Somatic Variants in SVIL in Cerebral Aneurysms

Publisher Copyright: © American Academy of Neurology.Background and ObjectivesWhile somatic mutations have been well-studied in cancer, their roles in other complex traits are much less understood. Our goal is to identify somatic variants that may contribute to the formation of saccular cerebral aneurysms.MethodsWe performed whole-exome sequencing on aneurysm tissues and paired peripheral blood. RNA sequencing and the CRISPR/Cas9 system were then used to perform functional validation of our results.ResultsSomatic variants involved in supervillin (SVIL) or its regulation were found in 17% of aneurysm tissues. In the presence of a mutation in the SVIL gene, the expression level of SVIL was downregulated in the aneurysm tissue compared with normal control vessels. Downstream signaling pathways that were induced by knockdown of SVIL via the CRISPR/Cas9 system in vascular smooth muscle cells (vSMCs) were determined by evaluating changes in gene expression and protein kinase phosphorylation. We found that SVIL regulated the phenotypic modulation of vSMCs to the synthetic phenotype via Krüppel-like factor 4 and platelet-derived growth factor and affected cell migration of vSMCs via the RhoA/ROCK pathway.DiscussionWe propose that somatic variants form a novel mechanism for the development of cerebral aneurysms. Specifically, somatic variants in SVIL result in the phenotypic modulation of vSMCs, which increases the susceptibility to aneurysm formation. This finding suggests a new avenue for the therapeutic intervention and prevention of cerebral aneurysms.Peer reviewe

Carotid web stenting

Background: Carotid webs are luminal, shelf-like protrusions at the carotid bulb. Considered to be a variant of fibromuscular dysplasia, carotid webs have been observed principally in African American females. The association between carotid webs and recurrent ischemic strokes continues to be established as patients without traditional stroke risk factors are found to have carotid webs as the only possible cause of symptomatic deficits. The majority of patients undergo endarterectomy; few stent placements are reported. We present the case of an African American female who underwent stent placement for treatment and secondary prevention of stroke attributed to a carotid web.Case Report: A 33-year-old African American female presented with acute onset left hemiparesis and left facial droop. Alteplase was administered; multiphase head and neck computed tomography angiography revealed an occlusion of the rightmiddle cerebral artery with a web at the carotid bulb. Aspiration catheter thrombectomy achieved a Thrombolysis in Cerebral Infarction (TICI) score of 3. She was placed on 2 antiplatelet agents, and 3 weeks later she underwent stent placement. Follow-up digital subtraction angiography at 3 months showed obliteration of the right carotid artery web and satisfactory integration of the stent into the vessel wall. She was reassessed at 1 year and reported no neurologic symptoms.Conclusion: Although carotid webs are most commonly treated with endarterectomy, they may be amenable to stent therapy with favorable clinical outcomes as shown with this patient

Fetal surgery: The Ochsner experience with in utero spina bifida repair

Background: Myelomeningocele is the most common form of congenital central nervous system defect that is compatible with life. Most patients with myelomeningocele have significant functional impairment of ambulation and bowel and bladder function, require permanent cerebrospinal fluid diversion with shunting, and have significant morbidity and mortality from hindbrain herniation (Chiari II malformation). The advent of intrauterine surgery has provided new opportunities to better address this lifelong debilitating disease. Case Report: The patient was a 19-year-old gravida 2 para 1 at 22-6/7 weeks whose fetus was diagnosed with an open neural tube defect and further demonstrated to have ventriculomegaly and hindbrain herniation. Amniocentesis confirmed normal karyotype and the presence of acetylcholinesterase. After an intrauterine procedure, the patient underwent cesarean section at 35-5/7 weeks and delivered a male infant. His spinal incision was well healed at birth without any evidence of cerebrospinal fluid leakage, and his extremities were normal in appearance, range of motion, and movement. The infant also has maintained relatively normal, age-appropriate bowel and bladder function and has no obvious neurologic deficit. Conclusion: As the benefit of fetal surgery becomes more widely accepted, quality of care and patient safety must be at the forefront of any institution's effort to offer fetal surgery. Given the current prevalence of spina bifida and the amount of resources required to treat this disease effectively either in utero or postnatally, it is our opinion that the treatment of spina bifida should be regionalized to tertiary referral centers with the interdisciplinary expertise to offer comprehensive treatment for all aspects of the disease and all phases of care for the patients

Diagnosis and Treatment of Arterial Dissections

Dissections of the cervical and intracranial vessels represent an important source of stroke in those less than 50 years of age. This can occur spontaneously or following trauma, minor or major. Rapid diagnosis is essential to limit subsequent sequelae and modern computed tomographic angiography represents an appropriately sensitive modality. Treatment must be individualized to the patient and can consist of an antiplatelet regimen, anticoagulation, or endovascular intervention. No evidence demonstrates superiority of either medical modality and even aspirin alone may be efficacious. Consideration should be given to this in the multi-trauma population in which more aggressive anticoagulation is contraindicated. In addition, thrombolytic administration should not be withheld would it otherwise be indicated. Endovascular intervention is reserved for those with hemodynamically significant narrowing, enlarging pseudoaneurysms, fistulas formation, or subarachnoid hemorrhage