Astroglial Inhibition of NF-κB Does Not Ameliorate Disease Onset and Progression in a Mouse Model for Amyotrophic Lateral Sclerosis (ALS)

Motor neuron death in amyotrophic lateral sclerosis (ALS) is considered a “non-cell autonomous” process, with astrocytes playing a critical role in disease progression. Glial cells are activated early in transgenic mice expressing mutant SOD1, suggesting that neuroinflammation has a relevant role in the cascade of events that trigger the death of motor neurons. An inflammatory cascade including COX2 expression, secretion of cytokines and release of NO from astrocytes may descend from activation of a NF-κB-mediated pathway observed in astrocytes from ALS patients and in experimental models. We have attempted rescue of transgenic mutant SOD1 mice through the inhibition of the NF-κB pathway selectively in astrocytes. Here we show that despite efficient inhibition of this major pathway, double transgenic mice expressing the mutant SOD1G93A ubiquitously and the dominant negative form of IκBα (IκBαAA) in astrocytes under control of the GFAP promoter show no benefit in terms of onset and progression of disease. Our data indicate that motor neuron death in ALS cannot be prevented by inhibition of a single inflammatory pathway because alternative pathways are activated in the presence of a persistent toxic stimulus

Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data

Background: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers. Methods: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0–1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0–2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4–6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903. Findings: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10–2·03]; p=0·011), with low heterogeneity across studies (I2=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05–1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06–2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4–6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52–1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03–4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [<1%], adjusted OR 5·58 [1·22–25·50]; p=0·024). Interpretation: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death. Funding: None

Elevated intracranial pressure and cerebral edema following permanent MCA occlusion in an ovine model

INTRODUCTION: Malignant middle cerebral artery (MCA) stroke has a disproportionately high mortality due to the rapid development of refractory space-occupying cerebral edema. Animal models are essential in developing successful anti-edema therapies; however to date poor clinical translation has been associated with the predominately used rodent models. As such, large animal gyrencephalic models of stroke are urgently needed. The aim of the study was to characterize the intracranial pressure (ICP) response to MCA occlusion in our recently developed ovine stroke model. MATERIALS AND METHODS: 30 adult female Merino sheep (n = 8-12/gp) were randomized to sham surgery, temporary or permanent proximal MCA occlusion. ICP and brain tissue oxygen were monitored for 24 hours under general anesthesia. MRI, infarct volume with triphenyltetrazolium chloride (TTC) staining and histology were performed. RESULTS: No increase in ICP, radiological evidence of ischemia within the MCA territory but without space-occupying edema, and TTC infarct volumes of 7.9+/-5.1% were seen with temporary MCAO. Permanent MCAO resulted in significantly elevated ICP, accompanied by 30% mortality, radiological evidence of space-occupying cerebral edema and TTC infarct volumes of 27.4+/-6.4%. CONCLUSIONS: Permanent proximal MCAO in the sheep results in space-occupying cerebral edema, raised ICP and mortality similar to human malignant MCA stroke. This animal model may prove useful for pre-clinical testing of anti-edema therapies that have shown promise in rodent studies.Adam J. Wells, Robert Vink, Stephen C. Helps, Steven J. Knox, Peter C. Blumbergs, Renée J. Turne

Guidelines for management of ischaemic stroke and transient ischaemic attack 2008

This article represents the update of the European Stroke Initiative Recommendations for Stroke Management. These guidelines cover both ischaemic stroke and transient ischaemic attacks, which are now considered to be a single entity. The article covers referral and emergency management, Stroke Unit service, diagnostics, primary and secondary prevention, general stroke treatment, specific treatment including acute management, management of complications, and rehabilitation

Patient outcomes in historical comparators compared with randomised-controlled trials

<b>Background</b>: Decompressive hemicraniectomy for malignant middle cerebral artery infarction has long been controversial. Recently, data from randomised-controlled trials have shown that the procedure is life-saving and improves outcome. However, these randomised-controlled trials were difficult to conduct, because of ethical considerations due to high mortality in control groups. While the use of historical comparators may not be ideal for phase III efficacy trials, these data may be useful to inform the selection of trial populations. We sought to replicate the findings of the DESTINY trial of decompressive surgery in malignant middle cerebral artery infarction using the Virtual International Stroke Trials Archive, to determine whether historical comparators could be used as an alternative to control groups in situations where randomised-controlled trials are infeasible or regarded as unethical due to the high mortality under conservative treatment. <b>Methods</b>: We extracted data on patients from Virtual International Stroke Trials Archive who displayed signs of malignant middle cerebral artery infarction (baseline National Institutes of Health Stroke Scale≥20, LOC1A score of ≥1 on the National Institutes of Health Stroke Scale at baseline, lesion volume ≥145 cm<sup>3</sup>). We used a χ<sup>2</sup>-test and logistic regression (adjusting for baseline National Institutes of Health Stroke Scale) to compare the functional outcomes (modified Rankin scores and Barthel index) at the last available follow-up assessment between the DESTINY surgical and the Virtual International Stroke Trials Archive comparator groups. We assessed 90-day survival rates using a Kaplan–Meier analysis and Cox proportional hazards modelling (adjusting for the baseline National Institutes of Health Stroke Scale score). <b>Results</b>: Fewer patients in the Virtual International Stroke Trials Archive comparator group (n=6/32, 19% with a 90-day follow-up) achieved a good functional outcome by mRS at the final follow-up, when compared with the DESTINY surgical group (n=8/17, 47% with a 6-month follow-up; χ<sup>2</sup>-test, P=0·04). This difference persisted after adjusting for baseline National Institutes of Health Stroke Scale (logistic regression, P=0·04), but not when accounting for patient age (P=0·66). Analysis of Barthel index at the final follow-up revealed no significant difference between the two groups (χ<sup>2</sup>-test, P=0·07), although a trend towards a better outcome in the DESTINY group was observed. In contrast with the findings of the DESTINY trial, we found no significant difference in 90-day survival rates between the surgical (88%) and the Virtual International Stroke Trials Archive (72%) comparator groups (Cox proportional hazards model, P=0·24). <b>Conclusion</b>: The beneficial effects of decompressive hemicraniectomy on survival were not confirmed using a historical comparator dataset. Our observations might be due to the fact that patients with malignant middle cerebral artery infarction are usually excluded from clinical trials of drug efficacy, and patients identified from Virtual International Stroke Trials Archive may not have been truly representative of patients with malignant middle cerebral artery infarction. This mismatch could be rectified through recruitment of population-based studies and stroke registries to Virtual International Stroke Trials Archive to increase the number of patients eligible for entry into the comparator patient data pool