Clinical Vignette

A 19-year-old woman presented to the emergency department with confusion, lethargy, and neck stiffness. Her dorm mates reported that she had experienced upper respiratory symptoms for 3 or 4 days before presentation. She had no significant past medical history. On physical examination, her temperature was 37° C (98.6° F), her pulse was 100 beats/min, respirations were 20/min, and her blood pressure was 110/70 mm Hg. Although her neck was stiff, Kernig and Brudzinski signs were absent. The pharynx was slightly injected without exudate. Heart and lung examination results were normal. No rash was present. Neurologic examination revealed a slightly obtund, sleepy woman with otherwise intact mental status, intact cranial nerves, no motor or sensory deficits, and normal reflexes.

The patient’s white blood cell (WBC) count was 22,900/mm³, with a marked left shift, including 34% bands and 62% polymorphonuclear neutrophils (PMNs). Her platelet count was 120,000/mm³. Her electrolytes revealed a mild metabolic acidosis. A chest radiograph and brain computed tomography (CT) were normal.

Initial cerebrospinal (CSF) fluid examination was normal. However, she was admitted for observation. Very soon thereafter, she complained of increasingly severe headache and neck pain. On exam, she was definitely confused and now had a fever of 39.1° C (102.4° F). Repeat lumbar puncture demonstrated a cloudy CSF with 670 WBCs (90% PMNs), a glucose level of 1 mg/dL, and a protein level of 220 mg/dL. Gram stain revealed rare gram-negative diplococci that on culture grew Neisseria meningitidis. Blood cultures also grew N. meningitidis. She was treated with 24 million U/day intravenous (IV) penicillin G and recovered completely. Before discharge, she was given rifampin to eliminate nasopharyngeal carriage of N. meningitidis.

One of the most serious neurologic emergencies involves the evaluation and care of patients with bacterial meningitis. Usually, these individuals are vigorous and previously healthy when they suddenly develop a severe headache, fever, and stiff neck. Despite more than 50 years of experience with antibiotic therapies, bacterial meningitis remains a very lethal disease. Expedient diagnosis is essential to prevent such an outcome. In the preceding vignette, typical for meningococcal meningitis, despite the history and findings suggestive of a meningeal infection, the initial CSF examination was normal. Emergency physicians wisely admitted the patient for observation. When she experienced sudden deterioration, repeat CSF examination led to diagnosis and appropriate therapy. Any delay in diagnosis and therapy of bacterial meningitis can be irretrievable as death may occur soon after a clinical change unless appropriate antibiotic therapy is begun immediately.

Pathophysiology

Bacterial meningitis is defined as a microbial infection primarily involving the leptomeninges (Fig. 48-1). Typically, bacteria seed the leptomeninges via the bloodstream or from a contiguous site of infection, such as sinusitis, otitis media, or mastoiditis. Rarely a defect in the normal anatomic barriers, as with a perforating cranial or spinal injury or congenital dural defect, leads to a predisposition to recurrent bacterial meningitis.

Figure 48-1 Bacterial Meningitis–I.

The responsible microorganisms often differ between children and adult patients. Those commonly responsible for meningitis in adults include Streptococcus pneumoniae, N. meningitidis, and Listeria monocytogenes. Haemophilus influenzae still causes 20–50% of meningitis in developing countries, but in the United States, this rate has been reduced 90% with the H. influenzae type b vaccine. In neonates, Escherichia coli and group B β-hemolytic streptococci comprise most cases. L. monocytogenes particularly leads to meningitis in immunocompromised patients and rarely in the newborn. N. meningitidis infection often occurs with a primary sepsis, and a characteristic petechial and/or purpuric rash, or disseminated intravascular dissemination. Conditions predisposing to pneumococcal meningitis in adults include sickle cell disease as well as conditions predisposing to immune deficiencies, including alcoholism, cirrhosis, splenectomy, and HIV/AIDS.

