Abstract
Current laboratory testing of cerebrospinal fluid (CSF) does not consistently discriminate between different central nervous system (CNS) disease states. Rapidly distinguishing CNS infections from other brain and spinal cord disorders that share a similar clinical presentation is critical. New approaches focusing on aspects of disease biology, such as immune response profiles that can have stimulus-specific attributes, may be helpful. We undertook this preliminary proof-of-concept study using multiplex ELISA to measure 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. Both agglomerative hierarchical clustering and mixture discriminant analyses revealed grouping of CNS disease types based on cytokine expression. To further investigate the ability of CSF cytokine levels to distinguish various CNS disease states, non-parametric statistical analysis was performed. Mann-Whitney test analysis demonstrated that CNS infections are characterized by significantly higher CSF lP-10/CXCL10 levels than the pooled non-infectious CNS disorders (p = 0.0001). Within the infection group, elevated levels of MDC/CCL22 distinguished non-viral from viral infections (p = 0.0048). Each disease group of the non-infectious CNS disorders independently showed IP-10/CXCL10 levels that are significantly lower than the infection group [(autoimmune /demyelinating disorders (p = 0.0005), lymphomas (p = 0.0487), gliomas (p = 0.0294), and controls (p = 0.0001)]. Additionally, of the non-infectious diseases, gliomas can be distinguished from lymphomas by higher levels of GRO/CXCL1 (p = 0.0476), IL-7 (p = 0.0119), and IL-8 (p = 0.0460). Gliomas can also be distinguished from autoimmune/demyelinating disorders by higher levels of GRO/CXCL1 (p = 0.0044), IL-7 (p = 0.0035) and IL-8 (p = 0.0176). Elevated CSF levels of PDGF-AA distinguish lymphomas from autoimmune/demyelinating cases (p = 0.0130). Interrogation of the above comparisons using receiver operator characteristic analysis demonstrated area under the curve (AUC) values (ranging from 0.8636–1.0) that signify good to excellent utility as potential diagnostic discriminators. In conclusion, our work indicates that upon formal validation, measurement of CSF cytokine levels may have clinical utility in both identifying a CNS disorder as infectious in etiology and, furthermore, in distinguishing viral from non-viral CNS infections.
Highlights
Rapid identification of CNS disease is critical to implement prompt measures and initiate appropriate disease-specific treatments [1,2,3,4,5]
A variety of different pathogens was included in the infectious group to reproduce the common clinical scenario in which a range of pathogens are in the CSF cytokine profiles help identify CNS disease as infectious differential diagnosis to exclude infection
Our observations suggest elevated levels of IL-7, IL-8, and GRO/CXCL1 are useful in identifying a CNS disease process as a diffuse glial neoplasm
Summary
Rapid identification of CNS disease is critical to implement prompt measures and initiate appropriate disease-specific treatments [1,2,3,4,5]. The differential diagnoses considered in a patient with symptoms of CNS disorder (e.g., acute mental status change, focal neurologic deficit, severe headache, and photophobia) are numerous and often include infection, autoimmune disorders, demyelinating disease and neoplasms [4,8,9]. Therapy for these various diseases is drastically different [3,4,10,11,12]. Immunosuppressive and immunomodulatory agents indicated in CNS autoimmune disease and demyelinating disorders (including multiple sclerosis) would be contraindicated and potentially detrimental in the setting of a CNS infection
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