CSF Leukocytes in Intracranial Infections: Diagnostic, Mechanistic, and Therapeutic Insights for Neurocritical Care

Intracranial infections remain a major neurocritical care challenge, causing high mortality and long-term deficits despite advances in antimicrobials, imaging, and intensive care. Because bacterial, viral, fungal, and parasitic pathogens trigger distinct immune pathways, they produce characteristic CSF leukocyte patterns shaped by pathogen sensing, endothelial adhesion molecule expression, chemokine gradients, and leukocyte migration across CNS barriers. Pleocytosis therefore reflects PRR activation and tends toward neutrophil, lymphocyte, or monocyte-macrophage predominance. Notably, promptly distinguishing infectious encephalitis (IE) from autoimmune encephalitis (AE) is crucial. Specifically, bacterial infections usually create neutrophil-predominant CSF via IL-1β, TNF-α, and G-CSF, whereas viral infections such as HSV and VZV promote lymphocytic profiles through interferons and CXCR3 ligands. Fungal pathogens (Cryptococcus, Candida, Aspergillus) and mycobacteria often produce mixed or mononuclear pleocytosis due to chronic antigen exposure. These patterns guide therapy: bacterial infections require immediate empiric antibiotics with corticosteroids; HSV and VZV encephalitis needs urgent IV acyclovir; enteroviruses and arboviruses rely on supportive care; and fungal infections require staged antifungal therapy with monitoring of CNS penetration, organ function, and intracranial pressure. Parasitic and amoebic infections such as Naegleria fowleri demand individualized antiparasitic treatment, corticosteroids, seizure control, and intensive supportive care. Because CSF leukocytes also influence barrier integrity, neuronal survival, and glial activation, advanced profiling-combining CSF leukocyte phenotyping with cytokine and chemokine analysis-enhances differentiation between IE and AE and supports more targeted treatment. This review elucidates the role of CSF leukocytes in CNS infections, highlighting their diagnostic, mechanistic, and therapeutic significance for guiding precision neurocritical care. Pathogens in CSF create distinct leukocyte patterns via PRR-PAMP signaling and chemokine-driven trafficking. Bacteria cause neutrophil-rich IL-1β/TNF-α responses; viruses (HSV/VZV) produce lymphocyte-dominant interferon profiles; and fungal or mycobacterial infections show mixed or granulomatous patterns. These signatures affect BBB integrity and help distinguish infections from autoimmune encephalitis.