NOTCH3 mutations in a cohort of Portuguese patients within CADASIL spectrum phenotype.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common inherited cerebral small vessel disease. It is caused by mutations in the NOTCH3 gene, which encodes a membranebound receptor protein with three main distinct functional domains. Thus far, several different NOTCH3 mutations, most of them cysteine altering variants, have been described and although they tend to cluster in certain exons, their distribution varies in different geographically populations. Therefore, in this study, we describe the mutation analysis of NOTCH3 gene in 24 Portuguese families with small vessel disease suspected to have CADASIL from the central region of Portugal. The genetic analysis revealed 15 different heterozygous variants, eight pathogenic cysteine altering variants, six cysteine sparing variants and one nonsense variant, located mainly in the exons 4, 8 and 11. Thus, in our population, the genetic testing should initially be focused on these exons. In addition, the genetic findings broaden the mutational and clinical spectrum of CADASIL related phenotype and provide additional evidences for genetic counseling and clinical management.

Single-phase CT angiography predicts ASPECTS decay and may help determine when to repeat CT before thrombectomy.

OBJETIVES: Time is relative in large-vessel occlusion acute ischemic stroke (LVO-AIS). We aimed to evaluate the rate of inter-hospital ASPECTS decay in patients transferred from a primary (PSC) to a comprehensive stroke center (CSC); and to identify patients that should repeat computed tomography (CT) before thrombectomy. MATERIALS AND METHODS: This was a retrospective cohort study of consecutive anterior circulation LVO-AIS transferred patients. The rate of ASPECTS decay was defined as (PSC-ASPECTS - CSC-ASPECTS)/hours elapsed between scans. Single-phase CT angiography (CTA) at the PSC was used to classify the collateral score. We compared patients with futile versus useful CT scan re-evaluation. RESULTS: We included 663 patients, of whom 245 (37.0%) repeated CT at a CSC. The median rate of ASPECTS decay was 0.4/h (0.0-0.9). Patients excluded from thrombectomy after a CT scan repeat (n=64) had a median ASPECTS decay rate of 1.18/h (0.83-1.61). Patients with absent collateral circulation had a median rate of 1.51(0.65-2.19). The collateral score was an independent predictor of the ASPECTS decay rate (aß = -0.35; 95%CI -0.45 - -0.19, p<0.001). Age (aOR: 1.04 95% CI 1.02-1.07, p<0.001), NIHSS (aOR: 1.11 95% CI 1.06-1.15, p<0.001), PSC ASPECTS (aOR: 0.74 95% CI 0.60-0.91, p=0.006) and the CTA collateral score (aOR: 0.14 95% CI 0.08-0.22, p<0.001) were independent predictors of the usefulness of a CT scan repeat. CONCLUSIONS: The rate of ASPECTS decay can be predicted by the CTA collateral score, helping in the selection of patients that would benefit from repeating a CT assessment on arrival at the CSC.

Blood Pressure Variability in Acute Ischemic Stroke: The Role of Early Recanalization.

We performed a retrospective study with the aim of investigating the association between blood pressure (BP) variability in the first 24 h after ischemic stroke and functional outcome, regarding arterial recanalization status. A total of 674 patients diagnosed with acute stroke and treated with revascularization therapies were enrolled. Systolic and diastolic BP values of the first 24 h after stroke were collected and their variation quantified through standard deviation. Recanalization state was evaluated at 6 h and clinical outcome at 3 months was assessed by modified Rankin Scale. In multivariate analyses systolic BP variability in the first 24 h post-stroke showed an association with 3 months clinical outcome in the whole population and non-recanalyzed patients. In recanalyzed patients, BP variability did not show a significant association with functional outcome.

Neurosonology Accuracy for Isolated Acute Vestibular Syndromes.

