Meningitis is the inflammation of the leptomeninges, the tissues surrounding the brain and spinal cord. Prompt identification and treatment of infectious meningitis may prevent irreversible neurological sequelae. Evaluation of the cerebrospinal fluid (CSF) for white blood cells (WBCs), red blood cells (RBCs), malignant cells, bacterial, viral or fungal elements, protein and glucose levels, as well as other markers is critical to determine correct treatment and optimal outcomes.
Diagnosis
Indications for Testing
- Fever
- Headache
- Altered sensorium
- Stiff neck
Laboratory Testing
- CDC meningitis overview
- Initial testing is nonspecific – CBC, electrolytes
- Normal WBC does not rule out meningitis
- CSF exam – necessary to determine presence of meningitis
- CSF opening pressure – limited value if normal; usually >300 mm in bacterial but ≤300 in all others
- Microscopic exam – white count >1,000 cells/µL in >90% of patients with bacterial meningitis
- Neutrophils (typically >80%) usually predominate in bacterial meningitis
- Lymphocytes/monocytes predominate in viral and fungal meningitis – early viral disease may have ≥50% neutrophils, but shift toward lymphocytes/monocytes
- Immunocompromised patients may not demonstrate elevated WBC results in bacterial meningitis
- Immunocompromised patients and those with Listeria monocytogenes may have normal CSF WBC results – Listeria may also present with normal WBC results and high protein CSF
- Normal WBC result does not exclude bacterial meningitis
- Neutrophils (typically >80%) usually predominate in bacterial meningitis
- Protein – usually elevated (>200 mg/dL) in bacterial and fungal meningitis; usually <200 in viral
- Glucose – usually low (<10mg/dL) in bacterial and tuberculous meningitis; normal to minimally low in viral and fungal meningitis
- Gram stain – useful if positive
- Culture
- Bacterial culture – gold standard for diagnosis of bacterial meningitis
- Anaerobic culture may be important for postneurosurgical meningitis or shunt meningitis
- Fungal and acid-fast bacilli (AFB) cultures require HIGH VOLUME taps (at least 10cc fluid)
- Viral culture from CSF not indicated
- Bacterial culture – gold standard for diagnosis of bacterial meningitis
- CSF antigen antibody testing, when appropriate (eg, pneumococcal antigen, dimorphic fungi serology, cryptococcal antigen)
- Polymerase chain reaction (PCR) testing for enterovirus, Epstein-Barr virus (EBV), herpes simplex virus (HSV), varicella-zoster virus (VZV), cytomegalovirus (CMV), arboviruses
- Blood cultures – may be positive in up to 2/3 of patients in Western countries in bacterial meningitis
- Less sensitive if antibiotics have been administered
- Other tests to consider
- Rapid serum HIV antibody and plasma viral load testing – rule out acute HIV infection
- Use for patients with risk factors and aseptic meningitis
- Rapid plasma reagin (RPR) – rule out syphilis
- Urinalysis – may reveal urinary tract infection as etiology of bacteremia
- Malaria blood film – in areas where malaria is endemic
- Has a negative predictive value of 98%
- Rapid serum HIV antibody and plasma viral load testing – rule out acute HIV infection
Imaging Studies
- Computed tomography (CT)/magnetic resonance imaging (MRI) – consider prior to CSF tap if focal findings are present or patient is significantly immunocompromised,
- Chest x-ray – may be useful in diagnosing pneumonia as etiology (usually Streptococcus pneumoniae)
Differential Diagnosis
- Encephalitis
- Connective tissue central nervous system (CNS) disease
- Vasculitic CNS disease
- Granulomatous CNS disease
- Sarcoidosis
- Migraine headache
- Malignant meningitis
- Carcinoma
- Lymphoma
- Leukemia
- Subarachnoid hemorrhage
- Stroke
- Seizure disorder
- Febrile seizures in children
- Fabry disease
- Medications – numerous drugs can cause aseptic meningitis
Monitoring
Serology should not be used to monitor status of disease.
