Research indicates that current laboratory testing of cerebrospinal fluid (CSF) does not consistently discriminate between different central nervous system (CNS) disease states; and quickly distinguishing CNS infections from other brain and spinal cord disorders that share a similar clinical presentation is critical in treating patients with CNS disorders.
Given that many pathogens are rapidly expanding their geographic ranges, certain infections may not be considered at the initial clinical presentation, creating a lag between clinical suspicion and diagnosis. Initial identification of a CNS disorder as infectious and distinguishing it from other non-infectious pathologic processes, however, is not entirely straightforward.
“Despite testing with various modalities—including but not limited to MRI, CSF cell count, glucose and protein levels, Gram stain, CSF cytology, analysis for anti-CNS antibodies, and molecular analysis of CSF for infectious pathogens—identifying the process causing the CNS symptoms may take days or weeks to identify or in some cases is not determined,” says Mark T. Curtis, MD, PhD
Timely identification of CNS disease is critical to implementing prompt measures and initiating appropriate disease-specific treatments. New approaches focusing on aspects of disease biology, such as immune response profiles that can have stimulus-specific attributes, may prove beneficial.
“Analysis of CSF cytokine profiles could be especially helpful in neonates and infants,” says Dr. Curtis. “Children are especially susceptible to meningitis and encephalitis. When a baby enters the ED with symptoms of sepsis or meningitis, a lumbar puncture is commonly performed. These young patients display symptoms of severe illness but are not able to inform the clinical team about how they feel or respond to questions such as ‘Is your neck stiff?’”
A Look at CSF Cytokines
For a study published in PLOS ONE, Dr. Curtis, Danielle Fortuna, MD, and colleagues measured CSF cytokine levels in various CNS disorders (infections, autoimmune/demyelinating diseases, lymphomas, and gliomas) to determine the potential utility of cytokine patterns in differentiating CNS infections from other CNS diseases.
CSF laboratory studies, such as white blood cell count, glucose concentration, and protein levels, were a component of the clinical evaluation among patients aged 2 to 80. Samples selected included seven control patients negative for neuro-inflammatory processes, 15 patients with CNS infections, three patients with malignant glial (astrocytic) neoplasms, 11 patients with autoimmune and demyelinating disease (autoimmune/DM), and six patients with B-cell lymphoma involving the CNS.
“We became interested in the innate immune response to CNS disease and how this is reflected by changes in levels of cytokines in the CSF because of the illness of a young patient in their teens who had very severe encephalitis due to human parechovirus type 3 (HPeV3),” says Dr. Fortuna. “To see how the immune system was responding to this virus that resulted in such a severe illness, we compared the CSF cytokine levels in the CSF from this patient to those of a variety of other infections and CNS disorders.” CSF cytokine levels were measured using multiplex enzyme-linked immunosorbent assay analysis.
A Big Picture Approach to Diagnosis
Within the infection group, elevated levels of macrophage-derived chemokine/CCL22 distinguished non-viral from viral infections. Each disease group of the non-infectious CNS disorders independently showed interferon gamma-induced protein 10 (IP-10)/ C-X-C motif chemokine ligand 10 (CXCL10) levels that were significantly lower than those of the infection group [(autoimmune/demyelinating disorders, lymphomas, gliomas, and controls].
“It’s a big picture approach to diagnosis,” says Dr. Fortuna. “Instead of asking the direct question of ‘what is it?’, the test allows us to ask ‘what is happening?’ by observing how the body’s own immune environment is reacting to the type of disease afflicting the patient.
“Based on the presence or absence and relative levels of these immune mediators, the cytokine profile reveals what the immune system has probably encountered,” adds Dr. Fortuna. “Time is brain, and our test allows these diseases to be rapidly triaged for prompt treatment and for the treating physicians to undertake the next steps in care.”
Using Algorithms for Diagnosis
The research team used a receiver operator characteristic (ROC) curve analysis to question the potential utility of cytokines as individual tests. Their results support the potential of using levels of these cytokines in CSF to distinguishing different CNS disorders. Based on the cut-off values suggested by ROC, they constructed a prototype diagnostic algorithm flowchart (Table).
“IP-10/CXCL10 levels were significantly higher in infections than in the pooled non-infectious group and significantly higher in the infectious group than in all of the non-infectious disease classes when analyzed separately,” says Dr. Curtis. “Importantly, our ROC analysis showed good to excellent diagnostic potential for these markers.”
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