Infections of the Central Nervous System

Saturday, August 16, 2008

INTRODUCTION

*The author is grateful to J. Richard Baringer, MD, Professor of Neurology, University of Utah School of Medicine, for his careful review of this chapter, his constructive suggestions, and the several sections he wrote on subjects that represent special areas of his expertise.

The signs and symptoms of infections of the central nervous system (CNS) are not specific to each type of infection (eg, brain abscess or meningitis), but certain clusters of signs and symptoms can limit the range of CNS infectious diseases that must be considered. The following elements of a patient's history, signs, and symptoms may indicate or accompany meningeal or parenchymal CNS infections, especially if one or more occur in the same patient: fever; headache; nausea and vomiting; confusion, obtundation, or uncharacteristic behavior; stiff neck; or focal neurologic dysfunction.

When these signs and symptoms follow those of infection of the upper or lower respiratory tract, the cluster suggests the transition of the respiratory tract infection to bacteremia or viremia and then its progression to meningitis or another type of CNS infection.

ACUTE BACTERIAL MENINGITIS

General Considerations

More than most other infectious diseases, acute bacterial meningitis threatens the life, personality, and functional ability of a patient. The disease may be obvious or quite subtle in its initial presentation. Empiric therapy usually relies on a one-step (or monosynaptic) thought process (disease ? antimicrobial agent) that is not optimal for managing most infectious diseases. Optimal recognition and management of acute bacterial meningitis use a progressive, three-step (or polysynaptic) thought process that is also effective for managing most other infectious diseases (Table 7-1).

1. DISEASE (DIAGNOSIS)

The key findings in meningitis are the presence of fever, headache, stiff neck, nausea and vomiting, and, often, variable states of confusion. Note that neck stiffness, although usually present, is often overlooked. Although a stiff neck is not required to make the diagnosis of meningitis, its presence demands immediate pursuit of the diagnosis of meningitis.

Perhaps the most helpful indication that the diagnosis of meningitis should be considered seriously enough to warrant the performance of a spinal tap (if a thorough examination yields no signs of an intracranial mass or increased intracranial pressure) is the transition of a sore throat or other upper respiratory tract irritation to nausea and vomiting. Whereas most patients who actually have meningitis have fever and headache, the pattern of evolution of meningitis, especially meningococcal meningitis, is from sore throat to tachypnea (perhaps a sign of early meningococcemia with disseminated intravascular coagulation) and then to nausea and vomiting as the meningococcemia seeds the cerebrospinal fluid (CSF) space and establishes meningitis with cerebral edema.

The constellation of headache, fever, nausea, vomiting, or a combination of these symptoms should immediately prompt the consideration of meningitis, especially in the context of previous disease or irritation of the upper respiratory tract (eg, sinusitis, otitis media, or pharyngitis). Often patients with meningitis will complain of ocular pain or an increase in headache when turning their eyes from side to side. Although this sign is not specific for meningitis, its presence should prompt suspicion of the disease.

Although the accuracy of the clinical examination in the diagnosis of meningitis is limited by the paucity of prospective data, Attia et al (1999) have evaluated the clinical findings in meningitis and cite the 97% sensitivity and 60% specificity of the jolt test of Uchihara and Tsukagoshi (1991) in diagnosing meningitis. The jolt test, accentuation of headache by rapid movement of the head from side to side, appears to have potential usefulness, but more widespread systematic evaluation is needed before incorporation of the test into routine practice can be recommended.

In a febrile patient with a history of previous upper respiratory tract irritation, vomiting should elicit concern about meningitis rather than being considered a sign of gastroenteritis or "the flu."

Note that almost all patients with bacterial meningitis give a history of upper respiratory tract irritation that can be interpreted as pharyngitis. However, health care personnel should consider the context of such complaints, and, if there is fever > 101 °F, nausea or vomiting, headache, confusion, or any signs of neurologic irritation, meningitis should be strongly suspected. The author has seen patients who suffered permanent neurologic damage because their meningitis was not recognized and health care personnel, using an algorithm for pharyngitis, gave oral antimicrobial therapy, which is inappropriate for meningitis.

