I. What every physician needs to know.
Bacterial meningitis is a potentially lethal infection resulting from bacterial invasion into the central nervous system (CNS). This is an infectious disease emergency that can result in hearing loss, learning disabilities and permanent neurological damage, thus it is critical to recognize the presence of this infection as soon as possible. This section will focus on bacterial meningitis, not other causes of acute meningitis such as viral infection, parasite or fungal meningitis.
Most often the infection results from bacteria gaining access through the nasopharynx. Individuals become exposed to pathogenic bacteria such as pneumococcus or meningococcus and develop bacteremia. In some cases this results in meningitis. Bacteria cross the blood-brain barrier and gain access to the subarachnoid space, where they multiply. Bacterial meningitis may also occur from direct invasion of the CNS following trauma or neurosurgery.
As bacterial replication occurs, neutrophils and macrophages enter into the CNS and release cytokines, resulting in inflammation. Most of the sequelae of meningitis are due to inflammation, which can also lead to edema and increased intracranial pressure.
Patients with meningitis often present with fever, headache and neck stiffness. A rash may also be present, and patients often have photophobia. Other foci of infection such as pneumonia or endocarditis may also be present. Symptoms can develop rapidly and patients may develop altered mental status. When there is acute onset of fever, headache and altered mental status, bacterial meningitis must be considered in the differential diagnosis.
II. Diagnostic Confirmation: Are you sure your patient has bacterial meningitis?
The only diagnostic test that can definitively establish the diagnosis of bacterial meningitis is the lumbar puncture. When performing a lumbar puncture, it is helpful to ascertain opening pressure as this is often elevated in bacterial meningitis, usually in the range of 200-500 millimeter water (O2).
Analysis of the cerebrospinal fluid (CSF) is essential in establishing the diagnosis. The gram stain is often positive, especially in patients not previously treated with antibiotics. This test is helpful in guiding antibiotic therapy.
In addition, pleocytosis (more than 5-10 white blood cells (WBCs)/cubic millimeter (mm3)) in the CSF is one of the indicators of meningitis. In bacterial meningitis, there is generally a predominance of neutrophils, although lymphocytes may predominate early on. The CSF WBC count is often 1000-5000 WBCs/mm3, but may be lower.
In addition, the CSF glucose is low when compared to the serum glucose. The presence of a CSF glucose to serum glucose ratio of less than 0.4 has a high sensitivity for bacterial meningitis. The total protein is elevated, and culture is positive in up to 85% of patients not previously treated with antibiotics. Blood culture is also often positive, and is helpful when the CSF culture is negative or when it is not possible to obtain CSF safely in a patient with symptoms of meningitis.
A. History Part I: Pattern Recognition:
The typical patient with bacterial meningitis presents with fever and headache. The patient often has an illness that progresses over hours to a few days, and this is often accompanied by a change in mental status. Seizures may be part of the presenting illness and are a poor prognostic indicator in adults.
In addition, patients may have focal neurological signs and may have evidence of disseminated disease such as pneumonia, endocarditis, septic arthritis, and endophthalmitis. Patients may be profoundly ill and present with septic shock and respiratory distress.
B. History Part 2: Prevalence:
Risk factors for meningitis vary by organism type. For adults, the most common organisms causing bacterial meningitis are Streptococcus pneumoniae and Neisseria meningitidis, with Listeria monocytogenes a distant third in the United States. Other organisms such as Haemophilus influenzae type B, Staphylococcus aureus (including methicillin-resistant Staphylococcus aureus (MRSA)), Group B Streptococcus, Enterococcus, Enterobacteriaceae, and other gram negatives may also cause meningitis.
The same risk factors that place individuals at risk for invasive pneumococcal disease serve as risk factors for meningitis. This includes diabetes mellitus, alcoholism, asplenia, acquired or congenital immunodeficiency (including human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS)), chronic lung disease or heart disease, cochlear implants for children, chronic kidney disease, and immunosuppressive therapy. In addition, some Alaskan Natives, American Indians and African American children may be at increased risk for invasive disease from pneumococcus.
Risk factors for N. meningitidis include terminal complement deficiency, living in close quarters such as a college dormitory or army barracks, travel to a highly endemic area, asplenia, and HIV infection.
Listeriosis occurs from ingestion of contaminated food products. Specific risk factors include pregnancy, HIV/AIDS, hematologic malignancy, chronic kidney disease, alcoholism, chronic immunosuppressive therapy, and liver disease. In addition, newborns are at increased risk of listeriosis.
