1 Describe the most common signs and symptoms of acute meningitis syndrome

Fever, neck stiffness, and altered mental status are the classic triad, but they occur together only approximately 45% of the time. In a systematic review, 95% of patients had two of the three classic signs. The onset is hours to days, although historical detail may be limited if the patient’s sensorium is altered.

2 What is the pathophysiology of meningitis?

The pathogen gains entry via attachment on epithelial mucosal cells, endocytosis by dendritic cells, or direct vascular access. In the setting of bacterial meningitis, infection causes cytokine production and influx of inflammatory cells. The blood-brain barrier may have changes in permeability, allowing for protein entry in addition to inflammatory cells and fluid. Vasculature initially vasodilates but then becomes stenotic with infiltration of inflammatory cells. This vasculitis can result in ischemia and/or infarction. Glucose metabolism is increased and transport across the blood-brain barrier possibly decreased.

3 What is the distinction between acute versus chronic meningitis?

Acute meningitis syndrome consists of fever, neck stiffness, and altered mental status with an onset of hours to days. Patients with acute bacterial meningitis may have rapid progression of signs and symptoms. This is in contrast to chronic meningitis, which is defined by presence of symptoms and abnormal cerebrospinal fluid (CSF) that persists for 4 weeks or more. The two syndromes have very distinct causes.

4 What host factors are important to consider regarding risk and cause for acute bacterial meningitis?

Factors such as age, immune deficiency or suppression, recent central nervous system (CNS) instrumentation, and possible exposures should be considered and will influence empirical therapy. See Table 34-1.

5 What are the most common causes of community-acquired acute bacterial meningitis in adults?

Table 34-2 includes the most common organisms in descending order based on case series with preferred antimicrobial therapy and suggested duration of treatment.

^{Table 34-2} Most Common Causes of Community-Acquired Bacterial Meningitis in Adults

MIC, Minimum inhibitory concentration; MSSA, methicillin-sensitive S. aureus; PCN, penicillin.

6 What is adequate empirical therapy while awaiting culture results?

Empirical therapy should reflect suspected pathogens on the basis of host factors as well as local antibiotic susceptibility patterns. For example, Streptococcus pneumoniae is commonly known to have resistance to penicillin. Some strains are also resistant to third-generation cephalosporins. As a result, empirical therapy for S. pneumoniae should include high-dose third-generation cephalosporin as well as vancomycin. Empirical therapy with third-generation cephalosporin is also suggested for Neisseria meningitidis. For Listeria monocytogenes, preferred treatment is ampicillin, although trimethoprim-sulfamethoxazole is another option if the patient is penicillin allergic. Thus in an adult older than 50 years, an initial empirical regimen including vancomycin, high-dose ceftriaxone, and ampicillin would be suggested to treat the most likely community-acquired pathogens.

In the event that a patient has undergone recent neurosurgical instrumentation and has risk for nosocomial pathogens, one would also want to include therapy directed at methicillin-resistant Staphylococcus aureus (MRSA) and resistant nosocomial gram-negative bacilli, such as Pseudomonas aeruginosa.

Risk factors that may additionally influence empiricism must be identified with each patient. Prompt and detailed history should be explored. Factors including exposures, such as contaminated food consumption, travel, and sick contacts should be identified. Presence of immune suppression should also be elicited. The type and degree of immune suppression, including medications, absence of spleen, advanced HIV, and administration of chemotherapy should be sought. Risk factors for nosocomial pathogens, including recent neurosurgical procedures, presence of a foreign body within the CNS (such as a ventricular drain), and trauma are also important to determine, as noted earlier.

7 When and to whom should steroids be administered?

Adults suspected of having bacterial meningitis should receive steroids before or with the administration of antibiotics. On the basis of a prospective, randomized, placebo-controlled trial, dexamethasone was shown to reduce morbidity and mortality in adults who received corticosteroid therapy before or at the same time as administration of antibiotics. This had the greatest benefit in patients with pneumococcal meningitis. The dose used in the study was 10 mg of dexamethasone every 6 hours for 4 days. Shorter durations and alternative dosing regimens have not been evaluated in adults.