Gram-negative bacilli (E. coli, Proteus, Pseudomonas, Serratia, Klebsiella, and Citrobacter) are rarely found in community-acquired meningitis but more commonly occur in association with head or spinal trauma or after neurosurgery. These organisms always need to be considered with the immunocompromised hosts. Meningitis due to Staphylococcus aureus may follow penetrating trauma, neurosurgery, or bacteremia. Coagulase-negative staphylococci (Staphylococcus epidermidis) or S. aureus and other organisms are associated with infected ventricular shunts.

Clinical Presentation and Diagnosis

The onset of acute bacterial meningitis is rapid: hours to a day or so. Classic clinical findings include signs of an acute cerebral disorder, with lethargy, seizures, and agitation as well as specific signs of meningeal involvement manifested by severe neck stiffness, called meningismus, and fever that may not be immediately present. The patient rapidly becomes confused, sleepy, obtunded, and often comatose.

The examining physician needs to carefully search for signs of nuchal rigidity in any febrile patient who presents with a headache or any changes in level of alertness. Two clinical maneuvers are very important for identifying the presence of inflamed meningeal coverings involving the lumbosacral nerve roots: the Kernig and Brudzinski signs (Fig. 48-2). The Kernig sign is elicited by flexing the patient’s hip to a 90-degree angle and then attempting to passively straighten the leg at the knee; pain and tightness in the hamstring muscles prevent completion of this maneuver. This sign should be present bilaterally to support a diagnosis of meningitis. The Brudzinski sign is positive if the patient’s hips and knees flex automatically when the examiner flexes the patient’s neck while the patient is supine. Because host responsiveness to the infection varies, these signs of meningeal irritation are not invariably present, especially in debilitated and elderly patients and infants. When the clinical picture is typical of meningitis, it is also very important to exclude the concomitant presence of a focal parameningeal source such as a brain abscess. Further history, careful neurologic examination, and various imaging studies are essential (Figs. 48-3 and 48-4). Frequently there may be concomitant dermatologic findings present. A maculopapular or petechial/purpuric rash usually indicates infection with N. meningitidis although an echovirus may mimic such. However, in these instances, the CSF findings are significantly different, usually with predominant lymphocytosis, normal CSF sugar, and negative Gram stain. The dermatologic findings of N. meningitidis are usually secondary to an underlying vasculitis; they are rarely related to concomitant coagulation defects or a combination of the two. Meningococcal infection more commonly has a rash that affects the trunk and extremities in contrast to the echovirus exanthem that usually involves the face and neck early in the infection. Purpuric lesions may also rarely be found in a fulminant pneumococcal bacteremia with meningitis as well as staphylococcal endocarditis, the latter primarily involving the finger pads.

Figure 48-2 Bacterial Meningitis–II.

Figure 48-3 Parameningeal Infections.

Figure 48-4 Multiple brain abscesses in a 32-year-old with septicemia.

Diagnostic Approach

CSF examination is essential to the diagnosis of bacterial and other microbial forms of meningitis. Generally, a brain CT must precede CSF examination to rule out a primary brain abscess or a parameningeal focus with significant mass effect, potentially causing cerebral herniation secondary to a sudden change in CSF dynamics. When there are signs of focal neurologic involvement or increased intracranial pressure in patients with suspected meningitis, a lumbar puncture may be contraindicated. These include papilledema, coma, and focal neurologic findings, such as dilated pupils, hemiparesis, and aphasia. Accompanying signs of increased intracranial pressure may include bradycardia, Cheyne–Stoke respirations, and even projectile vomiting.

As soon as diagnosis of meningitis is considered, even before proceeding with a CT scan and lumbar puncture, administration of empiric antibiotics covering the broad spectrum of gram-positive and gram-negative organisms is essential. One can later adjust the treatment once CSF culture examination results are available. If CT exam confirms that there is no mass lesion suggestive of a parameningeal focus with potential for herniation, one can then safely proceed with a CSF examination. If a parameningeal mass lesion is identified as a source of the meningitis, its treatment is paramount. The precise identification of the pathogenic bacteria, per se, will then become possible at the time of surgical decompression, and the spinal tap as such is not required.