Although patients often do not complain spontaneously of neck stiffness, they frequently will admit to the symptom if questioned. Detecting neck stiffness is best done by cupping the patients occiput in the examiner's hands, gently turning the head from side to side, which usually causes little discomfort, and then gently flexing the neck while observing the patient's face for signs of pain and feeling for sudden resistance as the neck is flexed. Modest degrees of meningeal irritation are usually evident with this procedure. Whereas the traditional Kernig and Brudzinski signs may be present in acute meningitis, in the author's experience they are present much less often than is neck stiffness and are less sensitive in the detection of minor degrees of meningeal irritation than is testing for neck stiffness as described above.

Once the diagnosis of meningitis has been seriously considered and care has been taken to assure that there are no signs of an intracranial mass (eg, no papilledema or focal neurologic abnormalities), a lumbar puncture should be performed.

2. PREDICTION OF THE MOST LIKELY CAUSATIVE ORGANISM

Introduction

Acute meningitis is most often caused by bacteria that have capsules (eg, Neisseria meningitidis, Haemophilus influenzae, and Streptococcus pneumoniae). These organisms are passed from person to person by droplet spread or mucosa-to-mucosa spread during close contact. Although some yeasts (eg, Cryptococcus neoformans) cause acute meningitis in patients with ostensibly normal immunity, they cause meningitis more often in patients whose cell-mediated immunity is compromised (eg, by lymphoma, AIDS, steroids, or other forms of iatrogenic immunosuppression), and yeast infections must be sought in such patients.

Empiric therapy entailing the choice of broad-spectrum antibiotics instead of organism-specific therapy is suboptimal for acute meningitis, because such therapy is at danger of being less active and less effective than therapy specifically targeted for the most likely organism. Therefore, optimal therapy entails predicting the most likely organism to be causing the meningitis and then administering the therapy that is optimal for that organism. Usually one can correctly deduce the most likely organism to be causing the meningitis by considering four kinds of information regarding the patient: (1) personal risk factors, (2) community risk factors, (3) physical examination, and (4) laboratory and imaging studies (see Tables 7-1, 7-2, 7-3, and 7-4).

Personal Risk Factors

The bacterial pathogen most likely to cause meningitis varies with the site of acquisition and the age of the patient (Table 7-2). Patients who are asplenic or alcoholic or who have preexisting ear or paranasal sinus infections are at greater risk of having infections with S pneumoniae.

Among patients who have conditions that allow access of stool to CSF, for instance, a pilonidal sinus or Strongyloides stercoralis infestation, Escherichia coli is often the most likely organism to be causing their meningitis.

In some cases, the most likely organism may be predicted by the nature of prior antimicrobial therapy. Certain broad-spectrum, oral antimicrobial agents such as ciprofloxacin or cefixime may predispose a patient to bacterial meningitis, apparently by eradicating normal nasopharyngeal flora and allowing overgrowth of meningitis-causing bacteria, especially S pneumoniae, which is less susceptible to these antibiotics than are normal flora. A substantial number of patients have developed fatal pneumococcal sepsis and meningitis while being treated with such antibiotics (Lee et al, 1991; Ottolini et al, 1991). Ironically, most of the antibiotics were prescribed for upper respiratory tract infections, bronchitis, and otitis media, which may not benefit from antimicrobial therapy (Gonzales et al, 1997; Nyquist et al, 1998).

The microorganism causing the antecedent respiratory tract or other type of infection is the likely cause of meningitis in many patients. Patients with enteroviral meningitis have sometimes had recent contact with children or others with diarrhea. A recent episode of genital herpes should prompt consideration of a herpetic etiology of the meningitis.

Community Risk Factors

Cases of meningococcal disease may occur in epidemics or clusters, and state or local health departments may be helpful in predicting the most likely organism from such epidemiologic data.

Similarly, clusters of meningitis caused by Listeria monocytogenes have occurred in conjunction with the ingestion of raw and cooked meat, poultry, and, especially, unpasteurized dairy products such as cheese that have entered the commercial food supply contaminated with L monocytogenes.

Physical Examination

Several physical signs, considered in light of the patient's age, can be extremely helpful in correctly predicting the infecting organism (Table 7-3). If there are no physical signs suggesting the most likely organism, the organism can be predicted on the basis of the locale of acquisition of the meningitis and the patient's age as described above (see Table 7-2).

