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Am Fam Physician. 2021;103(7):422-428

This clinical content conforms to AAFP criteria for CME.

Author disclosure: No relevant financial affiliations.

Cerebrospinal fluid (CSF) analysis is a diagnostic tool for many conditions affecting the central nervous system. Urgent indications for lumbar puncture include suspected central nervous system infection or subarachnoid hemorrhage. CSF analysis is not necessarily diagnostic but can be useful in the evaluation of other neurologic conditions, such as spontaneous intracranial hypotension, idiopathic intracranial hypertension, multiple sclerosis, Guillain-Barré syndrome, and malignancy. Bacterial meningitis has a high mortality rate and characteristic effects on CSF white blood cell counts, CSF protein levels, and the CSF:serum glucose ratio. CSF culture can identify causative organisms and antibiotic sensitivities. Viral meningitis can present similarly to bacterial meningitis but usually has a low mortality rate. Adjunctive tests such as CSF lactate measurement, latex agglutination, and polymerase chain reaction testing can help differentiate between bacterial and viral causes of meningitis. Immunocompromised patients may have meningitis caused by tuberculosis, neurosyphilis, or fungal or parasitic infections. Subarachnoid hemorrhage has a high mortality rate, and rapid diagnosis is key to improve outcomes. Computed tomography of the head is nearly 100% sensitive for subarachnoid hemorrhage in the first six hours after symptom onset, but CSF analysis may be required if there is a delay in presentation or if imaging findings are equivocal. Xanthochromia and an elevated red blood cell count are characteristic CSF findings in patients with subarachnoid hemorrhage. Leptomeningeal carcinomatosis can mimic central nervous system infection. It has a poor prognosis, and large-volume CSF cytology is diagnostic.

Cerebrospinal fluid (CSF) analysis is a diagnostic tool for many conditions affecting the central nervous system (CNS). The correct selection and interpretation of CSF tests can assist with diagnosing and treating a variety of conditions. Table 1 lists the normal values of CSF components.14

ComponentAdults and childrenNeonates
ColorClearClear
CSF:serum glucose ratio0.44 to 0.900.42 to 1.10
Differential70% lymphocytes, 30% monocytes, rare PMNs or eosinophilsPMN count may be normal
Gram stainNegative for organismsNegative for organisms
Lactate level*11.7 to 21.6 mg per dL (1.3 to 2.4 mmol per L)8.1 to 22.5 mg per dL (0.9 to 2.5 mmol per L)
Opening pressureAdults and children 8 years and older: 60 to 250 mm H2O
Children younger than 8 years: 10 to 100 mm H2O
10 to 100 mm H2O
Protein level*< 50 mg per dL (500 mg per L)≤ 150 mg per dL (1,500 mg per L)
White blood cell count*< 5 per μL< 20 per μL

CNS Infections

Suspected CNS infection is a medical emergency and is the most common indication for lumbar puncture. Bacterial meningitis has a 14% to 25% mortality rate; therefore, rapid CSF evaluation and early empiric antibiotic treatment are critical.5,6 CSF analysis is required to identify the causative organism and select appropriate antimicrobial coverage. An article on meningitis has been published previously in American Family Physician.7

When available, polymerase chain reaction (PCR) testing should be used to rapidly diagnose viral meningitis, which allows for early discontinuation of antibiotics.811 It can also detect common viral and bacterial etiologies with more than 95% sensitivity and specificity,8,12 whereas viral cultures require days to weeks and have lower accuracy.13 However, PCR testing does not assess drug sensitivities, is not universally available, and does not detect every infectious organism. Table 2 lists other suggested tests for various types of CNS infections.1,8,1425