CSF analysis provides the only conclusive proof of bacterial infection of the subarachnoid space. It must include a Gram-stained smear to define the offending organism morphology. The Gram stain correlates with the precise microbial etiology, as defined by the more specific bacteriologic culture, in approximately 80% of patients. This is a simple technique that allows for better selection of appropriate antibiotic therapy before definitive culture and sensitivity data are available. However, one does not need to await the results of the Gram stain before immediate initiation of appropriate antibiotic therapy. Rapid detection of microbial antigens by counterimmunoelectrophoresis or latex agglutination tests can aid diagnosis when CSF Gram stain and cultures are not diagnostic. Newer molecular diagnostic techniques are anticipated.

The initial CSF analysis needs to include measurement of the opening pressure, color (clear, turbid, or purulent), WBC count and differential, and levels of glucose and protein. Typically in bacterial meningitis, the CSF opening pressure is increased (>200 mm of CSF lying down and >35 mm Hg upright). The fluid is usually turbid or frankly purulent and contains predominantly (>90%) polymorphonuclear leukocytes. The CSF glucose level is very low, usually less than 50% of that found with measurement of concomitant serum glucose. A low glucose level (<40 mg/100 mL) is also found in some other types of microbial meningitides including L. monocytogenes, Mycobacterium tuberculosis, and Cryptococcus neoformans. Normal glucose levels are common in viral meningitis. Usually, CSF protein levels are increased, often greater than 100 mg/dL (reference range, <45 mg/dL). In patients with parameningeal foci, such as a brain or epidural spinal abscess, or with multiple septic emboli, CSF glucose may not be as low as with typical bacterial meningitis, even though in these instances the CSF protein level is significantly increased.

Optimum Treatment

Bacterial meningitis is an extremely life-threatening infection. Any delay in its diagnosis by not initially assessing the patient or not beginning therapy at the first consideration of this critical diagnosis will increase morbidity and mortality. Antibiotic treatment must be initiated as soon as possible, and later guided by CSF examination results. When CSF examination cannot be performed promptly, empiric therapy must be instituted immediately. Patients must receive at least 10 days of high-dose IV antibiotics that easily cross the blood–brain barrier. Empiric IV therapy with a third-generation cephalosporin, such as ceftriaxone or cefotaxime, plus vancomycin must commence pending results of the bacterial cultures. High-dose corticosteroids, administered before antibiotic therapy, are recommended for all children and should be seriously considered for adults with community-acquired meningitis. When culture and sensitivity data are available, a specific antimicrobial therapy can be determined. Penicillin G is recommended for documented meningococcal meningitis.

Antimicrobial therapy for meningitis caused by S. pneumoniae must be based on antibiotic sensitivity test results. If the strain is susceptible to penicillin, penicillin or ceftriaxone are recommended. Ceftriaxone or cefotaxime are recommended when the strain is not susceptible to penicillin and is susceptible to cephalosporins. If the strain is susceptible to neither cephalosporins nor penicillin, vancomycin must be added to a third-generation cephalosporin (cefotaxime or ceftriaxone). In patients older than age 50 years, empiric therapy with ampicillin must be added to vancomycin and a third-generation cephalosporin to provide coverage for L. monocytogenes.

Complications

Of patients with bacterial meningitis, approximately 15% experience acute and chronic complications, including various cranial nerve dysfunction, particularly those affecting extraocular function (cranial nerves [CNs] III, IV, and VI), CN-VII, and sometimes CN-VIII, although this is less common today with the antibiotics lacking specific ototoxicity or vestibular toxicity. However, permanent sensorineural hearing loss occurs occasionally, most commonly with pediatric meningococcal infections. Assorted cranial neuropathies are generally secondary to the exudate common with the more purulent forms of bacterial and tuberculous meningitis.

Focal or generalized seizures, various focal cerebral signs, coma, and acute cerebral edema occasionally occur. Findings mimicking a stroke, such as a hemiparesis, aphasia, and hemianopsia, are relatively infrequent; persistence of such findings suggests secondary cerebral arteritis, cerebral venous thrombosis, or rarely a mass lesion, especially an abscess. Even with astute and early diagnosis, mortality rates are still at least 10% for meningococcal and 30% for pneumococcal meningitis, although the latter has very significantly decreased in frequency with the recent introduction of a pneumococcal immunization. Whenever any diagnostic delay occurs leading to less than immediate treatment, mortality and morbidity are significantly higher.

