João Sargento-Freitas

Clinical predictors of an optimal response to natalizumab in multiple sclerosis

Despite the high level of effectiveness of natalizumab (NTZ) in the treatment of patients with multiple sclerosis (MS), concerns about its high direct cost and its safety have restricted its use. Our aim was to identify and quantify the clinical factors that predict an optimal response to NTZ. Patients with MS undergoing treatment with NTZ for at least 12 months were classified as optimal responders if, during treatment, they sustained a reduction in their Kurtzke Expanded Disability Status Scale (EDSS) score of 1 point or more or experienced a reduction in annualised relapse rate (ARR) of more than 1. The remaining patients were classified as suboptimal responders and non-responders. Our subject pool included 48 patients. The variables associated with optimal response included: ARR in the previous year of at least 2, an age at first administration of 37.5 years or less, a baseline EDSS score of 4.5 points or less, a disease duration of 9.5 years or less and, in patients with secondary-progressive MS, a progressive-phase duration of 4.5 years or less. The characteristics of the disease at its onset did not affect responsiveness, indicating that patients with highly active disease and low disability are the ideal candidates for NTZ treatment, regardless of previous clinical characteristics.

Cardioembolic stroke in a patient taking Dabigatran Etexilate: the first case report of clinical and pharmacologic resistance.

Dabigatran Etexilate (DE)was the first oral direct thrombin inhibitor approved for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (AF) [1,2]. One of its main advantages relies on predictable pharmacokinetics allowing a fixed dosage for each patient. In fact, although a range of pharmacokinetic response to DE has been demonstrated, up until now no case has been described of clinical and pharmacologic resistance.

POST-NOAC: Portuguese observational study of intracranial hemorrhage on non-vitamin K antagonist oral anticoagulants.

Background There is a lower reported incidence of intracranial hemorrhage with non-vitamin K antagonist oral anticoagulants compared with vitamin K antagonist. However, the functional outcome and mortality of intracranial hemorrhage patients were not assessed. Aims To compare the outcome of vitamin K antagonists- and non-vitamin K antagonist oral anticoagulants-related intracranial hemorrhage. Methods We included consecutive patients with acute non-traumatic intracranial hemorrhage on oral anticoagulation therapy admitted between January 2013 and June 2015 at four university hospitals. Clinical and demographic data were obtained from individual medical records. Intracranial hemorrhage was classified as intracerebral, extra-axial, or multifocal using brain computed tomography. Three-month functional outcome was assessed using the modified Rankin Scale. Results Among 246 patients included, 24 (9.8%) were anticoagulated with a non-vitamin K antagonist oral anticoagulants and 222 (90.2%) with a vitamin K antagonists. Non-vitamin K antagonist oral anticoagulants patients were older (81.5 vs. 76 years, p = 0.048) and had intracerebral hemorrhage more often (83.3% vs. 63.1%, pu2009=u20090.048). We detected a non-significant trend for larger intracerebral hemorrhage volumes in vitamin K antagonists patients (pu2009=u20090.368). Survival analysis adjusted for age, CHA2DS2VASc, HAS-BLED, and anticoagulation reversal revealed that non-vitamin K antagonist oral anticoagulants did not influence three-month mortality (hazard ratio (HR)u2009=u20090.83, 95% confidence interval (CI)u2009=u20090.39–1.80, pu2009=u20090.638). Multivariable ordinal regression for three-month functional outcome did not show a significant shift of modified Rankin Scale scores in non-vitamin K antagonist oral anticoagulants patients (odds ratio (OR) 1.26, 95%CI 0.55–2.87, pu2009=u20090.585). Conclusions We detected no significant differences in the three-month outcome between non-vitamin K antagonist oral anticoagulants- and vitamin K antagonists-associated intracranial hemorrhage, despite unavailability of non-vitamin K antagonist oral anticoagulants-specific reversal agents.

Nocturnal blood pressure dipping in acute ischemic stroke.

We aim to assess the impact of early nocturnal blood pressure (BP) variation in the functional outcome of patients after an acute ischemic stroke.