OBJECTIVES: The clinical approach to acute vestibular syndromes is often complex for the physician. Neurosonology offers a noninvasive method to study the cervicocephalic circulation when a vascular etiology is suspected. We aim to evaluate the diagnostic accuracy of a vascular neurosonological exam in isolated acute vestibular syndrome. METHODS: All patients submitted to cerebrovascular ultrasound and magnetic resonance imaging during the period between 2011 and 2015 with acute isolated vestibular syndrome. Those with any clinical sign of brainstem lesion on presentation were excluded. All patients performed the neuroimaging study (brain computed tomography and magnetic resonance imaging) and neurologic surveillance. Neurosonological exam included all intra- and extracranial segments of the vertebrobasilar circulation. Positive ultrasound exam was defined as the presence of stenotic or occlusive disease in any of these segments related to the infarcted area. RESULTS: A total of 108 patients were included: 60 (53.6%) were males (mean age: 60.75 years (standard deviation, 14.17)). In 27 patients (25.0%) a cerebral ischemic lesion was found to be the cause of the vertigo. Neurosonological assessment showed a sensitivity of 40.7% (95% confidence interval (CI): 22.4; 61.2), specificity of 100% (95% CI: 95.5; 100.0), positive predictive value (PPV) of 100% (95% CI: 71.5; 100.0), and negative predictive value (NPV) of 83.5% (95% CI: 74.6; 90.3). CONCLUSIONS: Our study suggests that cerebrovascular ultrasound is a highly specific method for the diagnosis of cerebrovascular vertigo. However, its low sensitivity makes it a poor candidate for screening.

The relevance of the socio-emotional deficits in cerebral small vessels disease (CSVD): An exploratory study with sporadic CSVD and CADASIL patients.

Background: Cerebral Small Vessels Disease (CSVD) is categorized in different forms, the most common being the sporadic form and a genetic variant - Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). Amongst the most frequent clinical manifestations are the neuropsychological changes of cognitive, behavioral, and emotional nature, whose features are still under debate. Objective: This exploratory study aimed to compare the neuropsychological profile of a sporadic CSVD sample and a CADASIL sample with an age, education, and gender matched control group, between the ages of 30-65 YO (total sample mean age=51.16; SD=4.31). Methods: 20 patients with sporadic CSVD, 20 patients with CADASIL and 20 matched controls completed a neuropsychological assessment battery. Global cognitive state, processing speed, working memory, attention, executive dysfunction, episodic memory, social cognition, impulsivity, apathy, alexithymia, depression, and anxiety were measured. White matter hyperintensities (WMH) volume were quantified and measured as lesion burden. Results: The cognitive differences found between the clinical groups combined (after confirming no differences between the two clinical groups) and matched controls were restricted to speed processing scores (d = 0.32 95 % CI [.12-.47]). The socio-emotional and behavioral profile revealed significantly higher levels of depression (d = 0.21, 95 % CI [.16-.33]). and anxiety (d = 0.25 95 % CI [.19-.32]) in CADASIL and sporadic CSVD groups, and the same for the alexithymia score (d = 0.533 95 % CI [.32-.65]) were the clinical groups revealed impoverished emotional processing compared to controls. WMH only significantly correlated with the cognitive changes and age. Conclusions: In our study, CADASIL and sporadic cSVD patients combined, present multiple emotional-behavioral symptoms - alexithymia, anxiety, depression, and in a lower extent apathy and impulsivity - suggesting for the presence of emotion dysregulation behaviors, present independently of age and of the presence of cognitive deficits. Despite of the small sample size that could underpower some findings, this exploratory research supported that these symptoms may have a significant impact in disease monitoring, progression, and prognosis, requiring further investigation regarding their neurophysiological substrates.

Can Morphometric Analysis of Cervical Spondylotic Myelopathy Be a Tool for Surgical Outcome Prediction?