Laboratory/Imaging Studies

The laboratory findings in the CSF can also be helpful in either predicting or determining with certainty the most likely organism or type of organism to be causing the meningitis (Table 7-4).

Chest x-rays showing pneumonia in conjunction with meningitis suggest that the cause of the pneumonia may be the same as that of the meningitis; this association has been observed with N meningitidis and S pneumoniae infections. If the pneumonia in conjunction with meningitis is cavitary, organisms that cause cavitary pneumonia such as Staphylococcus aureus or Pseudomonas aeruginosa should be suspected.

3. DESIGN OF OPTIMAL THERAPY FOR THE PARTICULAR PATIENT

Introduction

It is important to initiate therapy as promptly as possible. In general, it is preferable to begin therapy after CSF and blood cultures have been obtained, but before the results of the laboratory examinations are available. Therefore, the hypothesis about the most likely organism should be used to initiate therapy, then the hypothesis should be tested by examining the CSF with nonspecific tests such as the leukocyte count and differential and CSF protein and glucose concentrations, all of which can be helpful in indicating groups of causative agents (see Table 7-4). A more sensitive and specific identification of the most likely organism often can then be obtained by performing a Gram stain on CSF subjected to cytospin slide centrifugation and culture and, if the Gram stain is negative, also testing the CSF for evidence of cryptococcal antigen and tuberculous infection, using polymerase chain reaction (PCR) or culture. Microscopic detection of the organism causing meningitis is more effective if the CSF is first subjected to cytospin slide centrifugation, which substantially increases the sensitivity of the Gram-staining endeavor (Shanholtzer et al, 1982). Rapid bacterial antigen tests were once used to attempt identification of the causative microorganism if prior antimicrobial therapy made it undetectable. However, bacterial antigen tests were found to be of "no detectable clinical benefit" in diagnostic and therapeutic decision-making (Perkins et al, 1995), and many laboratories no longer perform these tests.

If pneumococcal meningitis is likely (see Table 7-2), a premium should be put on culturing the organism from blood or CSF so that knowledge of its penicillin susceptibility can help facilitate design of an optimal treatment regimen. If specific tests such as PCR analysis of the CSF point to an organism different from the one originally hypothesized, the therapy can be changed to another specific therapy (such a change will seldom be necessary).

Whereas the foregoing considerations represent the optimal approach to acute bacterial meningitis, one must remember that tuberculous, cryptococcal, and occasionally coccidioidal meningitis also may have an acute onset and may produce clinical findings indistinguishable from those in acute bacterial meningitis.

Differential Diagnosis

Note that vomiting, although a common symptom of gastrointestinal disease, occurs frequently in meningitis. Meningitis is likely to be much more threatening to the life and function of the individual than is gastrointestinal disease, so one should not assume that vomiting in the febrile patient represents gastroenteritis.

A patient with meningococcal sepsis may have a normal or low total peripheral leukocyte count, but there is often an increased proportion of "bands" or immature polymorphonuclear leukocytes in the peripheral blood. In patients who have such laboratory findings in conjunction with other signs or symptoms of sepsis, strongly consider initiating parenteral therapy for sepsis, using antimicrobial agents appropriate for the most likely causative microorganism.

Syphilitic meningitis develops more often during the secondary or tertiary stages of the disease, generally at a slower pace than meningitis caused by other microorganisms, and presents with seizures in ~ 18% of patients with this disease. Thus, in patients with signs and symptoms suggestive of meningitis, especially seizures, syphilitic meningitis should be considered as part of the differential diagnosis, and appropriate serologic tests for syphilis should be performed on the serum and CSF.

Cautions Prior to Lumbar Puncture

It is very important to establish whether the patient with signs and symptoms of acute meningitis has papilledema, which is rare in acute meningitis without complications such as a mass lesion. A thorough examination should also be performed to detect any lateralizing findings (eg, hemiparesis or hemianopic field defect) or localizing findings (eg, aphasia), which might suggest the presence of some other process such as a brain abscess, subdural empyema, or cerebral infarction with mass effect. The presence of papilledema, localizing signs, or lateralizing signs mandates an imaging study before the performance of a lumbar puncture. A lumbar puncture performed in the presence of a mass lesion, particularly one that displaces intracranial structures, can result in a herniation syndrome and possibly death. However, antimicrobial therapy for the meningitis should be initiated before the patient is sent for the imaging study, as noted below.