Chemoprophylaxis

Chemoprophylaxis is particularly recommended for persons in close contact with patients who acquired meningococcal meningitis, especially in confined settings such as college dormitories and army barracks. Rifampin is preferred; ciprofloxacin is also effective.

Future Directions: Vaccines

Vaccines are available for three common organisms. H. influenzae type b protein-polysaccharide vaccine is highly effective in preventing meningitis in newborns and young infants. N. meningitidis (meningococcus) serogroups A, C, Y, and W135 polysaccharide vaccine is recommended for high-risk adults and contacts of persons with meningococcal disease. Although group B accounts for >50% of cases, its capsule is an autoantigen and thus not a suitable vaccine target; several recombinant protein vaccines are in late-stage clinical development. S. pneumoniae (pneumococcus), pneumococcal protein-polysaccharide heptavalent vaccine, is recommended for children and is under study in adults. Currently, 23-valent pneumococcal polysaccharide vaccine is recommended for adults. Several new vaccines are in development.

Clinical Vignette

A 26-year-old woman had the sudden onset of numbness in her right hand and face. This cleared within a few minutes only to recur on two more occasions within the next 48 hours. She then suddenly became aphasic with numbness and weakness of her right hand and face. Neurologic examination demonstrated a fluent aphasia, with a right central facial and hand weakness. Her muscle stretch reflexes were enhanced in her right arm associated with a right Babinski sign. She had a grade III/IV systolic murmur at the apex of her heart. Brain imaging demonstrated a left parietal temporal mass suggestive of a cerebritis or an abscess. Empirical antibiotics were begun. Within 36 hours, blood cultures demonstrated a gram-positive diplococcus. The antibiotics were adjusted appropriately. Within 48 hours, her condition had stabilized. Repeat imaging studies 1 week later showed improvement. Surgical decompression was considered early on; however, the antimicrobial therapy was sufficient. She gradually improved having an almost complete recovery. When her speech improved, she subsequently recalled having had a dental hygiene appointment a few weeks before the onset of her illness. Previously, she had not been aware of having a mitral valve lesion. She was instructed that she needed antimicrobial therapy prior to any dental or other medically invasive procedure in the future.

Brain abscess, which may be indolent or fulminant, results from direct extension of a contiguous focus, such as middle ear or sinus infections, congenital heart disease with a right-to-left shunt, or very rarely a pulmonary arteriovenous malformation having similar shunt mechanisms. Hematogenous spread may occur from distant infection sites in the head and neck, heart (infectious endocarditis), lung, or abdomen, or direct introduction of bacteria after penetrating head injuries. Brain abscess can occur after surgical procedures, as in the vignette on p. 408. The cardinal symptom of brain abscess is relentless and progressive headache, usually followed by focal neurologic manifestations. Only two thirds of patients have fever. Papilledema and other signs of increased intracranial pressure may occasionally develop; however, the availability of imaging studies makes it more likely that the abscess will be identified prior to its obtaining significant enough mass to create increased intracranial pressure.

Most brain abscess cases are polymicrobial. Etiologic agents often include aerobic bacteria, such as streptococci, Enterobacteriaceae, and staphylococci. Streptococcus milleri normally resides in the oral cavity, appendix, and female genital tract and has a proclivity for abscess formation. Anaerobic microorganisms, such as Bacteroides and Prevotella species, are present in up to 40% of cases. Fungi are uncommon but increasingly recognized among immunosuppressed patients.

MRI is most helpful for making the initial diagnosis (Fig. 48-3). The characteristic appearance is a focal cerebral lesion with a hypodense center and a peripheral uniform ring enhancement subsequent to contrast material injection. Sometimes there is a concomitant area of surrounding edema. In these circumstances, if at all possible lumbar puncture should be avoided to prevent abscess herniation or rupture into the ventricular system.