Different locations but common associations in subcortical hypodensities of presumed vascular origin: cross-sectional study on clinical and neurosonologic correlates.

BackgroundSubcortical hypodensities of presumed vascular etiology (SHPVO) are a clinical, radiological and neuropathological syndrome with a still largely unexplained pathophysiology. Parallel to the clinical heterogeneity, there is also recognised cerebral topographical diversity with undetermined etiological implications. Our aim is to assess clinical and neurosonological predictors of SHPVO according to their location.MethodsCross sectional analysis of consecutive patients that underwent neurosonologic evaluation and head CT within one month, during a one year period. We excluded patients with absent temporal sonographic window, any pathology with a possible confounding effect on cerebral arterial pulsatility, atrial fibrillation and other etiologies of white matter diseases. The mean pulsatility index (PI) of both middle cerebral arteries was measured in the middle third of the M1 segment; intima media thickness was evaluated in the far wall of both common carotid arteries. SHPVO were rated by analysis of head CT in deep white matter (DWMH), periventricular white matter (PVWMH) and basal ganglia (BGH). We conducted a multivariate ordinal logistic regression model including all clinical, demographic and ultrasonographic characteristics to determine independent associations with SHPVO.ResultsWe included 439 patients, mean age 63.47 (SD: 14.94) years, 294 (67.0%) male. The independent predictors of SHPVO were age (ORu2009=u20091.067, 95% CI: 1.047-1.088, pu2009<u20090.001 for DWMH; ORu2009=u20091.068, 95% CI: 1.049-1.088, pu2009<u20090.001 for PVWMH; ORu2009=u20091.05, 95% CI: 1.03-1.071, pu2009<u20090.001 for BGH), hypertension (ORu2009=u20091.909, 95% CI: 1.222-2.981, pu2009=u20090.004 for DWMH; ORu2009=u20091.907, 95% CI: 1.238-2.938, pu2009=u20090.003 for PVWMH; ORu2009=u20091.775, 95% CI: 1.109-2.843, pu2009=u20090.017 for BGH) and PI (ORu2009=u200917.994, 95% CI: 6.875-47.1, pu2009<u20090.001 for DWMH; ORu2009=u20095.739, 95%CI: 2.288-14.397, pu2009<u20090.001 for PVWMH; ORu2009=u200911.844, 95% CI: 4.486-31.268, pu2009<u20090.001 for BGH) for all locations of SHPVO.ConclusionsAge, hypertension and intracranial pulsatility are the main independent predictors of SHPVO across different topographic involvement and irrespective of extracranial atherosclerotic involvement.

Endothelial Progenitor Cells influence acute and subacute stroke hemodynamics

BACKGROUNDnEndothelial Progenitor Cells (EPCs) are a circulating stem cell population with in vivo capacity of promoting angiogenesis after ischemic events. Despite the promising preclinical data, their potential integration with reperfusion therapies and hemodynamic evolution of stroke patients is still unknown. Our aim was to determine the association of EPCs with acute, subacute and chronic hemodynamic features.nnnMETHODSnIn this prospective study, we included consecutive patients with ages between 18 and 80years and non-lacunar ischemic stroke within the territory of a middle cerebral artery. All patients were subject to hemodynamic evaluation by ultrasound at baseline, seven days and three months. We quantified cerebral blood flow (CBF) and assessed early recanalization and collateral flow. Hemorrhagic transformation was graded in Magnetic Resonance imaging performed at seven days. EPCs were isolated from peripheral venous blood collected in the first 24h and seven days, counted and submitted to functional in vitro tests.nnnRESULTSnWe included 45 patients with a median age of 70±10years. The angiogenic and migratory capacities of EPCs were associated with increased collateral flow in the acute stage and day seven CBF, without statistically significant associations with recanalization nor haemorrhagic transformation. The number of EPCs was not associated with any hemodynamic variable.nnnCONCLUSIONSnThe functional properties of EPCs are associated with acute and subacute stroke hemodynamics, with no effect on haemorrhagic transformation.