In many emergency rooms, it is common practice to obtain a computed tomography (CT) scan for patients who have signs and symptoms suggestive of meningitis, before a diagnostic lumbar puncture is performed or antimicrobial therapy is instituted. Most authorities agree that any delay involved in obtaining such imaging studies could result in a significant hazard to the patient with meningitis if antibiotic treatment has not already been instituted. Bacteria multiply rapidly in the sheltered environment of the subarachnoid space, and the delays that are commonly encountered in obtaining imaging studies create a significant additional hazard to the patient. Therefore, if imaging studies are indicated (see previous paragraph), the patient should be stabilized, and optimal parenteral antibiotic therapy should be begun before such imaging studies are obtained. However, Baker et al (1994), after a systematic study of the efficacy of routine head CT scans prior to lumbar puncture in the emergency department concluded, "Routine use of CT scans in the absence of localizing signs prior to lumbar puncture in the emergency department is not indicated."

In some instances it may be necessary to perform a lumbar puncture without CT or magnetic resonance imaging (MRI) to establish the diagnosis of meningitis in order to permit initiation of prompt, optimal, specific antibiotic treatment. For instance, if a patient with signs of meningitis (but with no suggestion of papilledema or lateralizing or focal neurological deficits) is cared for in a setting where imaging studies are not available, eg, a rural office or clinic, it may be necessary to perform a lumbar puncture to establish the diagnosis of meningitis and institute optimal parenteral therapy. In such a situation, if the patient is to be transferred to a tertiary facility, the parenteral antimicrobial therapy should be continued and part of the CSF, as well as blood cultures obtained before therapy, should be transported with the patient. In addition, in the midst of a community-wide epidemic of meningococcal meningitis or when the patient has signs of meningococcal sepsis (eg, petechiae or purpura fulminans) with meningitis, it is probably safe to do a lumbar puncture without antecedent CT or MRI imaging if there are no signs of an intracranial mass.

Once treatment of meningitis has commenced and the patient has been stabilized, it is the practice of some experts to image the brain at some time during the course of therapy because of the frequency of associated pathologic processes. These associated processes include paranasal or mastoid sinusitis, subdural empyemas or effusions, basilar skull fractures, intracerebral abscesses or infarctions, and hydrocephalus, many of which may require neurosurgical intervention. Other experts reserve CT or MRI scans for patients with signs of a mass lesion, patients who remain febrile for > 5 days after initiation of optimal antimicrobial therapy, patients who have altered consciousness, or patients who were initially infected with bacteria such as S pneumoniae that are especially likely to cause sinusitis or loculated pus that requires drainage.

Optimally, for the diagnosis and therapy of most patients with known or suspected meningitis, the steps in Table 7-5 should be taken, but, if the presence of even questionable findings of papilledema, lateralizing signs, or localizing signs raises concerns over a possible mass lesion, or, if there is worsening headache or a diminishing level of consciousness, imaging studies should be considered as follows:

A. Immediately Available CT Scan. If a CT scan can immediately be performed, obtain a CT scan and proceed to a lumbar puncture if no mass lesion is present, and follow the remainder of the steps in Table 7-5.

B. CT Not Readily Available. If a CT scan is not readily available or a significant delay is anticipated, most experts recommend that blood cultures be obtained immediately and antibiotic treatment optimal for the most likely organism (see Tables 7-2 and 7-3) be instituted before the CT or other imaging study and before a lumbar puncture (see Treatment section below). The prior institution of antibiotic therapy will only minimally decrease the diagnostic sensitivity of CSF cultures and may still allow detection and identification of the causative microorganism by stains or PCR. The initial emergency therapy can be changed if findings of stains, cultures, or PCR on the CSF so indicate. A change in therapy will seldom be necessary. Especially in pneumococcal meningitis, with increasing resistance of pneumococci to beta-lactam antibiotics, it is helpful to culture the organism rather than simply detecting it with stains or PCR, because the viable organisms are necessary for determining the penicillin susceptibility of the infecting pneumococcus, which is information that may be important in designing an optimal antipneumococcal antimicrobial regimen.

