Coma in adult cerebral venous thrombosis: The BEAST study.

BACKGROUND AND PURPOSE: Coma is an independent predictor of poor clinical outcomes in cerebral venous thrombosis (CVT). We aimed to describe the association of age, sex, and radiological characteristics of adult coma patients with CVT. METHODS: We used data from the international, multicentre prospective observational BEAST (Biorepository to Establish the Aetiology of Sinovenous Thrombosis) study. Only positively associated variables with coma with <10% missing data in univariate analysis were considered for the multivariate logistic regression model. RESULTS: Of the 596 adult patients with CVT (75.7% women), 53 (8.9%) patients suffered coma. Despite being a female-predominant disease, the prevalence of coma was higher among men than women (13.1% vs. 7.5%, p = 0.04). Transverse sinus thrombosis was least likely to be associated with coma (23.9% vs. 73.3%, p < 0.001). The prevalence of superior sagittal sinus thrombosis was higher among men than women in the coma sample (73.6% vs. 37.5%, p = 0.01). Men were significantly older than women, with a median (interquartile range) age of 51 (38.5-60) versus 40 (33-47) years in the coma (p = 0.04) and 44.5 (34-58) versus 37 (29-48) years in the non-coma sample (p < 0.001), respectively. Furthermore, an age- and superior sagittal sinus-adjusted multivariate logistic regression model found male sex (odds ratio = 1.8, 95% confidence interval [CI] = 1.0-3.4, p = 0.04) to be an independent predictor of coma in CVT, with an area under the receiver operating characteristic curve of 0.61 (95% CI = 0.52-0.68, p = 0.01). CONCLUSIONS: Although CVT is a female-predominant disease, men were older and nearly twice as likely to suffer from coma than women.

Mechanical thrombectomy in young patients with large vessel occlusion-related ischemic stroke: Data from the Italian Registry of Endovascular Treatment in Acute Stroke.

BACKGROUND AND PURPOSE: The weight of outcome predictors in acute ischemic stroke (AIS) patients older than 60 years is not necessarily mirrored in the younger population, posing the question of whether outcome determinants specific for the latter might vary. Very few data are available on predictors of outcome in young AIS patients receiving endovascular treatment (EVT). METHODS: We analyzed data for patients aged between 16 and 55 years from the Italian Registry of Endovascular Treatment in Acute Stroke. We divided our population into patients <45 years old and patients aged between 45 and 55 years. After testing the differences between groups in terms of 90-day modified Rankin Scale (mRS) 0-2, mortality, and symptomatic intracranial hemorrhage, we looked for predictors of poor outcome (mRS 3-6), death, and symptomatic intracerebral hemorrhage in the two groups. RESULTS: A total of 438 patients younger than 45 years and 817 aged 45-55 years were included; 284 (34.8%) patients aged 45-55 years and 112 (25.6%) patients younger than 45 years old showed poor 90-day functional outcome (p = 0.001). Predictors of poor outcome in the older group were baseline National Institutes of Health Stroke Scale (NIHSS; p < 0.001), diabetes (p = 0.027), poor collateral status (p = 0.036), and groin puncture-to-recanalization time (p = 0.010), whereas Thrombolysis in Cerebral Infarction (TICI) 2b-3 had an inverse association (p < 0.001). Predictors of poor outcome in patients younger than 45 years were baseline NIHSS (p < 0.001) and groin puncture-to-recanalization time (p = 0.015), whereas an inverse association was found for baseline Alberta Stroke Program Early CT Score (p = 0.010) and TICI 2b-3 (p < 0.001). CONCLUSIONS: Approximately one third of young adults treated with EVT do not reach a good functional outcome. Fast and successful recanalization, rather than common risk factors, has a major role in determining clinical outcome.

IV thrombolysis plus thrombectomy versus IV thrombolysis alone for minor stroke with anterior circulation large vessel occlusion from the IRETAS and Italian SITS-ISTR cohorts.

