In central nervous system (CNS) disease, prompt diagnosis is critical for immediate intervention and therapy.  Despite technological advances,  barriers to rapid diagnosis remain. First: Although there is extraordinary diversity in etiology, the signs and symptoms of CNS disorders can be remarkably similar and vague, such as “change in mental status.” Second: The number of pathogens is expanding, and known pathogens are extending beyond their historic geographic range. Third: Although the microbiology lab can often detect the infection, no definite virus is identified in up to 30% of cases of suspected viral meningitis/encephalitis. Lastly, diagnoses must be definitive, as differences in treatment are not trivial. For instance, therapy to dampen the immune system used in CNS autoimmune diseases can be highly detrimental in diseases which rely heavily on the immune system for pathogen containment. The stakes are high, and the real estate is prime. For all of these reasons, there is room for novel laboratory approaches.

Although the CNS is generally regarded as “immune privileged", it has evolved to generate an immune response while carefully safeguarding the brain. Cellular representatives of the immune system continuously survey the environment. With any perturbation of the CNS, the innate immune system will react to biological signals such as microbial components, viral proteins, and constituents of a damaged host cell. Sensing potential danger triggers an inflammatory cascade, which hinges upon the elaboration of soluble inflammatory mediators called chemokines and cytokines. Chemokine/cytokine patterns represent a cross section in the inflammatory cascade, ultimately revealing a fairly specific inflammatory profile of disease.

Because of its close relationship to critical brain structures, the cerebrospinal fluid (CSF) compartment reflects the current state of the CNS. Acquisition of CSF for laboratory testing (cell counts, microbiology, etc.) is essential in the initial evaluation of certain disease processes, with results dependent on factors such as disease time course, organism burden, and test parameters. During CNS inflammation of any etiology, chemokines/cytokines are immediately released into the CSF at measurable levels.  We measured chemokine/cytokine levels in the CSF using multiplex sandwich enzyme-linked immunosorbent assay (ELISA) technology. Using the statistical methods of principal component analysis and Mann-Whitney tests, we analyzed our data for trends across disease groups and tested for significant differences among the disease groups. Using receiver operator curves, we looked closely at cytokines of interest and evaluated their clinical potential as tests.

We studied a select panel of cytokines to investigate whether we could reliably distinguish infectious from non-infectious CNS diseases. Univariate analysis utilizing Mann-Whitney tests demonstrated that CSF concentrations of IP-10/CXCL10, IFNγ, IL-15, MDC/CCL22, MCP-1/CCL2, Fractalkine, and FLT3L were all significantly higher in infectious versus non-infectious disease.  We found that IP10/CXCL10 can reliably distinguish between an infectious versus non-infectious disease (AUC 0.9778) and MDC/CCL22 can reliably differentiate between viral and non-viral CNS infection (AUC 0.9545).  

Our results suggest that CSF chemokine/cytokine quantification can serve as a useful laboratory tool for the rapid triage of CNS diseases to help guide prompt therapy and facilitate informed testing decisions. As we continue to expand the array of CNS diseases included in our studies, such measurements will ultimately help us better understand the disease pathophysiology, in addition to providing clinically useful information to guide the management of CNS diseases. 


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