Patients with known or suspected meningitis should not be sent out on oral antibiotics, but should be admitted to the hospital and treated with parenteral antimicrobial agents that are optimal for the most likely organism.

Treatment

To put the imperative for speed in initiating therapy into more concrete terms, some experts have suggested a goal of allowing no more than 30 min from the time of clinical diagnosis to starting an IV infusion of the best antibiotic for the most likely organism to be causing the meningitis. A suggested use of the 30 min appears in Table 7-5 and assumes that the above-mentioned precautions and procedures regarding signs of a mass lesion will be observed.

Intravenous antimicrobial agents are the optimal types of therapy for acute bacterial meningitis. Specific, optimal antimicrobial agents for the therapy of acute meningitis that is known or suspected to be caused by particular organisms are reviewed in Table 7-6. The antimicrobial agent chosen should meet a number of criteria, which are listed under "Best Antimicrobial" in Table 7-1. As noted, the antimicrobial agent chosen should avoid the patient's special vulnerabilities. For example, if possible, the patient should not be given an antibiotic to which he or she is allergic; patients with myasthenia gravis, which causes intrinsic neuromuscular blockade, should not be given aminoglycosides, which may induce further neuromuscular blockade; and, if possible, patients with hemolytic anemias such as sickle cell disease should not be given chloramphenicol, which diminishes erythrocyte production.

Complications

It may be difficult to separate the complications of the bacteremia and septicemia that are associated with the meningitis from the complications of the meningitis per se. The complications of the septicemia include coagulation disorders such as disseminated intravascular coagulation (manifested in meningococcemia as a petechial rash and "purpura fulminans" or in some cases as hemorrhagic adrenal necrosis—"Waterhouse-Friderichsen syndrome"), myocarditis with congestive heart failure, shock, and prolonged fever. The more frequent complications of the meningitis per se result from the inflammatory reaction, including tumor necrosis factor-alpha (TNF-a) induction, which may cause damage to cranial nerves with resulting ophthalmoplegias, deafness, and blindness. Seizures or hydrocephalus may occur as early or late complications. In meningitis caused by H influenzae in children, some of these complications appear to occur less frequently if dexamethasone is administered in conjunction with antimicrobial agents to diminish the production of TNF-a (see Table 7-6). No comparable information is available for meningitis in adults or for meningitis caused by other bacteria.

Prognosis

Although the mortality rate for bacterial meningitis varies with the specific etiologic agent and the clinical circumstances, especially the age of the host, with early diagnosis and prompt, targeted (not broad-spectrum) antimicrobial therapy, the mortality rates for meningococcal and H influenzae meningitis are generally < 10% and 5%, respectively. Pneumococcal meningitis has a worse prognosis, with mortality rates of ~ 20%; in addition, neurologic complications, such as hydrocephalus, subdural empyema, seizures, and cranial nerve palsies, occur more frequently in meningitis caused by S pneumoniae.

Prevention & Control

A first line of defense against meningitis is the induction of anticapsular antibodies by means of vaccines or natural exposure. Timely administration of H influenzae type b (Hib) conjugate vaccine has dramatically reduced the frequency of H influenzae meningitis in the United States; however, in some states, less than half of the eligible children have been immunized.

By reducing pneumococcal bacteremia, a pneumococcal vaccine theoretically should decrease the frequency of pneumococcal meningitis, and the limited immunogenicity of some of the pneumococcal serotype polysaccharides in children < 2 years old has recently been circumvented by conjugating the polysaccharides to a diphtheria protein. The resulting, currently available, 7-valent pneumococcal vaccine has been shown to prevent pneumococcal carriage and invasive pneumococcal infections, including meningitis, in children < 2 years old.

A 23-valent pneumococcal vaccine is recommended for all patients aged = 65 and for nursing home residents, as well as for immunocompromised and other high-risk patients. Anatomic or functional asplenia is an absolute indication for the vaccine, and the vaccine should be given, if possible, at least 2 weeks before splenectomy. The vaccine is also recommended 2 weeks before beginning any immunosuppressive treatment.