Background
Epidemiology
- Incidence
- Bacterial – 4-6/100,000
- Viral – ~10/100,000 in U.S. (Putz, 2014)
- Occurrence/transmission
- Hematogenous dissemination (bacteremia, viremia)
- Trauma – surgery, head trauma (basilar skull fracture, as nidus for development of infection)
Classification
- Viral (aseptic) – most common cause
- Enterovirus – most common cause
- HSV
- Arboviruses (eg, West Nile virus)
- Mumps virus
- Lymphocytic choriomeningitis
- Other viruses – EBV, CMV, acute HIV, human herpesvirus 6, VZV, and adenoviruses
- Bacterial
- Neisseria meningitidis
- S. pneumoniae
- Haemophilus influenzae
- L. monocytogenes
- Escherichia coli
- Beta-hemolytic group B streptococcus
- Mycobacterial – Mycobacterium tuberculosis
- Fungal
- Blastomyces dermatitidis
- Cryptococcus neoformans
- Histoplasma capsulatum
- Coccidioides immitis
- Parasites
- Amoeba – Acanthamoeba and Naegleria
- Angiostrongylus cantonensis
- Spirochetes
- Tickborne illnesses
- Rickettsia rickettsii (Rocky Mountain spotted fever)
- Ehrlichia chaffeensis
- Anaplasma phagocytophilum
Risk Factors
- Advanced age
- Male sex
- Low socioeconomic status
- Crowded living conditions
- African American ethnicity
- Dural defects
- Intravenous drug abuse
- Immunosuppression (eg HIV, connective tissue diseases, malignancy)
- Indwelling shunts
- Recent neurologic surgery
Clinical Presentation
- Headache
- Fever
- Meningismus, nuchal rigidity, altered sensorium, seizures, photophobia
- Kernig sign – resistance to passive extension of the knee when the hip is flexed at 90% (highly insensitive, very specific [Putz, 2014])
- Brudzinski sign – spontaneous flexion of hips and knees on passive flexion of the neck (highly insensitive, very specific [Putz, 2014])
- Nausea, emesis
- Focal neurologic deficits, hemiparesis
- Rash – VZV, meningococcus, Rocky Mountain spotted fever, ehrlichiosis
- Complications
- Shock
- Disseminated intravascular coagulation
- Focal permanent neurologic deficits
- Deafness, blindness, paresis
- Hydrocephalus
- CNS abscess
- Seizure disorder
- Recurrent meningitis
- Congenital anatomical defects
- Neurogenic cysts
- Asplenia
- Congenital immunodeficiencies (eg, complement deficiency)
- Acquired immunodeficiencies (eg, HIV)
- Mollaret meningitis (caused by HSV)
Prevention
- Viral – mumps vaccination
- Bacterial
- H. influenzae vaccination in childhood
- S. pneumoniae vaccination in childhood
- Conjugate vaccine for infants, polysaccharide vaccine for other at-risk groups
- N. meningitidis vaccination in children 11-18 years (if vaccinated between 11 and 15 years, recommend booster), freshmen entering college, complement-deficient patients, asplenic patients
- Chemoprophylaxis for close contacts of patients with N. meningitidis
ARUP Laboratory Tests
May be helpful in differentiating bacterial from viral etiology
Automated Cell Count/Differential
Useful in assessing metabolic derangement as cause of altered consciousness
Quantitative Ion-Selective Electrode/Enzymatic
Identify bacteria in CSF
Limited to the University of Utah Health Sciences Center only
Stain/Culture/Identification
Useful in assessing metabolic derangement as cause of altered consciousness
Quantitative Enzymatic
Aid in differentiating bacterial from viral meningitis
Cell Count/Differential
May be helpful in differentiating bacterial from viral etiology
Usually low (<10mg/dL) in bacterial meningitis and tuberculous disease
Enzymatic
May be helpful in differentiating bacterial from viral etiology
Reflectance Spectrophotometry
Detect presence of bacteria in blood
Limited to the University of Utah Health Sciences Center only
Continuous Monitoring Blood Culture/Identification
Gold standard test to diagnose fungi as agent of infection
Culture/Identification
Rapidly detect a panel of common viruses, bacteria, and fungi associated with meningitis and encephalitis
Do NOT use as a replacement for CSF bacterial and/or fungal culture and Cryptococcal antigen testing for at-risk patients
A negative result does not exclude a diagnosis of meningitis or encephalitis due to infection
Qualitative Polymerase Chain Reaction
Gold standard test for diagnosing the presence of mycobacteria organisms
Specimen from any suspected site, including sputum, CSF, tissue, urine, and other body fluid or gastric aspirate