C. History Part 3: Competing diagnoses that can mimic bacterial meningitis.
There are several diseases that must be considered in the differential diagnosis of a patient with suspected bacterial meningitis. Some viral infections can cause a clinical picture and CSF profile that is similar to bacterial meningitis such as West Nile Virus. Most viral infections result in aseptic meningitis, and are generally not in the differential diagnosis for bacterial meningitis.
This includes brain abscess, which is often more indolent than bacterial meningitis and classically presents with fever, headache and focal neurological signs. In addition, brain abscess is often preceded by infection elsewhere, as this usually occurs from hematogenous dissemination. Brain abscess may also be preceded by other infection in the head and neck such as sinusitis or mastoiditis.
Subdural empyema is another infection that can mimic bacterial meningitis and can progress very rapidly. This infection may also be preceded by sinusitis or otitis, and patients present with headache, fever and mass effect. This infection can be lethal, and it is critical to obtain neuroimaging prior to lumbar puncture in patients with this infection, as uncal herniation may result with lumbar puncture. These patients require emergent surgery for drainage.
Herpes simplex encephalitis (HSE) is often difficult to distinguish from bacterial meningitis. The CSF cell counts for patients with this infection can be the same as for bacterial meningitis. Patients are often described to have had behavioral changes for 1-2 days prior to presentation and may present with seizures. Because it is difficult to differentiate this infection from bacterial meningitis, it is often appropriate to treat empirically for this infection until it can be ruled out.
The presence of herpes simplex infection elsewhere is unrelated to occurrences of HSE, as this type of manifestation is generally a primary infection. The CSF polymerase chain reaction (PCR) test for herpes simplex is highly sensitive and specific.
CNS toxoplasmosis should also be considered in the differential diagnosis of a patient presenting with headache and fever. This infection is generally seen in the setting of AIDS, and often presents with seizures. Other infections that should be included in the differential diagnosis include fungal and tuberculous meningitis, both of which are more common in patients with underlying HIV infection. Both fungal and tuberculous meningitis are generally more indolent in presentation.
Other diseases that can mimic bacterial meningitis include lupus vasculitis, which is a diagnosis of exclusion, CNS sarcoidosis, lyme meningitis, syphilis, carcinomatous meningitis and West Nile encephalitis. All of these entities vary in their presentation from acute bacterial meningitis, and the CSF analysis is generally not consistent with bacterial meningitis.
One other item that should be mentioned is partially treated bacterial meningitis. Patients who have been on prior oral antibiotic therapy may have a negative gram stain, negative culture and their CSF WBC count may be lower than what is usually seen with bacterial meningitis. It is critical to obtain a careful history and physical exam in every patient in order to avoid misinterpretation of CSF results.
D. Physical Examination Findings.
Fever is present in more than 85% of patients with bacterial meningitis. In addition, patients may have altered mental status, photophobia or phonophobia, and neck stiffness or Kernig’s or Brudzinski’s sign.
Neck stiffness is found when there is pain with forward flexion of the neck. This sign is less sensitive in patients with underlying degenerative joint disease.
Both Kernig’s and Brudzinski’s signs are signs of resistance to meningeal stretching. Kernig’s sign is present when pain is elicited with passive flexion of the hip or knee. Brudzinski’s sign is present when forward flexion of the neck causes involuntary flexion of the hips or knees.
A petechial rash may be present, especially with meningococcal meningitis. If increased intracranial pressure is present, papilledema may be found.
E. What diagnostic tests should be performed?
The essential diagnostic test for bacterial meningitis is the lumbar puncture and CSF analysis as discussed above. In addition, there are some additional tests that can be helpful.
1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
The most important test is the CSF analysis. Keep in mind that early in the infection, there may be a predominance of lymphocytes in the CSF in about 10% of cases, especially in children.
While bacterial meningitis often has a very high neutrophil count, the presence of more than 5-10WBCs/mm3 in CSF requires an explanation. In patients with a predominance of lymphocytes, consider alternate diagnoses such as fungal or tuberculous meningitis, viral infection, vasculitis, meningeal carcinomatosis, etc.
Patients with prior antibiotic therapy, even one dose of an oral antibiotic may have a negative gram stain and/or culture. Also, it is very important to get serum glucose at the same time as the CSF glucose in order to interpret the values correctly. The CSF glucose is normally about 60% of the serum glucose. Herpes simplex virus (HSV) PCR should be obtained from the CSF in the appropriate setting. If there is a positive gram stain for a likely organism, this test is unnecessary.