The conjugate pneumococcal vaccine is indicated for the active immunization of infants and toddlers against invasive disease caused by pneumococci of the capsular types represented in the vaccine. The routine schedule is vaccination at 2, 4, 6, and 12-15 months of age. This vaccine is not for use in adults.

A quadrivalent meningococcal vaccine (including groups A, C, Y, and W135) is available. If there is an epidemic or cluster of cases in a closed population, such as that of a college campus or group home, or for individuals traveling to countries where meningococcal disease is epidemic, the use of the meningococcal vaccine should be considered. The quadrivalent vaccine is recommended for use in epidemics of meningococcal disease caused by strains of any group whose capsular type is represented in the vaccine. Help in determining the need for a vaccine administration program and in planning such a program should be sought from the appropriate state health department or from the Centers for Disease Control [telephone (404) 639-2215].

Protection of Contacts in Cases of Meningitis

A. Meningococcal Meningitis. Individuals who have had prolonged close contact with a meningococcal meningitis patient, especially those who have had mucosa-to-mucosa contact with such a patient, are at risk of becoming newly colonized with meningococci either from the patient or from the same source as the patient. It is newly colonized individuals, lacking serum anti-meningococcal antibodies, that are at greatest risk of developing meningococcemia or meningitis. The purpose of chemoprophylaxis is to eradicate the newly acquired meningococci and their progeny before they cross the nasopharyngeal epithelium and enter the bloodstream.

The physician managing a patient with meningococcal meningitis should notify local public health authorities about the case and work out a strategy for announcing promptly and proactively who does need and who does not need chemoprophylaxis.

Meningococcal vaccine should not be used instead of rifampin chemoprophylaxis for individuals at risk, because the response to meningococcal vaccine is not rapid enough to meet the immediate need of protecting the contacts of patients with meningococcal meningitis. Such at-risk individuals should be given chemoprophylaxis with rifampin.

Chemoprophylaxis should be given to close contacts of the patient (eg, family members, girlfriends or boyfriends, or others who may have had direct contact with the index patient's oral secretions). Chemoprophylaxis is not recommended for casual contacts, such as individuals with no history of direct exposure to the index patient's oral secretions (eg, school- or workmates). Those medical personnel who have had mucosa-to-mucosa contact with victims of meningococcal disease (eg, through mouth-to-mouth resuscitation, intubation, or suctioning before antibiotic therapy is begun) appear to be at risk and should receive chemoprophylaxis. Other medical personnel appear to be at minimal risk, but most experts would offer them chemoprophylaxis if they were exposed to a case.

The chemoprophylaxis regimens for protecting individuals exposed to a case of invasive disease caused by N meningitidis or Hib are the same as those used to eradicate the carrier state of the index patient prior to discharge from the hospital (see boldfaced text under the respective organisms in Table 7-6). The rifampin powder in the proper dosage can be made into a liquid formulation or incorporated into other vehicles such as applesauce for young children.

B. H influenzae Meningitis. The recommendation for chemoprophylaxis for contacts of cases of Hib meningitis is as follows: "In those households with at least one contact younger than 48 months whose immunization status against Hib is incomplete, rifampin prophylaxis is recommended for all household contacts, irrespective of age" (1997 Red Book, p. 223). See Table 7-6 for the recommended rifampin prophylaxis for protection of individuals exposed to a case of invasive Hib disease.

Because penicillins and some cephalosporins—antimicrobial agents often used to treat meningococcal or H influenzae meningitis—do not penetrate human cells well, meningococci and H influenzae organisms may remain safely inside cells of the nasopharyngeal mucosa of a patient cured of meningitis and emerge later to cause meningitis in the patient's siblings. Therefore, depending on the type of therapy of a patient with meningitis, the patient may need to be given chemoprophylaxis-like antimicrobial therapy to eradicate his or her carrier state before discharge. Such predischarge therapy is recommended for patients with either meningococcal or H influenzae meningitis and, for children older than 1 month, should consist of rifampin given essentially as indicated for chemoprophylaxis of contacts and detailed in Table 7-6. Some experts do not give such therapy if the cephalosporin used for treatment of the meningitis was cefotaxime or ceftriaxone, either of which appears to eradicate nasopharyngeal foci.

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