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

ABSTRACT 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 β [S100β]), 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 S100β protein levels (OR:0.997 [CI:0.994–0.999]; P = 0.007). Advanced age was associated with poor upper limb functioning. S100β 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 S100β 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.

S100β Protein as a Predictor of Poststroke Functional Outcome: A Prospective Study

BACKGROUNDnStroke is one of the leading causes of disability worldwide. Early prediction of poststroke disability using clinical models is of great interest, especially in the rehabilitation field. Although some biomarkers and neuroimaging techniques have shown potential predictive value, there are still insufficient data to support their clinical utility in predicting poststroke functional recovery. We aimed to assess the value of serum biomarkers (C-reactive protein [CRP], D-dimer, fibrinogen, and S100β protein) in predicting medium-term (12 weeks) functional outcome in patients with acute ischemic stroke.nnnMETHODSnThis is an observational, prospective study in a sample of patients hospitalized for ischemic stroke (Nu2009=u2009131). Peripheral blood levels of biomarkers of interest were determined at admission (CRP, D-dimer, and fibrinogen) or at 48 hours poststroke (S100β protein). Functional status was accessed at 48 hours and 12 weeks poststroke using the modified Rankin Scale (mRS).nnnRESULTSnS100β protein levels measured at 48 hours were significantly associated with mRS scores at 12 weeks (odds ratiou2009=u20091.005, 95% confidence interval [CI] [1.005-1.007]; Pu2009<.001). This association was not seen for the remaining biomarkers of interest. The S100β cutoff for poor functionality at 12 weeks was 140.5u2009ng/L or more (sensibility 83.8%; specificity 71.4%; area under the curveu2009=u2009.80, 95% CI [.722, .879]).nnnCONCLUSIONSnS100β levels in peripheral blood at 48 hours poststroke reflect acute stroke severity and predict functional outcome at 12 weeks with a cutoff value of 140.5u2009ng/dL. The value of S100β as predictor of functional recovery after stroke should be emphasized in further clinical research and clinical practice.

Neuroimaging and clinical outcomes of oral anticoagulant-associated intracerebral hemorrhage: NOAC-ICH vs VKA-ICH

Whether intracerebral hemorrhage (ICH) associated with non–vitamin K antagonist oral anticoagulants (NOAC‐ICH) has a better outcome compared to ICH associated with vitamin K antagonists (VKA‐ICH) is uncertain.

Cerebrovascular Dissemination in Time and Space as a Predictor of Cardioembolism

BACKGROUNDnCardioembolism has tendency to recur and cause lesions in distinct cerebrovascular territories. Using the imaging characteristics of cerebral lesions to determine dissemination in time and space (DTS) is a concept already used in other neurologic conditions; however, it has never been applied as a diagnostic tool in ischemic stroke etiology.nnnAIMnThis study aimed to assess DTS as a diagnostic marker of cardioembolism.nnnMETHODSnWe enrolled consecutive patients with acute ischemic stroke of various etiologies admitted in a cerebrovascular disease nursery from a university hospital in a retrospective cohort study. We excluded patients with coexisting etiologies, incomplete study, or without an acute vascular lesion on computed tomography scan. Lacunar infarctions were not considered. Cerebrovascular territory was divided into right anterior, left anterior, and posterior. Localization of the acute vascular lesion(s), existence of previous vascular lesions, and their respective areas were analyzed. The presence of dissemination in time, space, or DTS was determined.nnnRESULTSnWe included 661 patients (mean age: 74.05 years (SD: 13.01)). Cardioembolism was the etiology with most DTS (30.47% of cardioembolic strokes); DT occurred more frequently within the atherosclerotic subtype (9.88%); DS was more prevalent within the arterial dissection group (3.33%). There was a statistically significant difference in stroke etiology between patients with DTS and patients without dissemination (Pu2009<u2009.001). DTS had 81.67% specificity, 30.47% sensitivity, 66.67% positive predictive value, and 49.40% negative predictive value for the identification of cardioembolism.nnnCONCLUSIONnDTS is a specific diagnostic predictor of cardioembolic stroke and may be helpful in guiding etiologic investigation.