High mobility group box 1 prolongs inflammation and worsens disease in pneumococcal meningitis.

Neutrophilic inflammation, which often persists over days despite appropriate antibiotic therapy, contributes substantially to brain damage in bacterial meningitis. We hypothesized that persistent inflammation is the consequence of a vicious cycle in which inflammation-induced cell injury leads to the release of endogenous danger molecules (e.g. high mobility group box 1) that drive the inflammatory response, causing further damage. The present study aimed to assess the mechanisms of high mobility group box 1 protein release and its functional relevance for the development and progression of pneumococcal meningitis. High mobility group box 1 was found in large quantities in cerebrospinal fluid samples of patients and mice with pneumococcal meningitis (predominantly in advanced stages of the disease). By using macrophages, we demonstrated that the release of high mobility group box 1 from macrophages following pneumococcal challenge is passive in nature and probably not connected with inflammasome- and oxidative stress-dependent inflammatory cell death forms. In a mouse meningitis model, treatment with the high mobility group box 1 antagonists ethyl pyruvate or Box A protein had no effect on the development of meningitis, but led to better resolution of inflammation during antibiotic therapy, which was accompanied by reduced brain pathology and better disease outcome. Additional experiments using gene-deficient mice and murine neutrophils provided evidence that high mobility group box 1 acts as a chemoattractant for neutrophils in a receptor for advanced glycosylation end products-dependent fashion. In conclusion, the present study implicated high mobility group box 1, likely released from dying cells, as a central propagator of inflammation in pneumococcal meningitis. Because persistent inflammation contributes to meningitis-associated brain damage, high mobility group box 1 may represent a promising target for adjunctive therapy of this disease.

Effect of stroke thrombolysis predicted by distal vessel occlusion detection.

OBJECTIVE: Among ischemic stroke patients with negative CT angiography (CTA), we aimed to determine the predictive value of enhanced distal vessel occlusion detection using CT perfusion postprocessing (waveletCTA) for the treatment effect of IV thrombolysis (IVT). METHODS: Patients were selected from 1,851 consecutive patients who had undergone CT perfusion. Inclusion criteria were (1) significant cerebral blood flow (CBF) deficit, (2) no occlusion on CTA, and (3) infarction confirmed on follow-up. Favorable morphologic response was defined as smaller values of final infarction volume divided by initial CBF deficit volume (FIV/CBF). Favorable functional outcome was defined as modified Rankin Scale score of ≤2 after 90 days and decrease in NIH Stroke Scale score of ≥3 from admission to 24 hours (∆NIHSS). RESULTS: Among patients with negative CTA (n = 107), 58 (54%) showed a distal occlusion on waveletCTA. There was no difference between patients receiving IVT (n = 57) vs supportive care (n = 50) regarding symptom onset, early ischemic changes, perfusion mismatch, or admission NIHSS score (all p > 0.05). In IVT-treated patients, the presence of an occlusion was an independent predictor of a favorable morphologic response (FIV/CBF: ß -1.43; 95% confidence interval [CI] -1.96, -0.83; p = 0.001) and functional outcome (90-day modified Rankin Scale: odds ratio 7.68; 95% CI 4.33-11.51; p = 0.039; ∆NIHSS: odds ratio 5.76; 95% CI 3.98-8.27; p = 0.013), while it did not predict outcome in patients receiving supportive care (all p > 0.05). CONCLUSION: In stroke patients with negative CTA, distal vessel occlusions as detected by waveletCTA are an independent predictor of a favorable response to IVT.

Crossed cerebellar diaschisis in acute ischemic stroke: Impact on morphologic and functional outcome.

Crossed cerebellar diaschisis (CCD) is the phenomenon of hypoperfusion and hypometabolism of the contralateral cerebellar hemisphere caused by dysfunction of the related supratentorial region. Our aim was to analyze its influence on morphologic and functional outcome in acute ischemic stroke. Subjects with stroke caused by a large vessel occlusion of the anterior circulation were selected from an initial cohort of 1644 consecutive patients who underwent multiparametric CT including whole-brain CT perfusion. Two experienced readers evaluated the posterior fossa in terms of CCD absence (CCD-) or presence (CCD+). A total of 156 patients formed the study cohort with 102 patients (65.4%) categorized as CCD- and 54 (34.6%) as CCD+. In linear and logistic regression analyses, no significant association between CCD and final infarction volume (ß = -0.440, p = 0.972), discharge mRS ≤ 2 (OR = 1.897, p = 0.320), or 90-day mRS ≤ 2 (OR = 0.531, p = 0.492) was detected. CCD+ patients had larger supratentorial cerebral blood flow deficits (median: 164 ml vs. 115 ml; p = 0.001) compared to CCD-patients. Regarding complications, CCD was associated with a higher rate of parenchymal hematomas (OR = 4.793, p = 0.035). In conclusion, CCD is frequently encountered in acute ischemic stroke caused by large vessel occlusion of the anterior circulation. CCD was associated with the occurrence of parenchymal hematoma in the ipsilateral cerebral infarction but did not prove to significantly influence patient outcome.