Susceptibility will be performed on organisms isolated from a sterile source and for isolates of Mycobacterium chelonae, M. abscesses, M. fortuitumcomplex, M. immunogenum, M. mucogenicum; susceptibility testing will be performed by request only on M. kansaii and M. marinum; susceptibility testing of M. gordonae is inappropriate
Stain/Culture/Identification/Susceptibility
Aid in the diagnosis of pneumococcal meningitis
False positives may occur because of cross-reactivity with other members of S. mitis group; clinical correlation recommended
Patients who have received the S. pneumoniae vaccines may test positive in the 48 hours following vaccination; avoid testing within 5 days of receiving vaccination
Samples from patients taking antibiotics >24 hours may show a false-negative result
Qualitative Immunochromatography
Identify presence of Naegleria and Acanthamoeba in CSF specimen
Molecular testing is preferred for patients presenting with meningitis/encephalitis
Refer to meningitis/encephalitis panel by PCR
Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Chemiluminescent Immunoassay
Not a preferred test
Refer to relevant test for the specific pathogen suspected
Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Chemiluminescent Immunoassay
Panel components include WNV, measles, mumps, VZV, HSV-1, and HSV-2
Assess immunocompetence following N. meningitidis vaccination
For assessment of suspected immunodeficiency, use pre- and postvaccination serology
Not intended for diagnosis of infection or serotyping
Quantitative Multiplex Bead Assay
Detect Acanthamoeba spp and Naegleria fowleri in various specimen types
Qualitative Culture/Microscopy
Preferred test is West Nile IgM antibody
Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Preferred panel for diagnosing possible tickborne disease (ie, Anaplasmosis or Ehrlichiosis) during the acute phase of the disease
Detect and speciate A. phagocytophilum, E. chaffeensis, E. ewingii/E. canis, E. muris-like
Qualitative Polymerase Chain Reaction
Aid in the diagnosis of LCM viral infection in the central nervous system
Semi-Quantitative Indirect Fluorescent Antibody
Identify Cryptococcus as an etiological agent of meningitis
CAP requires confirmation by culture for this test; order with CSF culture and Gram stain
When test is ordered by the University of Utah Hospital, Huntsman Cancer Hospital, or VA Hospital of SLC, CSF culture will be ordered automatically; other clients should order culture separately
Semi-Quantitative Enzyme Immunoassay
Recommended test if serology is used to aid in the diagnosis of blastomycosis
Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Qualitative Immunodiffusion
Recommended test if serology is used to aid in the diagnosis of cerebral blastomycosis
Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Qualitative Immunodiffusion
Aid in the diagnosis of histoplasmosis
Recommend testing in conjunction with the combined complement fixation and immunodiffusion antibody and urine galactomannan antigen tests
Cross-reactivity withBlastomyces dermatiditis, Coccidioides immitis, and possibly Talaromyces marneffei has been observed
Quantitative Enzyme Immunoassay
Detect enterovirus in blood, CSF, or nasopharyngeal specimens
Qualitative Polymerase Chain Reaction
Detect parechovirus in CSF, plasma, or serum specimens
Qualitative Polymerase Chain Reaction
Detect enterovirus and parechovirus
Qualitative Polymerase Chain Reaction
Preferred test for detecting HSV infection in CSF, neonates, or when rapid diagnostic test for suspected HSV infection is necessary
Qualitative Polymerase Chain Reaction
Detect CMV but does not quantify viral load; potentially useful for specimen types other than blood
CMV by quantitative PCR on plasma is preferred for most clinical indications
Qualitative Polymerase Chain Reaction
Do not use for diagnosis of infectious mononucleosis
Order to detect EBV in individuals suspected of having EBV-related disease
Qualitative Polymerase Chain Reaction
Detect VZV in blood, CSF, ocular fluid, tissue, or vesicle fluid
Qualitative Polymerase Chain Reaction
Monitor respiratory specimens in previously diagnosed patients
Should NOT be ordered without culture in previously undiagnosed patients