8 What are the contraindications to lumbar puncture (LP)?

LP is critical to diagnostic evaluation. If clinical suspicion for meningitis exists, one should perform an LP. Conditions such as elevated intracranial pressure, mass lesion, uncorrected coagulopathy, and skin infection overlying intended puncture site are to be considered before LP.

9 When would one consider imaging before LP?

Most patients do not require imaging before LP. Computed tomography (CT) of the head should occur before LP if the patient has any signs or symptoms that suggest elevated intracranial pressure. These include new-onset neurologic deficits, new-onset seizure, and papilledema. Consideration should also be given to imaging in patients with moderate to severe cognitive impairment and immune compromise.

10 Is there harm in awaiting CT and LP results before initiating therapy?

Yes. Delay in initiating antimicrobial therapy has been associated with increase in mortality. If imaging is needed before LP:

11 What CSF studies are important?

A number of guides help determine likelihood for bacterial meningitis based on various CSF markers, although it is important to know that none are absolute. See Table 34-3 for specific indicators.

A positive Gram stain confirms bacterial meningitis. However, culture data remain important for speciation (especially if morphology is not characteristic) and antimicrobial sensitivities. Low glucose level can be very helpful in indicating acute bacterial meningitis, but it is important to remember that other factors can contribute to a low glucose finding. For example, Mycobacterium tuberculosis meningitis, which is typically chronic, is commonly associated with low CSF glucose level. Malignancies are also associated with low CSF glucose level.

In addition, other tests have been studied to improve performance when trying to distinguish bacterial versus nonbacterial causes of meningitis. One such marker, CSF lactate, was shown to add predictive value when trying to distinguish between bacterial meningitis and nonbacterial meningitis shortly after neurosurgery. In a study of patients after neurosurgery by Lieb and colleagues, a cutoff of 4 mmol/L CSF lactate was 88% sensitive and 98% specific for diagnosis of bacterial meningitis. Of interest, CSF lactate levels did not vary with the presence or absence of red blood cells (RBCs), nor was there a correlation with days after surgery.

12 How does one correct for a suspected traumatic LP?

In the event of traumatic LP, one general guideline is subtraction of one white blood cell (WBC) for every 500 to 1500 RBCs. More precise calculation would be to tabulate the predicted CSF WBC count per microliter. The formula:

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13 In the setting of documented bacterial meningitis, who gets postexposure prophylaxis?

The goal of postexposure prophylaxis is to eradicate nasopharyngeal carriage. There are two pathogens for which one would consider postexposure prophylaxis with specific indications listed as follows.

Exposure 1 week before symptom onset until after 24 hours of effective antibiotic therapy is considered significant. Postexposure prophylaxis should occur despite history of vaccination, because not all people respond to vaccination and there is one serotype not included in the vaccine.

Suggested regimens:

Suggested regimen: Rifampin 20 mg/kg per day for 4 days

14 What is aseptic meningitis?

Aseptic meningitis is defined by a syndrome of meningeal symptoms accompanied by abnormal CSF, usually with lymphocytic pleocytosis, in the setting of negative routine stains and cultures. Symptoms can be severe. Differential diagnosis includes infectious as well as noninfectious causes. This syndrome is usually associated with viral pathogens but can be caused by bacteria such as M. tuberculosis, Treponema pallidum, and Borrelia burgdorferi. This constellation of findings could also reflect a partially treated bacterial meningitis or a parameningeal focus. Medications, connective tissue disorders, and malignancy can also cause aseptic meningitis. It is imperative that the common bacterial causes be excluded.

15 What are important historical data to obtain to help determine possible etiologic viral pathogens?

The list of possible causes is extensive. Various factors can help narrow the possibilities. See Box 34-1.