INTRODUCTION: The aim of this study was to compare the outcomes of patients treated with intravenous thrombolysis (IVT) <4.5 h after symptom onset plus mechanical thrombectomy (MT) <6 h with those treated with IVT alone <4.5 h for minor stroke (NIHSS ≤5) with large vessel occlusion (LVO) in the anterior circulation. PATIENTS AND METHODS: Patients enrolled in the Italian Registry of Endovascular Treatment in Acute Stroke (IRETAS) and in the Italian centers included in the SITS-ISTR were analyzed. RESULTS: Among the patients with complete data on 24-h ICH type, 236 received IVT plus MT and 382 received IVT alone. IVT plus MT was significantly associated with unfavorable shift on 24-h ICH types (from no ICH to PH-2) (OR, 2.130; 95% CI, 1.173-3.868; p=0.013) and higher rate of PH (OR, 4.363; 95% CI, 1.579-12.055; p=0.005), sICH per ECASS II definition (OR, 5.527; 95% CI, 1.378-22.167; p=0.016), and sICH per NINDS definition (OR, 3.805; 95% CI, 1.310-11.046; p=0.014). Among the patients with complete data on 3-month mRS score, 226 received IVT plus MT and 262 received IVT alone. No significant difference was reported between IVT plus MT and IVT alone on mRS score 0-1 (72.1% versus 69.1%), mRS score 0-2 (79.6% versus 79%), and death (6.2% versus 6.1%). CONCLUSIONS: Compared with IVT alone, IVT plus MT was associated with unfavorable shift on 24-h ICH types and higher rate of 24-h PH and sICH in patients with minor stroke and LVO in the anterior circulation. However, no difference was reported between the groups on 3-month functional outcome measures.

Brain MRI in Monogenic Cerebral Small Vessel Diseases: A Practical Handbook.

Monogenic cerebral small vessel diseases are a topic of growing interest, as several genes responsible have been recently described, and new sequencing techniques such as Next-generation sequencing are available. Brain imaging is significant for the detection of these diseases. Since it is often performed at an initial stage, an MRI is a key to selecting patients for genetic testing and for interpreting nextgeneration sequencing reports. In addition, neuroimaging can be helpful in describing the underlying pathological mechanisms involved in cerebral small vessel disease. In this review, we aim to provide neurologists and stroke physicians with an up-to-date overview of the current neuroimaging knowledge on monogenic small vessel diseases.

Discriminative value of glial fibrillar acidic protein (GFAP) as a diagnostic tool in acute stroke. Individual patient data meta-analysis.

Glial fibrillar acidic protein (GFAP) in serum has been evaluated as a promising biomarker to differentiate between intracerebral hemorrhage (ICH) and acute ischemic stroke (AIS). We assessed its value as diagnostic and prognostic tool for ICH through a literature systematic review and individual patient data (IPD) meta-analysis.We performed a systematic search in PubMed database until November 2018 for publications that evaluated GFAP to differentiate AIS and ICH within 4.5 hours after symptoms onset. Thereafter, we invited authors of selected studies to participate in this work by providing IPD from their cohorts. We used standardized individual subject's data to evaluate the association of GFAP concentrations with stroke subtype, demographics, stroke characteristics and factors related with GFAP measurement.From 4 selected studies, we collected data of 340 patients (236 AIS and 104 ICH). Standardized GFAP blood levels were significantly elevated in ICH compared with those with AIS (median and IQR: 0.84 (0.781-1.24), 0.79 (0.74-0.81); p<0.0001). In both stroke types, GFAP concentrations correlated with baseline stroke severity (r=0.27, p<0.0001; r=0.36, p<0.001; for AIS and ICH, respectively) but no correlation was found regarding time to sampling. Limited data precluded the evaluation of GFAP levels and functional outcome.These findings demonstrate substantially different levels of GFAP in the blood of patients with ICH compared with patients with AIS soon after the event, while no association was found with outcome. In summary, GFAP could be a valuable diagnostic tool to assist in medical decision-making and to optimize management of stroke in the acute setting.

Endovascular Thrombectomy for Acute Ischemic Stroke Beyond 6 Hours From Onset: A Real-World Experience.

