurologic symptoms or findings antedating the onset of meningeal symptoms may suggest a parameningeal infection. Isolation of an anaerobic organism should suggest the possibility of intraventricular leakage of a cerebral abscess.

• 2.

  Bacterial endocarditis . Bacterial meningitis may occur during bacterial endocarditis ( Chapter 61 ) caused by pyogenic organisms such as S. aureus and enterococci. In subacute bacterial endocarditis, sterile embolic infarctions of the brain may produce meningeal signs and a pleocytosis consisting of several hundred cells, including polymorphonuclear leukocytes. A history of dental manipulation, fever, and anorexia antedating the meningitis should be sought; careful examination for heart murmurs and peripheral stigmata of endocarditis is indicated.

• 3.

  “Chemical” meningitis . The clinical and CSF findings (polymorphonuclear pleocytosis and even reduced glucose level) of bacterial meningitis may be produced by chemically induced inflammation. Acute meningitis after diagnostic lumbar puncture or spinal anesthesia may result from bacterial or chemical contamination of equipment or anesthetic agent. Chemical meningitis, characterized by polymorphonuclear pleocytosis, hypoglycorrhachia, and a latent period of 3 to 24 hours, occurs after 1% of metrizamide myelograms. Endogenous chemical meningitis resulting from material from an epidermoid tumor or a craniopharyngioma leaking into the subarachnoid space, a glioblastoma invading the ventricles ( Chapter 175 ), or carcinomatous meningitis (see later) can produce polymorphonuclear pleocytosis and hypoglycorrhachia.