What is the recommended diagnostic and treatment approach for central nervous system infections or inflammation, including cerebrospinal fluid (CSF) analysis and empiric antibiotic therapy?

CSF Analysis for CNS Diseases

Standard CSF Analysis Components

All patients with suspected CNS infection require a comprehensive CSF analysis panel including cell count with differential, glucose and protein concentrations, Gram stain, and bacterial cultures as the baseline workup. 1, 2

Essential Basic Tests

• Cell count with differential is mandatory for every CSF sample, as it provides critical diagnostic information about the inflammatory process 1, 2
• Protein concentration should be measured, with normal values typically <220 mg/dL; elevations suggest infection or inflammation 1, 2
• Glucose measurement with simultaneous serum glucose is essential; normal CSF glucose is >35 mg/dL with CSF-to-blood ratio >0.23 1, 2
• Gram stain and bacterial culture must be performed on all samples when infection is suspected 1, 2
• Opening pressure should be measured when clinically indicated, as normal pressure (<250 mm H₂O), fewer than 5 WBCs/μL, and normal protein essentially excludes meningitis in immunocompetent patients 1, 2

Characteristic CSF Findings by Disease

Bacterial meningitis typically presents with:

• ≥2,000 total WBCs/μL or ≥1,180 neutrophils/μL 1, 2
• CSF glucose <35 mg/dL with CSF-to-blood ratio <0.23 1, 2
• Protein concentration ≥220 mg/dL 1

Viral meningitis/encephalitis typically shows:

• Mild to moderate lymphocytic pleocytosis (5-1,000 cells/μL) 2
• Normal or mildly elevated protein 1
• Normal glucose 1

Autoimmune encephalitis commonly demonstrates:

• Mild to moderate lymphocytic pleocytosis (20-200 cells, but can reach 900 cells) 1
• Elevated protein 1
• Elevated IgG index/synthesis rate and oligoclonal bands in some cases 1
• Notably, routine CSF studies may be completely normal in some autoimmune encephalitis patients, which does not exclude the diagnosis 1

Specialized Testing Based on Clinical Context

For Suspected Bacterial Meningitis

• Gram stain, culture, and antimicrobial susceptibility testing are the cornerstone of bacterial diagnosis 2, 3
• If lumbar puncture is delayed for any reason (including imaging), start empirical antibiotics immediately after blood cultures for rapidly fatal etiologies like S. pneumoniae 1
• PCR multiplex testing is particularly valuable in patients already receiving antibiotics, as it can detect pathogens (especially S. pneumoniae) when cultures are negative 4

For Suspected Viral Encephalitis

• PCR testing for HSV-1/2 is mandatory in all suspected encephalitis cases, as HSV encephalitis requires urgent acyclovir therapy 1, 2
• VZV PCR and IgG/IgM should be included 1, 2
• Additional viral PCR (enterovirus, West Nile virus, adenovirus) based on epidemiologic factors and season 1, 2

For Immunocompromised Patients

Expanded testing is essential and should include:

• Cryptococcal antigen testing 1, 2
• Fungal stains and cultures 1, 2
• Acid-fast bacilli smears and cultures for tuberculosis 1, 2
• PCR for opportunistic pathogens: CMV, JC virus, West Nile virus, adenovirus, enterovirus 1, 2
• Cytology and flow cytometry to exclude malignancy 1, 2

For Suspected Autoimmune Encephalitis

CSF analysis is the most important test in autoimmune encephalitis evaluation and should be performed regardless of MRI findings 1:

• Neuronal antibody panels (NAAs) should be tested in both CSF and serum, as CSF is more sensitive for some antibodies (NMDAR, GFAP) while serum is more sensitive for others (LGI1, onconeuronal antibodies) 1
• IgG index, IgG synthesis rate, and oligoclonal bands should be measured 1, 2
• Broad viral studies including HSV-1/2 and VZV PCR must be performed to exclude infectious mimics 1
• Testing NAAs panels is recommended even if routine CSF studies are normal when clinical suspicion is high 1

For Suspected Neurosyphilis

• CSF VDRL or RPR testing is the diagnostic standard 2

For Suspected Multiple Sclerosis

• Oligoclonal bands, IgG index, and IgG synthesis rate are the key diagnostic markers 2

Special Considerations for Patients with Intracranial Devices

For patients with ventriculostomy catheters who develop fever or meningitis signs:

• Remove the catheter and culture the tip 1, 2
• Obtain CSF from the device reservoir 1, 2

For patients with shunt systems or Ommaya reservoirs:

• CSF should be obtained from the reservoir 1, 2
• When CSF flow is obstructed, consider sampling from both the device and lumbar space 1, 2

Critical Timing and Contraindications

When to Perform Lumbar Puncture

Proceed with LP immediately in any febrile patient with:

• Altered consciousness or focal neurologic signs that are unexplained 1
• Suspected meningitis or encephalitis 1

When Imaging is Required First

Obtain CT/MRI before LP in patients with:

• New focal neurologic findings suggesting disease above the foramen magnum 1
• Signs of increased intracranial pressure or risk of herniation 1

If imaging delays LP and bacterial meningitis is suspected, start empirical antibiotics immediately after blood cultures 1

Absolute Contraindications

• Mass lesion or obstructive hydrocephalus on imaging that creates herniation risk 1
• Significant coagulopathy (relative contraindication requiring correction first) 5

Common Pitfalls and How to Avoid Them

Inadequate sample collection is a major source of diagnostic failure:

• Use standardized LP packs to ensure all necessary samples are collected 6
• Collect sufficient volume for all planned tests, including PCR panels 4, 6

Premature antibiotic administration can sterilize cultures:

• However, never delay antibiotics for imaging or LP in suspected bacterial meningitis 1
• PCR testing can still detect pathogens after antibiotic administration, particularly for S. pneumoniae 4

Misinterpretation of normal CSF in autoimmune encephalitis:

• Normal routine CSF does not exclude autoimmune encephalitis 1
• Proceed with antibody testing when clinical suspicion is high despite normal cell count and protein 1

Failure to test both CSF and serum for antibodies:

• Different antibodies have different sensitivities in CSF vs. serum 1
• Always test both compartments for comprehensive autoimmune evaluation 1

Overlooking the need for simultaneous serum glucose:

• CSF glucose interpretation requires comparison to serum glucose drawn at the same time 1, 2