BACKGROUND: Cervical spondylotic myelopathy (CSM) is one of the leading causes of degenerative cervical myelopathy and the most common cause of spinal cord dysfunction in the elderly worldwide. Although there is emerging evidence that most patients improve after surgery, the key clinical and imaging factors predicting outcome remain uncertain. Our purpose is to evaluate preoperative and postoperative morphometric parameters on magnetic resonance imaging and their relation with neurological outcome at discharge and at 12-month follow-up. METHODS: Morphometric features (volume, area, and antero-posterior diameter of the major stenotic section) were acquired by manual segmentation of the spinal canal using OsiriX open-source software and confronted with neurological outcome (at discharge and 12 months after surgery) using Nurick's scale. RESULTS: Fifty-five patients (21 females and 34 males) with a mean age of 64.89 ± 11.95 years were analyzed. Recovery ratio was 2.44% ± 2.40% at discharge and 11.74% ± 2.50% at follow-up. Statistical analysis revealed a significant difference (P < .001) between Nurick's scale at admission versus discharge, at discharge versus follow-up at 1 year, and between admission and follow-up at 1 year. Morphometric changes (difference and ratio) between preoperative and postoperative measurements were also statistically significant (P < .001, paired samples t test). When linear regression was applied, volume difference was shown to have an influence on clinical improvement (P < .05; R = 0.519). Linear regression was also applied using recovery ratio at discharge and follow-up as dependent variables, with the same conclusion: volume difference between preoperative and postoperative measurements correlates with outcome improvement at 1 year after surgery. CONCLUSIONS: Acquisition of morphometric features might be useful in predicting surgical outcome in patients with CSM. This information can be used to inform patients of their long-term postoperative prognosis in the future with more accurate and standardized measurements.

Apolipoprotein E genotype does not influence the risk of symptomatic hemorrhage in acute ischemic stroke.

BACKGROUND: APOE ε4 is independently associated with lobar intracranial hemorrhages (ICH). Although the ε4 allele enhances amyloid deposition in blood vessels, the ε2 allele predisposes to vasculopathic changes leading to rupture of amyloid laden vessels. Thus, ε4 and ε2 carriers might have increased susceptibility to ICH. We aimed to study the impact of the apolipoprotein E alleles in the development of symptomatic ICH (sICH). METHODS: We included 384 consecutive ischemic anterior circulation stroke patients submitted to thrombolysis between January 2014 and March 2016. Admission CT-scans were reviewed to calculate the ASPECTS. Patients were followed for up to at least 6 months post-stroke or until death. Outcome was development of sICH, defined according to the ECASS III. RESULTS: Considering APOE genotyping, three patients had ε2/ε2, four had ε2/ε4, 38 had ε2/ε3, 284 had ε3/ε3, 51 had ε3/ε4 and four had ε4/ε4. sICH was associated with sex and diabetes. In multivariate analysis, sICH was not associated with carrying one or more ε4 alleles (OR: 0.483, 95%CI = [0.059, 3.939], p = 0.497) nor with carrying one or more ε2 alleles (OR: 1.369, 95%CI = [0.278, 6.734], p = 0.699). CONCLUSION: No association was found between APOE genotype and the development of symptomatic intracranial hemorrhage.

SQSTM1 gene as a potential genetic modifier of CADASIL phenotype.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common inherited cerebral small vessel disease and is caused by mutations in the NOTCH3 gene. Interestingly, CADASIL patients present a large phenotypic variability even harboring the same pathogenic variant. We describe two CADASIL siblings with a particularly aggressive clinical phenotype characterized by early-onset stroke, gait disturbances and/or dementia, severe emotional dysregulation, and dysexecutive syndrome together with a severe white matter burden on MRI. The genetic analysis revealed the co-occurrence of NOTCH3 (p.Gly420Cys) and SQSTM1 (p.Ser275Phefs*17) pathogenic variants which might worsen the aggressiveness of disease progression in both siblings. Interestingly, to the best of our knowledge, mutations in SQSTM1 gene have never been described in CADASIL patients before. Curiously, both Notch3 and p62 encoded proteins have a key role in the autophagy-lysosomal pathway which is impaired in CADASIL patients. Thus, the contribution of SQSTM1 gene to the clinical heterogeneity of CADASIL patients, in particular for those who develop cognitive impairment or dementia at an early age, is certainly overlooked. Therefore, we advocate expanding the genetic analysis to other genes associated with the phenotype spectrum of CADASIL patients using NGS-customized gene panel.

Neuroimaging, serum biomarkers, and patient characteristics as predictors of upper limb functioning 12 weeks after acute stroke: an observational, prospective study.

