Effect of intraventricularly administered low-dose recombinant tissue plasminogen activator on interleukin 1-beta and transforming growth factor beta concentrations in cerebrospinal fluid of patients with primary intracerebral hemorrhage associated with intraventricular hemorrhage

Abstract

It is increasingly recognized that modulation of brain inflammation may uncover new potential therapeutic strategies for stroke. Recent studies have shifted focus from immunological implications in ischemic stroke to a more devastating form; the hemorrhagic stroke. The aim of this study was to investigate the neuroinflammatory response in cerebrospinal fluid in patients with primary intracerebral hemorrhage (ICH) associated with intraventricular hemorrhage (IVH) in the presence of low-dose recombinant tissue plasminogen activator (rt-PA). This retrospective study included 88 adults with primary ICH associated with IVH. Patients were divided into 2 groups: rt-PA group and non-rt-PA group, which received normal standard of care for this diagnosis. The rt-PA group was treated via catheter-based clot lysis using low-dose rt-PA injected through the external ventricular drain (EVD) system, and the non-rt-PA group was treated with saline applied to EVD system in equivalent volume. Cerebrospinal fluid samples from rt-PA were obtained from the EVD system at 4 time points: once before the drug administration, and then on day 1, 3, and 7. No attempt at randomization was made. The decision to inject rt-PA was based on the preference of the primary attending neurologist and the ability to obtain consent. Temporal interleukin-1 beta and transforming growth factor beta concentration changes were analyzed and compared between the 2 groups. The concentration of interleukin-1 beta was significantly lower in the rt-PA group than in the non-rt-PA group on day 7. In addition, the concentration of transforming growth factor beta was significantly higher in the rt-PA group than in the non-rt-PA group on day 1. There was a significant difference in interleukin-1 beta concentration between days 0 and 1 in comparison to day 3 in the rt-PA group, and between day 0 in comparison to day 3 and 7 in the non-rt-PA group. We also observed a significant difference in transforming growth factor beta concentration between days 0 and 1 and between days 3 and 7. The different pattern of pro- and anti-inflammatory cytokines in patients with ICH associated with IVH suggest distinct characteristics of secondary brain injury depending on the treatment modality.

Early Inflammatory Cytokine Expression in Cerebrospinal Fluid of Patients with Spontaneous Intraventricular Hemorrhage

“…Levels of IL-1α, TNF-α and IL-6 were relatively higher in CSF from control SAH patients compared to our observed very low levels in spontaneous IVH, whereas IL-1β was higher in our cohort. CSF IL-1β levels over first 7 days were even higher in a report of 41 adults with primary ICH associated with IVH who did not receive tPA [22]. Whether such comparisons are meaningful in a small sample, however, is not clear and may simply reflect sampling variation.…”

CSF and serum inflammatory response and association with outcomes in spontaneous intracerebral hemorrhage with intraventricular extension: an analysis of the CLEAR-III Trial

“…While alteplase increases neutrophil degranulation and MMP-9 production, it also increases levels of protective tissue inhibitor of metalloproteinase [ 40 , 41 ] Alteplase also suppresses macrophage cytokine production dependent on NMDA-R expression. Sošić et al demonstrated an increased anti-inflammatory cytokine (TGF-β) compared with proinflammatory cytokine (IL-1β) response in the CSF in patients with primary ICH and IVH treated with recombinant tissue plasminogen activator [ 42 ]. Although alteplase increases all CSF leukocyte cell counts, its ability to suppress innate immune cell function and shift toward anti-inflammatory cytokine production may mitigate the effect of increased CSF leukocytes on mRS outcomes.…”

“…demonstrated an increased anti-inflammatory cytokine (TGF-β) compared with proinflammatory cytokine (IL-1β) response in the CSF in patients with primary ICH and IVH treated with recombinant tissue plasminogen activator [42]. Although alteplase increases all CSF leukocyte cell counts, its ability to suppress innate immune cell function and shift toward anti-inflammatory cytokine production may mitigate the effect of increased CSF leukocytes on mRS outcomes.…”