Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy revisited: Genotype-phenotype correlations of all published cases.

OBJECTIVE: The aim of this study was to evaluate the correlation between the various NOTCH3 mutations and their clinical and genetic profile, along with the presentation of a novel mutation in a patient. METHODS: Here, we describe the phenotype of a patient with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) harboring a novel mutation. We also performed an extensive literature research for NOTCH3 mutations published since the identification of the gene and performed a systematic review of all published cases with NOTCH3 mutations. We evaluated the mutation pathogenicity in a great number of patients with detailed clinical and genetic evaluation and investigated the possible phenotype-genotype correlations. RESULTS: Our patient harbored a novel mutation in the NOTCH3 gene, the c.3084 G > C, corresponding to the aminoacidic substitution p.Trp1028Cys, presenting with seizures as the first neurologic manifestation. We managed to find a correlation between the pathogenicity of mutations, severity of the phenotype, and age at onset of CADASIL. Significant differences were also identified between men and women regarding the phenotype severity. CONCLUSIONS: The collection and analysis of these scarce data published since the identification of NOTCH3 qualitatively by means of a systematic review and quantitatively regarding genetic profile and pathogenicity scores, highlight the significance of the ongoing trend of investigating phenotypic genotypic correlations.

Risk of perioperative neck hematoma in TIA and non-disabling stroke patients with symptomatic carotid artery stenosis undergoing endarterectomy within 14 days from cerebrovascular event.

BACKROUND & PURPOSE: Perioperative neck hematoma (PNH) requiring re-intervention is an important complication after carotid endarterectomy (CEA). There are limited data regarding the potential risk factors associated with PNH. The aim of this prospective, multicenter study was to document the rate of PNH in symptomatic carotid artery stenosis (sCAS) patients treated with CEA within the first 14 days of cerebrovascular symptom onset and to identify possible predictors of this complication. METHODS: Patients with non-disabling (mRS ≤ 2) acute ischemic stroke or transient ischemic attack due to sCAS (≥70%) underwent CEA at three stroke-centers during a seven-year period. PNH requiring surgical re-intervention or transfusion during a 30-day follow-up period was determined by the attending surgeon but was also confirmed by an independent neurologist. RESULTS: A total of 280 patients with sCAS underwent CEA within 14 days of ictus. PNH occurred in 10 cases (3.6%; 95%CI: 1.4%-5.8%). Pretreatment with therapeutic anticoagulation (TA) and history of atrial fibrillation were more prevalent in patients with PNH (20% vs. 3.1%, p= 0.047 & 30% vs. 8.2%, p = 0.05 respectively). Elapsed time between symptom onset and carotid surgery, pretreatment with dual antiplatelets, intravenous thrombolysis or prophylactic anticoagulation were not related to PNH in univariable analyses. Pretreatment with TA was independently associated with higher likelihood of PNH [OR: 10.69, 95%CI (1.74-65.72), p = 0.011] in multivariate logistic regression models adjusting for potential confounders. CONCLUSION: PNH is uncommon in patients with sCAS that are operated during the first 14 days of ictus. Pretreatment with TA appears to be associated with higher risk of PNH.

Impaired Arterial Elastic Properties and Endothelial Glycocalyx in Patients with Embolic Stroke of Undetermined Source.

BACKGROUND AND PURPOSE: Cardioembolism is a postulated mechanism of embolic stroke of undetermined source (ESUS). We investigated endothelial glycocalyx, aortic elastic properties, oxidative stress, and their association with left atrial (LA) function in ESUS and healthy individuals. METHODS: In 90 ESUS patients (age 50.4 ± 13.2) and 90 controls with similar risk factors, we measured: (1) perfused boundary region (PBR) of the sublingual arterial microvessels (range 5-25 µm), a marker inversely related with glycocalyx thickness, (2) pulse wave velocity (PWV), central systolic blood pressure (cSBP), and augmentation index (AIx), (3) LA volume and strain using speckle-tracking imaging, and (4) malondialdehyde (MDA) and protein carbonyls (PCs), as oxidative stress markers. RESULTS: Compared with controls, ESUS had higher PWV, PBR, MDA, and PC levels as well as higher LA volume and reduced reservoir LA strain (p < 0.05). PBR > 1.2 µm of microvessel ranging from 5 to 9 µm and PWV > 10.2 m/s were associated with ESUS on multivariable analysis (odds ratio: 2.374 and 5.429, p < 0.05, respectively) and increased the c-statistic of the initial model from 0.54 to 0.71. In ESUS, glycocalyx damage (increased PBR) was related with increased PWV (p < 0.01) which was linked with LA reservoir strain after controlling for age, sex, and risk factors (p = 0.03). Increased MDA and PC were related with glycocalyx damage, increased PWV (r = 0.67 and r = 0.52), AIx, cSBP, and aortic atheroma (p < 0.01). CONCLUSION: Arterial function and endothelial glycocalyx are severely impaired in ESUS and are linked to LA dysfunction suggesting their contribution to ESUS pathogenesis. CLINICAL TRIAL REGISTRATION: URL-http://www.clinicaltrials.gov. Unique identifier: NCT03609437.

The Role of Transcranial Doppler Monitoring in Patients with Multi-Territory Acute Embolic Strokes: A Review.

Acute multi-territory, embolic cerebral infarctions are often associated with serious underlying clinical conditions including the presence of highly "active" emboligenic sources causing that in turn may result in high early recurrence rates. Prompt diagnosis, risk stratification, and treatment are substantial for the prevention of subsequent embolization that would result in further clinical deterioration. Among other clinical investigations, transcranial Doppler (TCD) monitoring is highly efficacious for the detection of microembolic signals (MES) that correspond to microthrombi entering the intracranial circulation. The presence and burden of MES, especially in multiple intracranial arteries, is clearly associated with an increased risk of symptomatic, recurrent embolization, and thus can justify a more aggressive treatment approach (clopidogrel load followed by dual antiplatelet therapy or alternatively therapeutic dose of low-molecular-weight heparin). In this narrative review, we discuss the most important causes of multi-territory embolic ischemic strokes and also underscore the utility of TCD as a noninvasive tool for the diagnosis, risk stratification, and treatment.