The CSF should be sent for the following tests:
Tube 1: cell count and differential
Tube 2: glucose and protein levels
Tube 3: gram stain and culture
Tube 4: cell count and differential
Other tests should be added on, as needed, including Venereal Disease Research Laboratory (VDRL), cryptococcal antigen, HSV PCR, etc.
It is also important to obtain blood cultures in patients with suspected bacterial meningitis, especially if the patient is going to have a head computed tomography (CT) scan prior to lumbar puncture and antibiotics are being administered. The blood culture may be the only culture that is positive and can aid in guiding management.
Patients with bacterial meningitis should have evaluation of renal function as patients may present with shock and acute kidney injury (AKI). Most of the antibiotics require adjustment for renal impairment.
A HIV test should be considered for any patient presenting with bacterial meningitis, as this is an underlying risk factor for invasive bacterial infection.
Patients with meningococcal meningitis should be checked for terminal complement deficiency, as this may be present in family members as well, and they can be vaccinated.
2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
One of the most dreaded complications of lumbar puncture is brain herniation. The exact risk of this is unknown, and even in the presence of elevated intracranial pressure this is an uncommon occurrence. Individuals who have a mass lesion in the brain are at increased risk for herniation.
Not all patients with bacterial meningitis require diagnostic imaging, however, those at risk for a mass lesion should have a head CT prior to lumbar puncture. Risk for a mass lesion includes prior CNS disease, immunocompromised state (including chemotherapy, HIV infection, chronic immunosuppressive therapy), age greater than 60 years, seizure within 1 week prior to presentation, altered mental status, and focal neurological deficits.
F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.
Latex agglutination tests have been used by some as rapid diagnostic tests for meningitis. These tests have varying sensitivity and specificity depending on the organism and may be false negative in the presence of meningitis. Although these tests are not routinely recommended, they may be considered in patients who have a negative gram stain or culture, or patients previously treated with antibiotics. However, they are not recommended for routine testing.
The limulus lysate assay is a test that can detect the presence of endotoxin, and has been suggested when gram-negative meningitis is suspected. However, the test cannot distinguish the type of organism and the sensitivity is not sufficient to recommend its use as a screening test.
Head CT is also an overused test. There are specific criteria for individual who are at risk for mass lesions or increased intracranial pressure. In general, physicians are able to distinguish those individuals who require a head CT from those who do not. Recommendations are that individuals who are immunocompromised (HIV/AIDS, corticosteroids, immunosuppressive therapy, chemotherapy or radiation therapy within the last 3 months) have new onset seizures, focal neurological signs, papilledema, prior CNS disease (mass, stroke, or infection) or have an altered level of consciousness, undergo head CT prior to LP.
III. Default Management.
Patients with suspected bacterial meningitis should have a thorough history and physical exam, including a careful neurological exam to look for papilledema or focal neurological signs. If risk factors for a mass lesion are present, then blood cultures should be obtained and dexamethasone should be administered followed by empiric antibiotics. Dexamethasone has been demonstrated to decrease mortality and morbidity in some patients with pneumococcal meningitis.
A. Immediate management.
Dexamethasone should be given about 15-20 minutes prior to the first dose of antibiotic. The dose is 0.15 milligram/kilogram (mg/kg) every 6 hours for 2-4 days. Empiric antibiotics for adults include vancomycin 30-45 mg/kg in divided doses every 8-12 hours, and ceftriaxone 2 grams intravenous (IV) every 12 hours. If risk factors for listeria are present, then ampicillin 2 grams IV every 4 hours should be added.
Dexamethasone has been demonstrated to decrease morbidity and mortality in individuals with pneumococcal meningitis. It is recommended to give the dose listed above for individuals with suspected or proven pneumococcal meningitis. If an alternative diagnosis is established with gram stain or culture, dexamethasone should be stopped. However, since the most common cause of bacterial meningitis in adults in the United States is pneumococcus, it is appropriate to administer dexamethasone empirically to individuals with suspected bacterial meningitis, and stop the medication if an alternate diagnosis is established. Some experts recommend dexamethasone only for patients with a Glasgow Coma Scale less than 11, but the Infectious Disease Society of America recommend empiric administration for all adults with suspected/proven pneumococcal meningitis in order to avoid delays in therapy.
Also, if the patient is at risk for HSE, then acyclovir 10 mg/kg every 8 hours should be added. For patients with serious penicillin allergies, fluoroquinolones or carbapenems may be used as alternative agents for pneumococcus, and trimethoprim/sulfamethoxazole (TMP/SMX) is the second line choice for listeria.
