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In an ongoing, open-label, phase 1b study on the intrathecal administration of rituximab for progressive multiple sclerosis, an intraventricular catheter was inserted for drug delivery. The objective of this study was to characterize the limited white matter axonal injury evoked by catheter insertion by analyzing a panel of markers for tissue damage in CSF and serum.Lumbar CSF and serum were collected before catheter insertion and at regular intervals during the follow-up period of 1 year. Levels of neurofilament light polypeptide (NF-L), glial fibrillary acidic protein, microtubule-associated protein tau, and S100 calcium binding protein B were measured in the CSF, and NF-L was also quantified in serum at each time point.One month after neurosurgical trauma, there was a distinct peak in NF-L concentration in both CSF and serum. In contrast, the biomarkers S100 calcium binding protein B, glial fibrillary acidic protein, and microtubule-associated protein tau did not show any significant changes. NF-L levels in both CSF and serum peaked at 1 month post surgery, returning to baseline after 6 to 9 months. A strong correlation was observed between the concentrations of NF-L in CSF and serum.The NF-L level, in CSF and serum, appears to be both a sensitive and specific marker for white matter axonal injury. This makes NF-L a valuable tool with which to evaluate acute white matter axonal damage in a clinical setting. Serum analysis of NF-L may become a convenient way to follow white matter axonal damage longitudinally.NCT01719159.