BACKGROUND AND PURPOSE: To evaluate outcome and safety of endovascular treatment beyond 6 hours of onset of ischemic stroke due to large vessel occlusion in the anterior circulation, in routine clinical practice. METHODS: From the Italian Registry of Endovascular Thrombectomy, we extracted clinical and outcome data of patients treated for stroke of known onset beyond 6 hours. Additional inclusion criteria were prestroke modified Rankin Scale score ≤2 and ASPECTS score ≥6. Patients were selected on individual basis by a combination of CT perfusion mismatch (difference between total hypoperfusion and infarct core sizes) and CT collateral score. The primary outcome measure was the score on modified Rankin Scale at 90 days. Safety outcomes were 90-day mortality and the occurrence of symptomatic intracranial hemorrhage. Data were compared with those from patients treated within 6 hours. RESULTS: Out of 3057 patients, 327 were treated beyond 6 hours. Their mean age was 66.8±14.9 years, the median baseline National Institutes of Health Stroke Scale 16, and the median onset to groin puncture time 430 minutes. The most frequent site of occlusion was middle cerebral artery (45.1%). Functional independence (90-day modified Rankin Scale score, 0-2) was achieved by 41.3% of cases. Symptomatic intracranial hemorrhage occurred in 6.7% of patients, and 3-month case fatality rate was 17.1%. The probability of surviving with modified Rankin Scale score, 0-2 (odds ratio, 0.58 [95% CI, 0.43-0.77]) was significantly lower in patients treated beyond 6 hours as compared with patients treated earlier No differences were found regarding recanalization rates and safety outcomes between patients treated within and beyond 6 hours. There were no differences in outcome between people treated 6-12 hours from onset (278 patients) and those treated 12 to 24 hours from onset (49 patients). CONCLUSIONS: This real-world study suggests that in patients with large vessel occlusion selected on the basis of CT perfusion and collateral circulation assessment, endovascular treatment beyond 6 hours is feasible and safe with no increase in symptomatic intracranial hemorrhage.

The path to biomarker-based diagnostic criteria for the spectrum of neurodegenerative diseases.

Introduction: The postmortem examination still represents the reference standard for detecting the pathological nature of chronic neurodegenerative diseases (NDD). This approach displays intrinsic conceptual limitations since NDD represent a dynamic spectrum of partially overlapping phenotypes, shared pathomechanistic alterations that often give rise to mixed pathologies.Areas covered: We scrutinized the international clinical diagnostic criteria of NDD and the literature to provide a roadmap toward a biomarker-based classification of the NDD spectrum. A few pathophysiological biomarkers have been established for NDD. These are time-consuming, invasive, and not suitable for preclinical detection. Candidate screening biomarkers are gaining momentum. Blood neurofilament light-chain represents a robust first-line tool to detect neurodegeneration tout court and serum progranulin helps detect genetic frontotemporal dementia. Ultrasensitive assays and retinal scans may identify Aß pathology early, in blood and the eye, respectively. Ultrasound also represents a minimally invasive option to investigate the substantia nigra. Protein misfolding amplification assays may accurately detect α-synuclein in biofluids.Expert opinion: Data-driven strategies using quantitative rather than categorical variables may be more reliable for quantification of contributions from pathophysiological mechanisms and their spatial-temporal evolution. A systems biology approach is suitable to untangle the dynamics triggering loss of proteostasis, driving neurodegeneration and clinical evolution.

Correlation of blood biomarkers with early-onset seizures after an acute stroke event.