B. Physical Examination Tips to Guide Management.
Patients with meningitis generally start to improve over 48-72 hours on appropriate therapy. Neck stiffness decreases, mental status should improve and temperature should start to decrease. In patients who have received dexamethasone, fever may be lost as a clinical indicator. If fever resolves, but mental status does not improve, it may be necessary to repeat lumbar puncture 48 hours after the initial test.
C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.
Complete blood count (CBC) and renal function is generally checked for the first 2-3 days. If these values are stable, they should be checked weekly unless there is a specific indication for testing, such as acute kidney injury.
D. Long-term management.
Management of meningitis consists of 7-21 days of IV antibiotics depending on the organism. Most patients will have resolution of symptoms, and will not require long-term management. Patients who develop specific neurological deficits will require management of those specific problems.
E. Common Pitfalls and Side-Effects of Management
One of the most common problems in treatment of infections is not giving the correct dose of antibiotics. All antibiotics should be dosed at the highest possible dose adjusted for renal function. Ceftriaxone is not adjusted for renal function and needs to be dosed 2 grams IV every 12 hours, which is twice the usual dose for other infections. In addition, assessing whether the patient is at risk for bacteria other than pneumococcus and meningococcus can lead to inadequate antibiotic therapy. For example, individuals with alcohol dependence, HIV/AIDS, age greater than 50 years, pregnancy, liver or kidney disease, diabetes and immunocompromised state are at increased risk for infection with Listeria monocytogenes. These individuals require additional antibiotic therapy to cover listeria.
Also, it is imperative to start antibiotics as soon as possible when meningitis is suspected. There should not be any delay in starting antibiotics due to inability to perform LP or due to need for brain imaging. When bacterial meningitis is suspected, blood cultures should be obtained immediately and dexamethasone and antibiotics should be administered. It is also important to avoid delays in administration of antibiotics after dexamethasone is administered. The antibiotics should be started within 15-20 minutes of the administration of the dexamethasone.
IV. Management with Co-Morbidities
A. Renal Insufficiency.
In patients with acute or chronic kidney disease, all of the antibiotics used for the treatment of meningitis require dose adjustment with the exception of ceftriaxone.
B. Liver Insufficiency.
Consider alternate diagnoses including hepatic encephalopathy and disseminated fungal infection. Most antibiotics do not require dose adjustment for liver insufficiency.
C. Systolic and Diastolic Heart Failure
IV antibiotics are often administered in normal saline and patients may develop decompensated systolic or diastolic heart failure over time. Dose adjustments in diuretics may be necessary.
D. Coronary Artery Disease or Peripheral Vascular Disease
No change in standard management.
E. Diabetes or other Endocrine issues
Patients with meningitis require careful control of blood glucose.
No change in standard management.
G. Immunosuppression (HIV, chronic steroids, etc).
Consider an expanded differential diagnosis, especially in the setting of AIDS. Cryptococcal meningitis and CNS toxoplasmosis are more likely in this setting and more common than bacterial meningitis. Neurosyphilis should also be considered, especially as more neuroinvasive disease is being reported.
H. Primary Lung Disease (COPD, Asthma, ILD)
No change in standard management.
I. Gastrointestinal or Nutrition Issues
No change in standard management.
J. Hematologic or Coagulation Issues
In patients who have an uncorrected coagulopathy, lumbar puncture may not be feasible. Having a platelet count less than 50 cells/microliter or an international normalized ratio (INR) more than 1.4 may be considered a relative contraindication for lumbar puncture. However, most patients with suspected meningitis do not need to have coagulation tests prior to lumbar puncture unless there is a specific reason to do so.
If it is not possible to obtain CSF for analysis, patients may end up with empiric antibiotic therapy. If possible, it is best to correct the coagulopathy in order to obtain CSF.
K. Dementia or Psychiatric Illness/Treatment
No change in standard management.
V. Transitions of Care
A. Sign-out considerations While Hospitalized.
Most complications from meningitis occur within the first 3-4 days after presentation. Complications may include focal neurological deficits, seizures, hydrocephalus, stroke, hyponatremia, or nosocomial infections. The most important sign to be alert for is deterioration in mental status or new focal neurological deficits. Patients with bacterial meningitis are generally managed in the intensive care unit in order to have frequent neurological checks until they are clearly improving.
B. Anticipated Length of Stay.
Patients with meningitis may receive their entire course of IV antibiotics while in the hospital. Length of therapy is determined by the specific organism. Patients with meningococcal meningitis or H. influenzae meningitis only require a 7-day course of treatment. Most of the complications will develop within the first 4 days, so most patients will stay at least this long.