OBJECTIVE: To evaluate the potential of neuroimaging, serum biomarkers, stroke etiology, and clinical characteristics as predictors of upper limb functioning 12 weeks after stroke. METHODS: This was a prospective, observational study of patients (18-85 years-old) hospitalized due to acute ischemic stroke in the territory of the middle cerebral artery. Patients were hospitalized at a stroke rehabilitation center, where they underwent a standardized rehabilitation program. Clinical, imagiology, laboratory (biomarkers: C-reactive protein, D-dimer, and fibrinogen, and S100 calcium binding protein ß [S100ß]), and functionality assessments were conducted four different times: within 24 hours, and at 48 hours, 3 weeks, and 12 weeks after acute stroke. RESULTS: Upper limb functioning at 12 weeks was significantly associated with Alberta Stroke Program Early CT Score (ASPECTS) score (OR:2.012 [CI:1.349-3.000]; P = 0.001) and S100ß protein levels (OR:0.997 [CI:0.994-0.999]; P = 0.007). Advanced age was associated with poor upper limb functioning. S100ß protein levels < 140.5 ng/L at 48 hours and ASPECTS scores ≥ 7.5 within 24 hours of admission predicted good hand functioning at 12 weeks. Upper limb functioning and general functioning were significantly correlated (P < 0.001), with strong negative correlations (all correlation coefficients ≤-0.586) for all comparisons. CONCLUSION: ASPECTS score ≥ 8 within 24 hours and S100ß protein < 140.5 ng/L at 48 hours predict better upper limb functioning, while advanced age predicts worse upper limb functioning 12 weeks after stroke.

Collateral pial circulation relates to the degree of brain edema on CT 24 hours after ischemic stroke.

Background Cerebral edema is frequent in patients with acute ischemic stroke (AIS) who undergo reperfusion therapy and is associated with high mortality. The impact of collateral pial circulation (CPC) status on the development of edema has not yet been determined. Methods We studied consecutive patients with AIS and documented M1-middle cerebral artery (MCA) and/or distal internal carotid artery (ICA) occlusion who underwent reperfusion treatment. Edema was graded on the 24-hour non-contrast computed tomography (NCCT) scan. CPC was evaluated at the acute phase (≤6 hours) by transcranial color-coded Doppler, angiography and/or CT angiography. We performed an ordinal regression model for the effect of CPC on cerebral edema, adjusting for age, baseline National Institutes of Health Stroke Scale, Alberta Stroke Program Early Computed Tomography Score (ASPECTS) on admission, NCCT, parenchymal hemorrhagic transformation at 24 hours and complete recanalization at six hours. Results Among the 108 patients included, 49.1% were male and mean age was 74.2 ± 11.6 years. Multivariable analysis showed a significant association between cerebral edema and CPC status (OR 0.22, 95% CI 0.08-0.59, p = 0.003), initial ASPECTS (OR 0.72, 95% CI 0.57-0.92, p = 0.007) and parenchymal hemorrhagic transformation (OR 23.67, 95% CI 4.56-122.8, p < 0.001). Conclusions Poor CPC is independently associated with greater cerebral edema 24 hours after AIS in patients who undergo reperfusion treatment.

STROKE34 Study Protocol: A Randomized Controlled Phase IIa Trial of Intra-Arterial CD34+ Cells in Acute Ischemic Stroke.

RATIONALE/AIM: Despite the increasing efficacy of recanalization therapies for acute ischemic stroke, a large number of patients are left with long-term functional impairment, devoid of efficacious treatments. CD34+ cells comprise a subset of bone marrow-derived mononuclear cells with the capacity to promote angiogenesis in ischemic lesions and have shown promising results in observational and in vitro studies. In this study, we aim to assess the efficacy of an autotransplant of CD34+ cells in acute ischemic stroke. SAMPLE SIZE ESTIMATES: 30 patients will be randomized for a power of 90% and alpha of 0.05 to detect a difference in 3 months infarct volume. METHODS AND DESIGN: We will screen 18-80 years old patients with acute ischemic stroke due to occlusion of a middle cerebral artery (MCA) for randomization. Persistent arterial occlusions, contra-indications to magnetic resonance imaging (MRI), premorbid dependency, or other severe diseases will be excluded. Treatment will involve bone marrow aspiration, selection of CD34+ cells, and their administration intra-arterially in the symptomatic MCA by angiography. Patients will be randomized for treatment at 7 (±2) days, 20 (±5 days) or sham procedure, 10 in each group. STUDY OUTCOMES: The primary outcome will be infarct volume in MRI performed at 3 months. Secondary outcomes will include adverse events and multidimensional functional and neurological measures. DISCUSSION/CONCLUSION: STROKE34 is a PROBE design phase IIa clinical trial to assess the efficacy of intra-arterial administration of CD34+ cells 7 and 20 days after acute ischemic stroke. TRIAL REGISTRATION EU CLINICAL TRIALS REGISTER: 2017-002456-88.