INTRODUCTION: Blood biomarkers have not been widely studied in stroke-related seizures. In this study, we aimed to describe clinical factors and biomarkers present during acute stroke and to analyze their association with early-onset seizures. METHODS: We retrospectively evaluated a panel of 14 blood biomarkers in 1115 patients with ischemic and hemorrhagic stroke. Biomarkers were normalized and standardized using Z scores. We also recorded stroke and epilepsy-related variables, including stroke severity (National Institute of Health Stroke Scale [NIHSS] scores), type, and causes, time from onset of stroke to occurrence of early seizures, and type of seizure. Adjusted logistic regression models were built to identify clinical variables and biomarkers independently associated with early seizures. RESULTS: Mean ±â€¯standard deviation (SD) age was 72.3 ±â€¯13.2 years, and 56.8% of the patients were men. Thirty-eight patients (3.9%) developed early seizures with a median time to onset of 1 day (interquartile range (IQR), 0-4). A higher NIHSS score (odds ratio [OR] = 1.046; 95% confidence interval (CI): 1.001-1.094; p = 0.044) and hemorrhagic stroke (OR = 2.133; 95% CI: 1.010-4.504; p = 0.047) were independently associated with a greater risk of early seizures. Independent blood biomarkers predictive of early seizures were lower levels of tumor necrosis factor receptor 1 (TNF-R1) (<0.013) (p = 0.006; OR = 3.334; 95% CI: 1.414-7.864) and higher levels of neural cell adhesion molecule (NCAM) (>0.326) (p = 0.009; OR = 2.625; 95% CI: 1.271-5.420). The predictive power of the regression model was greater when clinical variables were combined with blood biomarkers (73.5%; 95% CI: 65.1%-81.9%) than when used alone (64%; 95% CI: 55%-72.9%). CONCLUSION: Higher NCAM and lower TNF-R1 levels may help predict the occurrence of early seizures. The combined use of these biomarkers and clinical variables could be useful for identifying patients at risk of seizures. This article is part of the Special Issue "Seizures & Stroke".

Hemispheric language organization after congenital left brain lesions: A comparison between functional transcranial Doppler and functional MRI.

This study investigated whether functional transcranial Doppler ultrasound (fTCD) is a suitable tool for studying hemispheric lateralization of language in patients with pre-perinatal left hemisphere (LH) lesions and right hemiparesis. Eighteen left-hemisphere-damaged children and young adults and 18 healthy controls were assessed by fTCD and fMRI to evaluate hemispheric activation during two language tasks: a fTCD animation description task and a fMRI covert rhyme generation task. Lateralization indices (LIs), measured by the two methods, differed significantly between the two groups, for a clear LH dominance in healthy participants and a prevalent activation of right hemisphere in more than 80% of brain-damaged patients. Distribution of participants in terms of left, right, and bilateral lateralization was highly concordant between fTCD and fMRI values. Moreover, right hemisphere language dominance in patients with left hemispheric lesions was significantly associated with severity of cortical and subcortical damage in LH. This study suggests that fTCD is an easily applicable tool that might be a valid alternative to fMRI for large-scale studies of patients with congenital brain lesions.

Functional magnetic resonance imaging with encoding task in patients with mild cognitive impairment and different severity of leukoaraiosis.

Leukoaraiosis is one of the main contributors to mild cognitive impairment due to vascular damage (vascular MCI, VMCI), whose pathophysiology has not been fully elucidated yet. We aimed to shed light on such issue using functional MRI (fMRI). Sixteen patients with VMCI were enrolled and compared with twenty-five patients with MCI but without significant vascular damage (non-vascular MCI, NVMCI) and with fifteen healthy controls (HC). They all underwent fMRI with incidental verbal learning paradigm, using a 3T scanner. Differently from cases with NVMCI (versus HC), VMCI patients presented a higher BOLD activation in the right parieto-occipital cortex and a lower activation in the left superior and middle frontal gyri, anterior cingulum and in left fronto-opercular area when compared to HC. Cortical activation evaluated by fMRI may reflect specific patterns of damage and attempt of compensation in patients with MCI and different severity of leukoaraiosis.

Aging with Cerebral Small Vessel Disease and Dizziness: The Importance of Undiagnosed Peripheral Vestibular Disorders.

Recent studies showed a link between cerebral small vessel white matter disease (SVD) and dizziness: patients whose dizziness cannot be explained by vestibular disease show severe SVD and gait abnormalities; however, little is still known about how SVD can cause this symptom. The primary aim of this study is to examine the possible underlying causes of dizziness in neurovascular patients; this is in order to assess whether treatable causes could be routinely disregarded. A secondary aim is to possibly define a central oculomotor pattern induced per se by SVD. This could help the diagnosis of SVD-related dizziness. In this single-blind prospective study, 60 patients referred to a neurovascular clinic because of dizziness and SVD on imaging were divided into an L-SVD and a H-SVD group (low and high SVD burden, respectively), and then blindly examined with vestibulometric tests. In H-SVD group, the percentage of unexplained dizziness reached 82.8%. There was a higher prevalence of peripheral vestibular abnormalities in the L-SVD patient group (51.6%) than in the H-SVD (17.2%; p = 0.012). We found no differences in central oculomotor findings between the two groups. Although oculomotricity does not show any consistent pattern, a severe SVD can directly represent a cause of dizziness. However, a patient with mild SVD is more likely to suffer by a peripheral vestibular disorder. Therefore, given the high incidence of vestibular disease in neurovascular or geriatric clinics, clinicians should be cautious when ascribing dizziness solely to the presence of SVD as easily treatable peripheral vestibular causes may be missed.

