Person:

Stapleton, Christopher

Acute ischemic stroke resulting from intracranial vessel occlusion is associated with high morbidity and mortality. The mainstays of therapy are fibrinolytics and mechanical thrombectomy in properly selected patients. A new Food and Drug Administration-approved technology to perform thrombectomy, retrievable stenting, may provide superior revascularization rates and improved patient outcomes. We analyzed the cumulative human experience reported for the Trevo Pro Retrieval System (Stryker, Kalamazoo, MI, USA) and the Solitaire FR Revascularization Device (ev3, Irvine, CA, USA) as the definitive treatment for acute ischemic stroke. A literature search was undertaken to identify studies using the retrievable stents published up to September 2012. Nineteen studies identified a total of 576 patients treated with either the Trevo (n = 221) or Solitaire (n = 355) devices. Pooled data analysis identified baseline National Institutes of Health Stroke Scale scores of 18.5 ± 0.289 (standard error of the mean) and 17.9 ± 0.610, and time to recanalization of 53.9 ± 23.6 minutes and 59.0 ± 8.0 minutes for the Trevo and Solitaire groups, respectively. Recanalization was variably defined by individual studies, most commonly achieving at least a thrombolysis in cerebral infarction score of 2a–3 or a thrombolysis in myocardial infarction score of 2–3. Revascularization (83%, 82%), mortality (31%, 14%), hemorrhage (8%, 6%), device complications (5%, 6%), and good patient outcomes (51%, 47%) were found with the Trevo and Solitaire devices, respectively. Preliminary analysis reveals excellent clinical outcomes for retrievable stent technology. This may be attributable to both high rates of revascularization with a relatively short time to perfusion restoration.

Brain arteriovenous malformations (AVMs) are abnormal connections between arteries and veins that can result in hemorrhagic stroke. A genetic basis for AVMs is suspected, and we investigated potential mutations in a 14-year-old girl who developed a recurrent brain AVM. Whole-exome sequencing (WES) of AVM lesion tissue and blood was performed accompanied by in silico modeling, protein expression observation in lesion tissue and zebrafish modeling. A stop-gain mutation (c.C739T:p.R247X) in the gene SMAD family member 9 (SMAD9) was discovered. In the human brain tissue, immunofluorescent staining demonstrated a vascular predominance of SMAD9 at the protein level. Vascular SMAD9 was markedly reduced in AVM peri-nidal blood vessels, which was accompanied by a decrease in phosphorylated SMAD4, a downstream effector protein of the bone morphogenic protein signaling pathway. Zebrafish modeling (Tg kdrl:eGFP) of the morpholino splice site and translation-blocking knockdown of SMAD9 resulted in abnormal cerebral artery-to-vein connections with morphologic similarities to human AVMs. Orthogonal trajectories of evidence established a relationship between the candidate mutation discovered in SMAD9 via WES and the clinical phenotype. Replication in similar rare cases of recurrent AVM, or even more broadly sporadic AVM, may be informative in building a more comprehensive understanding of AVM pathogenesis.