16 What are the most common viral causes of meningitis?

The most common viruses associated with meningitis are nonpolio enteroviruses. These include various coxsackievirus, echovirus, and enterovirus strains. Diagnosis was historically made by viral culture, although polymerase chain reaction (PCR) evaluation of CSF is now readily available in many laboratories. Treatment is supportive in nature, and the illness is usually self-limited with complete recovery. Exceptions to this are neonates less than 2 weeks of age and persons with immune deficiencies, such as agammaglobulinemia, in whom severe disease can develop. Other common viruses include flaviviruses, such as St. Louis encephalitis (SLE) and West Nile virus (WNV), and herpes family viruses, such as herpes simplex virus 2 (HSV-2) and varicella-zoster virus (VZV). These too can be confirmed by PCR. It is important to note that other viral illnesses can cause meningitis. These include acute HIV infection and various respiratory viruses such as influenza and parainfluenza. It is important to remember that, to diagnose acute HIV, viral load RNA quantification is necessary because antibody testing is usually negative during acute seroconversion.

17 What symptoms and signs are commonly associated with encephalitis?

Encephalitis is defined by inflammation of brain parenchyma. Most causal pathogens are viral and gain access to the CNS via the bloodstream, although some viruses such as herpes simplex virus 1 (HSV-1) and rabies directly invade via neuronal transport. Acute encephalitis usually occurs over a brief period of time (days) as compared with chronic encephalitis, which can progress over weeks to months. Many patients will be seen with a prodromal illness with symptoms of fever, myalgias, and anorexia, which corresponds to viremia. Neurologic manifestations can range from headache, focal neurologic defect, and behavioral changes to seizure and coma. Meningeal inflammation can also occur resulting in symptoms suggestive of meningitis. Various viruses may have slightly different neural tropism, which can suggest cause based on presentation. For example, HSV-1 has a predilection for the temporal lobe. Encephalitis is associated with high morbidity and mortality.

18 What are the most common causes of acute encephalitis?

Despite often aggressive diagnostics, the cause of encephalitis in the majority of patients remains unknown. Any epidemiologic clues should be identified to guide diagnostic work-up as well as to initiate prompt empirical therapy. In the United States, when a cause is identified, the most common pathogens are HSV-1, WNV, and enteroviruses.

Possible infectious causes include but are not limited to the following:

Up to 5% to 10% of sporadic cases of encephalitis, when diagnosis is available, are attributable to HSV-1. Postinfectious, postimmunization, and noninfectious causes, such as connective tissue disease and paraneoplastic phenomena, must also be explored if diagnosis is elusive. Acute disseminated encephalomyelitis may follow a viral illness or vaccine and is important to differentiate from an infectious cause.

19 What should the initial diagnostic work-up include?

After careful history and physical examination, neuroimaging is recommended. This can suggest possible causes, dependent on regions of involvement, and may also exclude other possible causes, such as brain abscess. The most sensitive neurologic imaging is magnetic resonance imaging (MRI). If MRI cannot be performed, CT with contrast is the next preferred method. CSF evaluation is also suggested, unless contraindicated. CSF studies should include the usual cell count with differential, protein, and glucose markers. CSF should be sent for PCR evaluation for HSV and enteroviruses. A positive test is helpful, but a negative first test does not exclude infection if the clinical suspicion is high. Repeated testing within 3 to 7 days is suggested. Of note, the presence of hemoglobin can interfere with HSV PCR and cause a false negative result. PCR can also be performed to evaluate for VZV and CMV. If acute HIV is considered, one would need to obtain serum quantification of HIV RNA levels, because initial antibody testing may be negative. CSF cultures have not been helpful in elucidating viral causes but should be obtained if concern exists for nonviral causes, including bacteria and fungal organisms. Brain biopsy is usually reserved for those cases in which initial evaluation has been unrevealing and the patient continues to have clinical decline.

Additional studies should be obtained in the context of a patient’s epidemiologic risks. For example, travel to endemic areas could heighten concern for rickettsial disease or flaviviruses. An animal bite, particularly in a developing nation, could increase suspicion for rabies.

20 What empirical therapy is suggested?

In any person with suspected encephalitis, acyclovir should be initiated at 10 mg/kg every 8 hours. If a patient has had travel to regions where rickettsial disease is endemic, doxycycline should also be administered. Given the overlap of encephalitis and meningitis syndromes, in the appropriate clinical context, empirical therapy for bacterial meningitis can be considered. However, the combination of tetracyclines and β-lactam antibiotics should be used cautiously because historical data suggest this combination to have static-cidal inhibition and an increase in mortality when used in patients with pneumococcal meningitis.