C. When is the Patient Ready for Discharge.
Patients who have received 6 or more days of IV antibiotics, who have not had fever for 24-48 hours, and who have no focal neurological deficits or seizures can be considered for outpatient IV antibiotic therapy. In addition, patients should have a family member or other individual who can help to supervise the patient’s condition and compliance with therapy and follow-up. Patients should be seen at least once a week while completing antibiotic therapy.
D. Arranging for Clinic Follow-up
1. When should clinic follow up be arranged and with whom.
Patients with meningitis should be seen by an infectious disease specialist, and the time for follow-up depends on the clinical status at discharge. Patients who are stable and improving generally can be seen in 1 week, and once a week while on IV antibiotic therapy. In addition, individuals who have developed any complication, such as a focal neurological deficit, hearing loss, seizures, or hydrocephalus will also need follow-up with appropriate specialists depending on the type of complication.
2. What tests should be conducted prior to discharge to enable best clinic first visit.
If a patient has hearing loss, it is helpful to have audiology testing performed, but this does not have to occur prior to first follow-up visit.
3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.
CBC with differential and renal function should be checked on the day of the clinic visit in order to monitor for the side effects of IV antibiotics.
E. Placement Considerations.
Patients with neurological deficits or underlying comorbidities are likely to be discharged to a skilled nursing facility. These patients will require peripherally inserted central catheter (PICC) line placement prior to discharge.
F. Prognosis and Patient Counseling.
Prognosis depends on any complications that develop. While complications may be evident during initial hospitalization, some impairments become apparent later on. Approximately 30% of patients with bacterial meningitis may have long-term sequelae. Individuals who recover from bacterial meningitis can have hearing loss, focal neurological deficits, cognitive impairment, seizures, and hydrocephalus. The need for rehabilitative services and follow-up care will be determined by the type of impairment.
VI. Patient Safety and Quality Measures
A. Core Indicator Standards and Documentation.
As of January 1, 2012, all individuals over age 65 years and all individuals aged 6-64 years at high risk for invasive pneumococcal disease must be vaccinated prior to discharge.
B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.
Vaccination is now available for most meningococcal subtypes. Individuals at increased risk for meningococcal infection should consider meningococcal vaccination once they have recovered from meningitis. Vaccination is recommended for adolescents. In addition, microbiologists who are routinely exposed to meningococcus, individuals with persistent complement deficiencies, functional or anatomic asplenia, first-year college students living in dormitories, and those traveling to areas where meningococcal disease is endemic should consider vaccination.
Pneumococcal conjugate vaccine is now recommended for all individuals ages 65 years and older, and for those 19 years and older with immunocompromising conditions. All individuals who have recovered from bacterial meningitis should be assessed to ensure that they are up to date on all recommended vaccines.
VII. What’s the evidence?
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- I. What every physician needs to know.
- II. Diagnostic Confirmation: Are you sure your patient has bacterial meningitis?
- A. History Part I: Pattern Recognition:
- B. History Part 2: Prevalence:
- C. History Part 3: Competing diagnoses that can mimic bacterial meningitis.
- D. Physical Examination Findings.
- E. What diagnostic tests should be performed?
- 1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
- 2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
- F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.
- III. Default Management.
- A. Immediate management.
- B. Physical Examination Tips to Guide Management.
- C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.
- D. Long-term management.
- E. Common Pitfalls and Side-Effects of Management
- IV. Management with Co-Morbidities
- A. Renal Insufficiency.
- B. Liver Insufficiency.
- C. Systolic and Diastolic Heart Failure
- D. Coronary Artery Disease or Peripheral Vascular Disease
- E. Diabetes or other Endocrine issues
- F. Malignancy
- G. Immunosuppression (HIV, chronic steroids, etc).
- H. Primary Lung Disease (COPD, Asthma, ILD)
- I. Gastrointestinal or Nutrition Issues
- J. Hematologic or Coagulation Issues
- K. Dementia or Psychiatric Illness/Treatment
- V. Transitions of Care
- A. Sign-out considerations While Hospitalized.
- B. Anticipated Length of Stay.
- C. When is the Patient Ready for Discharge.
- D. Arranging for Clinic Follow-up
- 1. When should clinic follow up be arranged and with whom.
- 2. What tests should be conducted prior to discharge to enable best clinic first visit.
- 3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.
- E. Placement Considerations.
- F. Prognosis and Patient Counseling.
- VI. Patient Safety and Quality Measures
- A. Core Indicator Standards and Documentation.
- B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.