No abstract

Hypoxia can injure brain white matter tracts, comprised of axons and myelinating oligodendrocytes, leading to cerebral palsy in neonates and delayed post-hypoxic leukoencephalopathy (DPHL) in adults. In these conditions, white matter injury can be followed by myelin regeneration, but myelination often fails and is a significant contributor to fixed demyelinated lesions, with ensuing permanent neurological injury. Non-myelinating oligodendrocyte precursor cells are often found in lesions in plentiful numbers, but fail to mature, suggesting oligodendrocyte precursor cell differentiation arrest as a critical contributor to failed myelination in hypoxia. We report a case of an adult patient who developed the rare condition DPHL and made a nearly complete recovery in the setting of treatment with clemastine, a widely available antihistamine that in preclinical models promotes oligodendrocyte precursor cell differentiation. This suggested possible therapeutic benefit in the more clinically prevalent hypoxic injury of newborns, and we demonstrate in murine neonatal hypoxic injury that clemastine dramatically promotes oligodendrocyte precursor cell differentiation, myelination, and improves functional recovery. We show that its effect in hypoxia is oligodendroglial specific via an effect on the M1 muscarinic receptor on oligodendrocyte precursor cells. We propose clemastine as a potential therapy for hypoxic brain injuries associated with white matter injury and oligodendrocyte precursor cell maturation arrest.

Acute ischemic stroke therapy has rapidly evolved over the past two decades. Recently, a paradigm shift has occurred in the treatment of acute ischemic stroke due to large vessel occlusion with the publication of several randomized trials proving that mechanical thrombectomy with stent retriever devices improves clinical outcome in comparison to intravenous thrombolysis. Furthermore, pooled data from the clinical trials suggest that mechanical thrombectomy can improve outcome in a broad range of patients, and that the sooner the intervention can be performed, the greater the benefit. Delays in endovascular stroke therapy can occur during multiple time points during a patient's encounter, and these time delays are associated with worse outcomes. This association emphasizes the importance of enhancing speed-of-care processes in patients undergoing endovascular reperfusion. Efforts to reduce time delays in endovascular stroke treatment can be achieved by reflecting on the health care initiatives that took place for the treatment of acute myocardial infarction almost 20 years ago. The ideal system of care to reduce delays in endovascular stroke therapy will likely include rapid transport of all eligible patients directly to the angiography suite to bypass the inefficiencies of workflow during the early inhospital setting. These strategies will undoubtedly take time to implement, as they require further research, infrastructure funding, and policy changes at local, regional, and national levels.

Introduction: The CLEAR III trial found that removal of intraventricular hemorrhage was not associated with a dichotomized improvement in 6-month outcome measured by the modified Rankin Scale score (p=0.554). Despite this, shifts towards improved outcome were evident for the alteplase (n=249) versus saline (n=251) group measured by the extended Glasgow Outcome Score (GOS-E). Shared patient/physician decision-making would be aided by characterizing the magnitude of this benefit, using the common clinical metrics of number needed to treat (NNTB), number needed to harm (NNH), and benefit per hundred (BPH) treated. Methods: Analyses were performed on CLEAR III findings using a 6-level version of the GOS-E (GOS-E6), in which the 3 poorest outcome levels of the original GOS-E (extremely severe disability, vegetative state, and death) are combined into a single worst outcome category. In this way, shifts between these categories are not counted as improved outcome. For all possible dichotomizations of the GOS-E6 net NNTB values were derived by taking the inverse of absolute risk difference, and net BPHs by multiplying absolute risk difference by 100. For benefits accruing across all disability state transitions on the GOS-E6 (shift analysis), net NNTB, and net BPH, values were derived using automated, algorithmic min-max joint outcome table derivation technique. In addition, NNTB and NNH values for dichotomous and shift outcomes were derived using expert’s joint outcome tables, and are presented as the geometric mean. Results: For the 6 level GOS-E, automated algorithmic analysis indicated that the net NNTB for 1 additional patient to have a better outcome by ≥ 1 grade at 6 months, with thrombolytic rather than saline irrigation, was 7.4. Expert joint outcome table analyses indicated that the NNTB for improved final outcome at 6 months was 6.3 (range 5.8-6.7) and NNH 39.0 (32.3-47.6). For every 100 patients treated, 15.9 had a better outcome and 2.6 a worse outcome. The likelihood of help to harm ratio was 6.2. Conclusions: Thrombolytic removal of intraventricular hemorrhage confers net benefit on 9% of treated patients. Approximately 1 in 11 patients has a better outcome, while 1 in 39 has a worse outcome.