Genetics of ischaemic stroke in young adults.

BACKGROUND: Stroke may be a clinical expression of several inherited disorders in humans. Recognition of the underlined genetic disorders causing stroke is important for a correct diagnosis, for genetic counselling and, even if rarely, for a correct therapeutic management. Moreover, the genetics of complex diseases such the stroke, in which multiple genes interact with environmental risk factors to increase risk, has been revolutionized by the Genome-Wide Association Study (GWAS) approach. SCOPE OF REVIEW: Here we review the single-gene causes of ischemic stroke, bringing the reader from the candidate gene method toward the exciting new horizons of genetic technology. MAJOR CONCLUSIONS: The aetiological diagnosis of ischemic stroke in young adults is more complex than in the elderly. The identification of a genetic cause is important to provide appropriate counseling and to start a correct therapy, when available. The advent of GWAS technology, such as for other complex pathological conditions, has contributed enormously to the understanding of many of these genetic bases. For success large, well phenotyped case cohorts are required, and international collaborations are essential. GENERAL SIGNIFICANCE: This review focuses on the main causes of genetically-based ischemic stroke in young adults, often classified as indeterminate, investigating also the recent findings of the GWAS, in order to improve diagnostic and therapeutic management.

"Cardioembolic profile" in patients with ischemic stroke: data from the analysis of 1037 cases.

BACKGROUND: Basing on easily available clinical and instrumental data, we aimed to define an "atrial fibrillation profile" able to discriminate cases of stroke due to atrial fibrillation from cases due to atherothrombosis of large vessels or small-vessel disease. METHODS: A total of 1037 consecutive patients with ischemic stroke were enrolled. Cases with undetermined stroke, rare causes, and cardioembolic sources of emboli other than atrial fibrillation were excluded from further analysis. Thus, 653 patients were evaluated, dividing them into 2 groups for comparison (164 with stroke due to atrial fibrillation and 489 with atherothrombotic/lacunar stroke). Clinical, echocardiography, and neuroradiologic data were considered to characterize such groups. RESULTS: Atrial fibrillation and atherothrombotic-lacunar group presented a differential phenotypic profile. Binary multiple logistic regression identified age older than 75 years, female sex, left atrial dilation, cortical-subcortical cerebral index infarct, ischemic lesions in multiple vascular grounds, and spontaneous hemorrhagic transformation of brain infarction as significant predictors of cardioembolic stroke due to atrial fibrillation. CONCLUSIONS: A simple profile, based on commonly available data, seems suitable to characterize patients with stroke due to atrial fibrillation. If further validated, it may be useful to identify patients with undetermined stroke (or other well-defined causes of stroke) at high risk of being affected by undetected subclinical paroxysmal atrial fibrillation, prompting further diagnostic work-up and with potential therapeutic implication.

Cerebral sinus venous thrombosis: clinical and pathogenetic perspectives from Tuscany.

Cerebral sinus venous thrombosis (CSVT) is a rare condition representing the 0.5-1% of all stroke cases which can have serious consequences. Early diagnosis and complete screening for acquired or inherited risk factors is crucial for decreasing morbidity and mortality. We have investigated clinical and aetiological factors in an Italian cohort of 43 patients with cerebral sinus venous thrombosis. Common presentation complaints were headache (81.4%), focal signs (20.9%), vomiting (11.6%) and seizures (6.9%). Acquired or inherited conditions were observed in more than 80% of cases. The commonest aetiological factors were contraceptives (74.1% of women), congenital thrombophilia (34.9%), infections and dysthyroidism (16.3%), hyperhomocysteinemia (9.3%), migraine (11.6%), cranial trauma (9.3%) and chronic myeloproliferative diseases (11.6%). Outcome was favourable in more than 80% of patients. Early diagnosis and anticoagulant treatment may decrease mortality and/or morbidity rates related with CVST in these patients. Thrombophilic abnormalities, either inherited or acquired, are worthy to be widely investigated.

