What are the initial cerebrospinal fluid (CSF) laboratory tests for a patient presenting with symptoms suggestive of central nervous system (CNS) infection, inflammation, or hemorrhage?

Initial CSF Laboratory Tests for Suspected CNS Infection, Inflammation, or Hemorrhage

For any patient with suspected CNS infection, inflammation, or hemorrhage, immediately send CSF for: cell count with differential, glucose (with simultaneous plasma glucose), protein, opening pressure, Gram stain, bacterial culture, and HSV-1/2 PCR. 1

Essential Basic CSF Studies (Send on All Patients)

Cell Counts and Pressure

• Opening pressure measurement is mandatory 1
• Total white blood cell (WBC) count with differential to distinguish lymphocytic from neutrophilic predominance 1
• Red blood cell (RBC) count to identify hemorrhage or traumatic tap 1
• Collect at least 20 cc of fluid if possible, and freeze 5-10 cc for additional testing 1

Biochemical Parameters

• CSF glucose must be compared with plasma glucose obtained just before the lumbar puncture—interpretation is impossible without simultaneous plasma glucose 1
• CSF protein concentration 1
• The CSF:plasma glucose ratio should normally be approximately 2/3 (0.6-0.7) 2

Microbiological Studies

• Gram stain and bacterial culture (requires 2-2.5 ml) 1
• HSV-1 and HSV-2 PCR is essential for all patients, as HSV is the most common treatable cause of viral encephalitis 1
• If test available, consider HSV CSF IgG and IgM 1

Critical First-Line Viral PCR Testing

All patients should have CSF PCR for HSV-1, HSV-2, VZV, and enteroviruses, as these identify 90% of known viral encephalitis cases. 1

• Varicella-zoster virus (VZV) PCR 1
• Enterovirus PCR (including parechovirus in children) 1
• EBV PCR should be considered, especially in immunocompromised patients 1

Additional Testing Based on Clinical Context

For Immunocompromised Patients

• Cytomegalovirus (CMV) PCR 1
• HHV-6 and HHV-7 PCR 1
• Fungal testing including cryptococcal antigen, fungal culture 1
• Mycobacterium tuberculosis testing (requires 6 ml): acid-fast bacilli smear, mycobacterial culture, and MTB PCR 1

For Specific Clinical Presentations

• CSF lactate if bacterial meningitis is in the differential—a level <2 mmol/L essentially rules out bacterial disease 1
• Oligoclonal bands and IgG index if autoimmune encephalitis or multiple sclerosis is suspected 1
• Arbovirus testing (IgM and IgG) based on geographic exposure and season 1

Important Correction for Traumatic Tap

When blood contamination occurs during lumbar puncture, apply these corrections 1, 2:

• Subtract 1 WBC for every 700-7000 RBCs present in CSF (most commonly use 1:700 ratio)
• Subtract 0.1 g/dL protein for every 100 RBCs 1
• Alternative formula: True CSF WBC = Actual CSF WBC - [(WBC in blood × RBC in CSF) / RBC in blood] 2

Critical Pitfalls to Avoid

Normal CSF Does Not Exclude Disease

• 5-10% of adults with proven HSV encephalitis have completely normal initial CSF with no pleocytosis and negative HSV PCR 1, 2
• If clinical suspicion remains high with negative initial studies, repeat lumbar puncture in 24-48 hours—the second CSF is likely to be abnormal 1
• Immunocompromised patients frequently have acellular CSF despite active infection 1

Timing of HSV PCR

• HSV PCR remains positive during the first week of acyclovir therapy 1
• An initially negative HSV PCR may become positive if repeated 3-7 days after treatment initiation 1
• The presence of <10 WBCs/mm³ in CSF is associated with higher likelihood of false-negative HSV PCR 1

Distinguishing Bacterial from Viral Meningitis

• Lymphocytic pleocytosis does not exclude bacterial infection—tuberculosis, listeriosis, brucellosis, and partially treated bacterial meningitis can all present with lymphocytic predominance 1, 2
• Low CSF:plasma glucose ratio (<0.4) and markedly elevated protein (>100 mg/dL) suggest bacterial rather than viral etiology 1
• Polymorphonuclear cells may predominate early in viral infections if CSF is obtained very early in the illness 1

Hemorrhagic CSF

• HSV encephalitis is hemorrhagic in approximately 50% of cases, so elevated RBC count does not exclude viral infection 1
• Serial CSF specimens that remain blood-stained suggest true hemorrhage rather than traumatic tap 1

Storage for Future Testing

Always store 2-5 ml of CSF frozen for future virological or other investigations as clinically indicated, since the etiology may not be immediately apparent 1