Brain atrophy and physical disability in primary progressive multiple sclerosis: A volumetric study.

UNLABELLED: Grey matter atrophy has been shown in primary progressive multiple sclerosis (PPMS), but its association with physical incapacity is unclear. We submitted 19 patients with PPMS to a neurological evaluation and brain magnetic resonance imaging (MRI) with volumetric analysis using FreeSurfer. We found no relation between the Expanded Disability Status Scale or disease duration and the grey matter or white matter structures analysed. Lesion load was negatively correlated with cortical and subcortical grey matter volumes, but not with total white matter volume. We concluded that physical disability in PPMS is not directly related to brain atrophy and that focal inflammatory white matter lesions may contribute to progressive neuronal degeneration. INTRODUCTION: Primary progressive multiple sclerosis (PPMS) is characterized by chronic progression since onset, with predominant involvement of the spinal cord and prominent neurodegeneration. Grey matter atrophy has been shown in patients with PPMS, but its association with clinical incapacity is uncertain. We investigated the relationship between regional brain atrophy and physical disability in patients with PPMS. METHODS: Patients with an established diagnosis of PPMS underwent a neurological evaluation followed by brain MRI at 1.5 T. Volumetric analysis was performed with FreeSurfer software, and evaluated the neocortex, total white matter, total subcortical grey matter, putamen, caudate, globus pallidus, thalamus, hippocampus, brainstem, corpus callosum and pre-central gyrus volumes. Clinical data obtained included physical disability as measured by the Expanded Disability Status Scale (EDSS). RESULTS: Nineteen patients were included, 14 female (73.7%), mean age of 55.7 (SD 7.6) and mean disease duration of 13.0 years (SD 8.8). Median EDSS score was 6.0 (3.5-8.0). The average T1 lesion load (4.9 cm³, SD 3.4) and T2 load (10.5 cm³, SD 9.9) did not relate to disease duration. There was no significant correlation between EDSS score or disease duration and the cortical grey matter, deep grey matter or white matter structures analysed. Lesion load was negatively correlated with cortical and subcortical grey matter volumes (p < 0.05), but not with total white matter volume. CONCLUSIONS: Physical disability in PPMS is not directly related to brain volume loss. Grey matter atrophy correlates with lesion load in patients with PPMS, indicating that focal inflammatory white matter lesions may contribute to progressive neuronal degeneration.

Monitoring balloon test occlusion of the internal carotid artery with transcranial Doppler. A case report and literature review.

Angiographic balloon test occlusion (BTO) allows preoperative risk evaluation of patients undergoing permanent therapeutic occlusion of the internal carotid artery (ICA). The sensitivity of the BTO can be increased using different complementary techniques. Transcranial Doppler (TCD) stands out as a non-invasive, bedside method providing real-time monitoring of cerebral haemodynamics, therefore accurately identifying patients at risk of stroke. A case of a 30-year-old woman with a giant intracavernous aneurysm of the left ICA presenting with subacute left VI nerve palsy is described. A pre-operative TCD- and EEG-monitored BTO of the left ICA was performed. The 16.7% drop found in the middle cerebral artery's peak systolic velocity (PSVMCA) predicts clinical and haemodynamic tolerance to the permanent loss of that vessel. This case illustrates the potential of TCD monitoring during temporary BTO of the ICA. It highlights its ability to provide a complete preclinical evaluation of collateralization and autoregulatory adaptation to unilateral ICA occlusion. TCD may also decrease the time of occlusion required for the BTO.