Cerebral lateralization for language in deaf children with cochlear implantation.

Functional Transcranial Doppler ultrasonography (fTCD) was used to investigate the effects of early acoustic deprivation and subsequent reafferentation on cerebral dominance for language in deaf children provided with Cochlear Implantation (CI). Twenty children with CI (13 in right ear and 7 in left ear) and 20 controls matched for age, sex and handedness were administered a fTCD animation description task. Left hemisphere dominance for language with comparable mean Laterality Indexes (LIs) was found in children with CI and controls; right-ear implanted subjects showed cerebral activation controlateral to implanted ear more frequently than left-ear implanted ones. Linguistic proficiency of CI recipients was below age expectation in comparison to controls; language scores did not significantly differ between children with left and right LI, whereas both age and side of implantation were significantly related to language outcome. Theoretical implication and potential clinical application of fTCD in CI management are discussed.

Transient ischemic attack in hereditary hemorrhagic telangiectasia.

Transient ischemic attack or ischemic stroke in hereditary hemorrhagic telangiectasia (HHT), a rare genetic disease, is frequent in clinical practice and often associated to pulmonary arteriovenous malformations (PAVMs), potentially determining paradoxical cerebral embolism. We describe the case of a 53-year-old woman with a previous history of recurrent epistaxis, admitted to our unit for a transient episode of diplopia and unbalance. Cerebrovascular screening showed the presence of a right to left shunt at saline contrast transcranial Doppler, related to 3 PAVMs detected by subsequent chest computed tomographic scan. Genetic screening evidenced deletion in endoglin gene (ENG), suggesting diagnosis of HHT type 1. Secondary cerebrovascular prevention with antithrombotic therapy was early stopped for the worsening of epistaxis. Neurologic symptoms are common in HHT, and saline contrast transcranial Doppler can be a reliable alternative to echocardiography for detection of right to left shunt commonly related to underlying PAVMs.

Periprocedural outcome for patients with carotid stenosis treated with endovascular therapy: a single center evaluation.

Endovascular procedures are a less invasive revascularization strategies than endoarterectomy for carotid stenosis, but to date Guidelines recommend surgery for a major periprocedural safety. Evidences come from randomized studies where operator's experience in endovascular group was not considered. We retrospectively evaluated 524 endovascular procedures (carotid angioplasty ± stenting, CAS) performed between 1996 and 2010 on 486 patients (mean age 71.3 ± 7.8 years) with symptomatic or asymptomatic carotid stenosis from a single center. We evaluated efficacy (residual stenosis ≤30 % after postprocedural angiography) and safety [minor (TIAs or myocardial infarcts) and major (stroke or death) complications in the first 30 days] of procedures and correlated them with the increasing experience of the operator. CAS was successful in 504/524 cases (96.2 %); unsuccessful procedures occurred more frequently in case of angioplasty alone rather than angioplasty and stenting (13/61, 21.3 % vs. 7/463, 1.5 %, OR 17.64, 95 % CI 6.69-46.06). 17/524 (3.2 %) CAS met the combined safety endpoint: stroke in 2.4 % and death in 0.8 %; the rate of disabling stroke/death was 1.6 %. Center experience was inversely related to the rate of stroke/death (R (2) = 0.9375), passing from 5.0 % after 100 CAS to 2.8 % after 500 CAS; for disabling stroke/death (R(2) = 0.9386), the rate was 4 % after 100 CAS and 1.6 % after 500 CAS. CAS is an effective and safe revascularization procedure in both symptomatic and asymptomatic patients, if effected in experienced centers. The use of carotid artery stenting than angioplasty alone and emboli protection devices can much more improve the previous considerations.