Infection typeDifferentialGlucose levelOpening pressureProtein levelWhite blood cell countOther studies
Bacterial (typical)*Usually 80% to 90% PMNs; > 50% lymphocytes possible< 40 mg per dL (2.22 mmol per L) in 50% to 60% of cases; CSF:serum glucose ratio < 0.4 is 80% sensitive and 98% specificAdults and children 8 years and older: 200 to 500 mm H2O
Children younger than 8 years can have lower pressures
Almost always elevatedUsually 1,000 to 5,000 per μL
99% of children have > 100 per μL
Gram stain, CSF culture, CSF lactate (> 35.1 mg per dL [3.9 mmol per L]), PCR testing; latex agglutination if Gram stain is negative and antibiotics were given before lumbar puncture
CryptococcalLymphocyte predominanceUsually > 40 mg per dL> 250 mm H2O in severe cases; serial lumbar punctures or ventriculoperitoneal shunt required to drain CSF if pressure persistently > 250 mm H2OUsually < 40 mg per dL (400 mg per L)Usually mildly elevated; normal count possible, especially in patients with HIV infectionCSF culture, CSF cryptococcal antigen test, India ink capsule stain, latex agglutination, enzyme immunoassay, lateral flow assay, HIV test
Fungal (excluding cryptococcal)Possible early PMNs progressing to lymphocyte predominance; eosinophils possibleSignificant decrease possibleVariable50 to 250 mg per dL (500 to 2,500 mg per L)Usually elevated, up to several hundred per μLCSF (1–3)-beta-D-glucan (elevated level is 95% to 100% sensitive and 83% to 99% specific), CSF fungal culture, Gram stain (hyphae); PCR test is only 29% sensitive
NeurosyphilisVariablePossibly decreasedUsually elevated in immunocompetent patients; may not be elevated in immunocompromised patients> 45 mg per dL (450 mg per L)Early stage: 10 to 400 per μL
Late stage: 5 to 100 per μL
Declines over decades
HIV test, CSF Venereal Disease Research Laboratory test (30% to 75% sensitive and 100% specific), CSF fluorescent treponemal antibody absorption test (100% sensitive and 50% to 70% specific)
ParasiticEosinophilia (> 10 eosinophils per μL or > 10% of total cells)Usually low normal or normalVariable but can be persistently elevated, requiring CSF drainingUsually elevated150 to 2,000 per μLPCR test; enzyme-linked immunosorbent assay for Angiostrongylus cantonensis, Gnathostoma spinigerum, and Baylisascaris procyonis
TuberculosisEarly lymphocyte and PMN predominance progressing to lymphocyte predominanceMedian: 40 mg per dL; lower in advanced stagesVariable depending on stageUsually 100 to 200 mg per dL (1,000 to 2,000 mg per L)Usually 5 to 300 per μL; 500 to 1,000 per μL in 20% of casesMultiple cultures with acid-fast stain; PCR test (56% sensitive and 98% specific), CSF adenosine deaminase (> 10 U per L [166.67 nkat per L]); “pellicle” appearance of CSF
ViralLymphocyte predominance; possible PMN predominance in early infectionUsually normal; decreased in 25% of patients with mumps; mild decrease possible in patients with HIV infectionUsually normalNormal or mildly elevatedUsually 100 to 1,000 per μL; higher in patients with enterovirus infection (elevated red blood cell count possible in patients with herpes infection)PCR test preferred; other tests include CSF lactate (low), Gram stain, CSF or serum immunoglobulin M antibodies for arboviruses, electroencephalography or other neuroimaging for suspected encephalitis

BACTERIAL MENINGITIS

Opening pressure is the first CSF component assessed when performing a lumbar puncture. It is obtained before draining CSF fluid and should be measured with the patient in the lateral decubitus position. Opening pressure is greater than 300 mm H2O in 39% of patients with bacterial meningitis.26 The color of the CSF supernatant can be cloudy, green, or purulent.8 The white blood cell (WBC) count is often greater than 1,000 per μL, and polymorphonuclear leukocytes are typically predominant.27 However, 6% of patients with culture-diagnosed bacterial meningitis do not have an elevated WBC count, and lymphocytes are predominant in up to 10% of patients.28,29 WBC elevations can be caused by traumatic lumbar punctures rather than infections. The classic method to correct for traumatic WBC elevations has been to subtract one WBC for every 500 to 1,500 red blood cells (RBCs)26; a more accurate method is to use the formula WBCs (predicted) = CSF RBCs × (blood WBCs/blood RBCs).30

Nearly all patients with bacterial meningitis have an elevated CSF protein level.8 The ratio of CSF glucose to serum glucose can be normal to significantly decreased depending on the type of pathogen, time since infection onset, and presence of dextrose in any intravenous fluids the patient has received.31 Bacterial meningitis can be diagnosed with more than 99% certainty in patients with any of the following CSF measurements: glucose less than 34 mg per dL (1.89 mmol per L), protein greater than 220 mg per dL (2,200 mg per L), WBCs greater than 2,000 per μL, or neutrophils greater than 1,180 per μL.32 Gram stain testing is recommended for all patients with suspected CNS infection.28,29 It has a specificity of 97% for bacterial meningitis and a sensitivity of 33% to 90%,8,27,33 depending on the type of pathogen, cytocentrifugation, infection severity, laboratory personnel experience, the number of slides prepared, and the patient's exposure to antibiotics.27,31,34,35 Therefore, a negative CSF Gram stain cannot exclude bacterial infection, particularly in patients who have already started antibiotic therapy.

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