For panel test that includes culture and stain, refer to AFB culture and AFB stain test
Auramine O Stain
Panel includes PCR testing to detect M. tuberculosis complex (MTBC) isolates and determine possible resistance to rifampin treatment
Test may be ordered for client-processed specimens; refer to specimen requirements
Qualitative Polymerase Chain Reaction
Diagnose and monitor B. dermatitidis
For urine specimens, refer to Blastomyces antigen quantitative by EIA, urine
Quantitative Enzyme Immunoassay
Diagnose and monitor B. dermatitidis
For serum specimens, refer to Blastomyces antigen quantitative by EIA
Quantitative Enzyme Immunoassay
Rapid test for identifying B. dermatitidis (yeast or mold form) from a pure isolate
Nucleic Acid Probe/MALDI (Matrix-Assisted Laser Desorption/Ionization)
Not recommended as a stand-alone test; refer to the enzyme-linked immunosorbent assay with reflex to immunodiffusion
Qualitative Immunodiffusion
Rapid test for identifying C. immitis (yeast or mold form) from a pure isolate
Nucleic Acid Probe/MALDI (Matrix-Assisted Laser Desorption/Ionization)
Preferred serology test to detect coccidioidomycosis (Valley fever)
Semi-Quantitative Enzyme-Linked Immunosorbent Assay, Semi-Quantitative Complement Fixation, Qualitative Immunodiffusion
Panel includes Coccidioides antibody IgG and IgM, Coccidiodes immitus antibodies, and coccidiode titer
For initial establishment of diagnosis, refer to Coccidioides Antibodies Reflexive Panel
Semi-Quantitative Complement Fixation/Qualitative Immunodiffusion/Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Panel includes coccidioides antibody by CF; coccidioides immitis antibodies by immunodiffusion; coccidioides antibody, IgG and IgM by ELISA
Aid in diagnosis of coccidioidal meningitis (Valley fever)
Semi-Quantitative Complement Fixation/Qualitative Immunodiffusion/Semi-Quantitative Enzyme-Linked Immunosorbent Assay
May aid in diagnosis of coccidioidomycosis (Valley fever)
Preferred test for establishment of diagnosis is Coccidioides Antibodies Reflexive Panel
Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Aid in diagnosis of coccidioidal meningitis (Valley fever)
Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Titers may aid in monitoring coccidioidomycosis (valley fever) and treatment response
Preferred test for establishment of diagnosis is Coccidioides Antibodies Reflexive Panel
Semi-Quantitative Complement Fixation
Aid in diagnosis of coccidioidal meningitis (Valley fever)
Semi-Quantitative Complement Fixation
Not recommended as a stand-alone test
Preferred test for establishment of diagnosis is Coccidioides Antibodies Reflexive Panel
Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Not recommended as a stand-alone test
Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Not recommended as a stand-alone test
Preferred test for establishment of diagnosis is Coccidioides Antibodies Reflexive Panel
Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Not recommended as a stand-alone test
Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Identify C. neoformans as the infectious agent of invasive cryptococcal disease
Semi-quantitative Enzyme Immunoassay
Aid in the diagnosis of histoplasmosis
Recommend testing in conjunction with the combined complement fixation and immunodiffusion antibody and serum antigen tests
Quantitative Enzyme Immunoassay
Rapid test for identifying H. capsulatum (yeast or mold form) from a pure isolate
Nucleic Acid Probe/MALDI (Matrix-Assisted Laser Desorption/Ionization)
Aid in the diagnosis of histoplasmosis
Recommend testing in conjunction with serum antigen and urine galactomannan antigen tests
Semi-Quantitative Complement Fixation/Qualitative Immunodiffusion
Not recommended as a stand-alone test
Refer to the combined complement fixation and immunodiffusion test
Qualitative Immunodiffusion
Reflectance Spectrophotometry/Microscopy
Gold standard test to diagnose fungi as agent of infection in blood
Continuous Monitoring Blood Culture/Identification
Preferred test for diagnosing West Nile encephalitis
Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Medical Experts
Couturier

Fisher

Hillyard

Panel components include West Nile virus (WNV), measles, mumps, VZV, HSV-1, and HSV-2