What are the appropriate diagnostic and treatment steps for suspected inflammation in the cerebrospinal fluid (CSF) indicated by elevated white blood cell count, increased protein, or oligoclonal bands?

Diagnostic Approach to Cerebrospinal Fluid Inflammation

When inflammatory indicators are found in cerebrospinal fluid (CSF), a systematic diagnostic approach focusing on viral encephalitis, bacterial meningitis, and autoimmune encephalitis should be implemented, with treatment guided by the specific etiology identified.

Initial CSF Analysis

• CSF analysis is the cornerstone of diagnosis for suspected CNS inflammation and should include opening pressure, cell count with differential, protein, glucose (with simultaneous blood glucose), and appropriate microbiological studies 1
• Normal CSF typically contains <5 white blood cells/μL, protein <45 mg/dL, and a CSF:blood glucose ratio >0.6 1
• In viral encephalitis, expect moderate pleocytosis (tens to hundreds of cells/μL, typically lymphocytic), mildly elevated protein, and normal CSF:plasma glucose ratio 1
• For traumatic taps, correct white cell count by subtracting 1 white cell for every 7000 red blood cells/μL in the CSF 1
• CSF lactate <2 mmol/L helps rule out bacterial meningitis 1
• CSF/blood glucose ratio is a precise indicator for bacterial meningitis (optimal cut-off=0.36, sensitivity=92.9%, specificity=92.9%) 2

Specific Testing for Viral Causes

• All patients with suspected encephalitis should have CSF PCR testing for HSV-1, HSV-2, VZV, and enteroviruses as these account for 90% of identified viral cases 1
• If the first CSF examination is normal in suspected HSV encephalitis, a second CSF examination 24-48 hours later is likely to show abnormalities 1
• For patients where PCR was not performed acutely, obtain CSF and serum samples 10-14 days after illness onset for HSV-specific IgG antibody testing 1
• Intrathecal synthesis of HSV-specific IgG antibodies is typically detected after 10-14 days of illness and can persist for years 1

Testing for Autoimmune Causes

• Consider autoimmune encephalitis when encountering:
  • Subacute onset (weeks to months)
  • Intractable seizures
  • Orofacial dyskinesia, choreoathetosis, or faciobrachial dystonia
  • Hyponatremia (especially with LGI1 antibodies)
  • Psychiatric symptoms 1
• Test for neuronal surface antibodies (NSAbs) and intracellular antibodies in both serum and CSF 1
• CSF findings in autoimmune encephalitis vary by antibody type:
  • NMDAR, GABAB, and AMPA receptor antibodies: frequent inflammatory CSF changes
  • CASPR2, LGI1, GABAA, or glycine receptor antibodies: often normal CSF
  • GAD antibodies: positive oligoclonal bands without other changes 3

Oligoclonal Bands

• Oligoclonal bands (OCBs) in CSF but not in serum indicate intrathecal IgG synthesis and reflect local B-cell response in CNS inflammation 4
• OCBs are present in >95% of multiple sclerosis patients but can also be found in other inflammatory neurological conditions 4
• When ADEM (acute disseminated encephalomyelitis) is in the differential diagnosis, CSF should be tested for oligoclonal bands with a paired serum sample 1
• Increased white blood cell count is associated with the presence of oligoclonal bands in CSF 5

Additional Diagnostic Tests

• Collect acute and convalescent blood samples for serological testing, especially when EBV, arboviruses, Lyme disease, cat scratch disease, rickettsiosis, or ehrlichioses are suspected 1
• Consider throat and rectal swabs for enterovirus investigations in all patients with suspected viral encephalitis 1
• When respiratory symptoms are present, collect respiratory samples for PCR testing of respiratory viruses 1
• For suspected mumps encephalitis, perform CSF PCR and collect parotid gland duct or buccal swabs 1

Imaging Considerations

• Brain MRI should be performed before lumbar puncture if there are clinical contraindications such as focal neurological signs, papilledema, seizures, or reduced consciousness 1
• In suspected spine infection, imaging is important for suggesting diagnosis, guiding biopsy procedures, and defining extent of infection 1

Common Pitfalls and Caveats

• CSF may be normal in early viral encephalitis (especially HSV), particularly in immunocompromised patients and children - repeat LP after 24-48 hours if clinical suspicion remains high 1
• Acellular CSF can occur in viral encephalitis caused by VZV, EBV, and CMV, especially in immunocompromised patients 1
• Lymphocytic pleocytosis can be seen in both viral and bacterial infections (particularly tuberculosis, listeriosis, and partially treated bacterial meningitis) 1
• Routine CSF studies may be normal in some autoimmune encephalitis patients; testing neuronal autoantibody panels is recommended even with normal CSF if clinical suspicion is high 1
• Blood samples should be collected prior to treatment with intravenous immunoglobulins or plasmapheresis to avoid false positive or false negative antibody results 1