Leukoaraiosis and risk of intracranial hemorrhage and outcome after stroke thrombolysis

<div><p>Background</p><p>The impact of leukoaraiosis on the risk of symptomatic intracerebral hemorrhage (SICH) after stroke thrombolysis is conflicting, and the data on Asian populations are lacking. Therefore, in this study, we assessed the association between leukoaraiosis and SICH, and the association between leukoaraiosis and the 90-day functional outcome in the Asian population.</p><p>Methods</p><p>Data were collected from a two-center prospective registry of acute ischemic stroke patients given intravenous tissue plasminogen activator between 2006 and 2014. A total of 614 pretreatment brain CT and 455 posttreatment MRI were retrospectively assessed using two different rating scales for the presence of leukoaraiosis. Outcome measures were the occurrence of SICH with three definitions and any hemorrhage after thrombolysis and functional outcome at 3 months.</p><p>Results</p><p>Of the 614 patients assessed, 30.3% showed severe leukoaraiosis on the baseline brain CT. The SICH rate was 4.6% - 7.2% based on different definitions, and overall, 24.9% of patients showed any post-tPA hemorrhage. No association was observed between the severity of leukoaraiosis and SICH, regardless of having used different leukoaraiosis rating scales or as assessment using different imaging modalities. However, severe leukoaraiosis was independently associated with poor functional outcome at 3 months (OR 1.96, 95% C1 1.24–3.11, <i>P</i> = 0.004) after adjustment for confounders.</p><p>Conclusions</p><p>Our results showed no association between leukoaraiosis and the risk of SICH. Although the presence of severe leukoaraiosis predicted a poor functional outcome after stroke, IV thrombolysis might not be withheld in acute ischemic stroke patients solely based on the presence of severe leukoaraiosis on pre-thrombolytic CT scans.</p></div

The risk of SICH and any hemorrhage in patients with different levels of severity of leukoaraiosis based on MRI examination (N = 455).

<p>The risk of SICH and any hemorrhage in patients with different levels of severity of leukoaraiosis based on MRI examination (N = 455).</p

Flow chart of this study.

<p>Four patients were excluded in the association analysis of leukoaraiosis and SICH (Expired without post-tPA brain CT). Total 83 patients were excluded (poor pre-morbid function and loss of follow-up at 3 months) in the association analysis of leukoaraiosis and 90-day functional outcome. Note that all 455 patients with post-tPA MRI had post-tPA CT follow-up images, too.</p

Demographic data and baseline characteristics.

<p>Demographic data and baseline characteristics.</p

The incidence of SICH and any hemorrhage in patients with different severity of leukoaraiosis and the effect of leukoaraiosis on SICH.

<p>The incidence of SICH and any hemorrhage in patients with different severity of leukoaraiosis and the effect of leukoaraiosis on SICH.</p

Clinical and Molecular Characterization of <i>BSCL2</i> Mutations in a Taiwanese Cohort with Hereditary Neuropathy

<div><p>Background</p><p>A small group of patients with inherited neuropathy that has been shown to be caused by mutations in the <i>BSCL2</i> gene. However, little information is available about the role of <i>BSCL2</i> mutations in inherited neuropathies in Taiwan.</p><p>Methodology and Principal Findings</p><p>Utilizing targeted sequencing, 76 patients with molecularly unassigned Charcot-Marie-Tooth disease type 2 (CMT2) and 8 with distal hereditary motor neuropathy (dHMN), who were selected from 348 unrelated patients with inherited neuropathies, were screened for mutations in the coding regions of <i>BSCL2</i>. Two heterozygous <i>BSCL2</i> mutations, p.S90L and p.R96H, were identified, of which the p.R96H mutation is novel. The p.S90L was identified in a pedigree with CMT2 while the p.R96H was identified in a patient with apparently sporadic dHMN. <i>In vitro</i> studies demonstrated that the p.R96H mutation results in a remarkably low seipin expression and reduced cell viability.</p><p>Conclusion</p><p><i>BSCL2</i> mutations account for a small number of patients with inherited neuropathies in Taiwan. The p.R96H mutation is associated with dHMN. This study expands the molecular spectrum of <i>BSCL2</i> mutations and also emphasizes the pathogenic role of <i>BSCL2</i> mutations in molecularly unassigned hereditary neuropathies.</p></div

The pedigrees and sequencing data of the two families carrying <i>BSCL2</i> mutations.

<p>(A) The pedigree and the electropherograms of the individuals of the family carrying the <i>BSCL2</i> p.S90L (c.269C>T) mutation. The proband (III-1) is denoted by an arrow. Filled symbols represent affected members with neuropathy, open symbols indicate unaffected individuals, circles stand for female, and squares stand for male. (B) The pedigree and the electropherogram of the patient carrying the <i>BSCL2</i> p.R96H (c.287G>A) mutation. (C) The <i>BSCL2</i> p.S90L and p.R96H mutations reside in an evolutionarily conserved region, as shown by aligning the amino acid sequences of seipin protein orthologs from various species.</p

<i>In vitro</i> expression of <i>BSCL2</i> in HEK293 cells.

<p>(A) Representative western blot analysis of seipin in the HEK293 cells transfected with plasmids expressing wild-type (WT), S90L, or R96H seipin, or empty vector (vector control). Actin was used as a loading control. Densitometric quantification is shown below. The error bars indicate standard error of the mean (SEM) from 3 independent experiments. IB, immunoblotting. (B) HEK293 cells were transfected with expression plasmids for the WT, S90L, or R96H seipin for 48 hours and subsequently subjected to cycloheximide-chase assays. Representative western blots is shown above. All values are shown as means ± SEM (n = 4). (C) The messenger RNA (mRNA) levels of <i>BSCL2</i> in the HEK293 cells transfected with WT, S90L, or R96H seipin expression plasmids for 24 hours. The expression levels of <i>BSCL2</i> were normalized to those of GAPDH and expressed as a fraction of the WT samples, which was set as 100%. The error bars indicate SEM (n = 3). The asterisk indicates statistically significant difference (**, p < 0.01).</p

Deleterious consequences of the <i>BSCL2</i> variants predicted by <i>in silico</i> analyses.

<p>Deleterious consequences of the <i>BSCL2</i> variants predicted by <i>in silico</i> analyses.</p

Clinical and electrophysiological features of the patients with <i>BSCL2</i> mutations.

<p>Clinical and electrophysiological features of the patients with <i>BSCL2</i> mutations.</p