Fibrinogen Depletion Coagulopathy Predicts Major Bleeding After Thrombolysis for Ischemic Stroke: A Multicenter Study.

BACKGROUND: Symptomatic intracerebral hemorrhage (sICH) and major bleeding can be fatal complications of intravenous thrombolysis (IVT) for acute ischemic stroke. We investigated the impact of early fibrinogen depletion after IVT on major bleeding events. METHODS: This multicenter observational prospective cohort study enrolled 1678 consecutive patients receiving IVT for acute ischemic stroke at 6 Italian centers, undergoing fibrinogen concentration assessment at baseline, 2 hours and 6 hours after IVT. Fibrinogen depletion was defined as a reduction below 200 mg/dL after 2 hours from IVT, or as a reduction below 50% of baseline fibrinogen levels after 2 hours from IVT. Main outcomes were (1) sICH (National Institute of Neurological Disorders and Stroke criteria) and (2) major bleeding defined as fatal bleeding, decrease in the hemoglobin level>2 g/dL/>1 unit transfusion, or bleeding at critical site. Additional outcomes were (1) any ICH, (2) any bleeding, (3) fatal ICH, and (4) sICH according to ECASSII definition. Good functional recovery was defined as modified Rankin Scale score 0 to 2 at 3 months. RESULTS: Overall, 1678 patients were included (mean age 72 years, 46% female). sICH (n=116) and major bleeding (n=297) were associated with lower rate of good functional recovery (P<0.001). Despite similar fibrinogen levels at admission, fibrinogen depletion after 2 hours from IVT was more common in people with sICH, major bleeding and all additional bleeding outcomes. In the backward stepwise multivariable logistic regression model, fibrinogen depletion remained a significant predictor of sICH (OR, 1.55 [95% CI, 1.04-2.32]) and major bleeding (OR, 1.36 [95% CI, 1.03-1.8]). Thirty-one percent of sICH could be attributable to fibrinogen depletion. The association between fibrinogen depletion and worse clinical outcome at 3 months after stroke (P=0.012) was attributable to the higher risk of major bleeding/sICH. CONCLUSIONS: Fibrinogen depletion significantly increases the risk of sICH and major bleeding after IVT for acute ischemic stroke. Fibrinogen depletion represents an independent risk factor for bleeding, and routine assessment could be considered to stratify the risk of ICH. Trials on early fibrinogen repletion are needed to investigate mitigation of bleeding risk.

Intravenous Thrombolysis in Patients With Ischemic Stroke Aged ≥90 Years: A Cohort Study From the TRISP Collaboration.

BACKGROUND: The probability to receive intravenous thrombolysis (IVT) for treatment of acute ischemic stroke declines with increasing age and is consequently the lowest in very elderly patients. Safety concerns likely influence individual IVT treatment decisions. Using data from a large IVT registry, we aimed to provide more evidence on safety of IVT in the very elderly. METHODS: In this prospective multicenter study from the TRISP (Thrombolysis in Ischemic Stroke Patients) registry, we compared patients ≥90 years with those <90 years using symptomatic intracranial hemorrhage (ECASS [European Cooperative Acute Stroke Study]-II criteria), death, and poor functional outcome in survivors (modified Rankin Scale score 3-5 for patients with prestroke modified Rankin Scale score ≤2 and modified Rankin Scale score 4-5 for patients prestroke modified Rankin Scale ≥3) at 3 months as outcomes. We calculated adjusted odds ratio with 95% CI using logistic regression models. RESULTS: Of 16 974 eligible patients, 976 (5.7%) were ≥90 years. Patients ≥90 years had higher median National Institutes of Health Stroke Scale on admission (12 versus 8) and were more often dependent prior to the index stroke (prestroke modified Rankin Scale score of ≥3; 45.2% versus 7.4%). Occurrence of symptomatic intracranial hemorrhage (5.7% versus 4.4%, odds ratioadjusted 1.14 [0.83-1.57]) did not differ significantly between both groups. However, the probability of death (odds ratioadjusted 3.77 [3.14-4.53]) and poor functional outcome (odds ratioadjusted 2.63 [2.13-3.25]) was higher in patients aged ≥90 years. Results for the sample of centenarians (n=21) were similar. CONCLUSIONS: The probability of symptomatic intracranial hemorrhage after IVT in very elderly patients with stroke did not exceed that of their younger counterparts. The higher probability of death and poor functional outcome during follow-up in the very elderly seems not to be related to IVT treatment. Very high age itself should not be a reason to withhold IVT.

In-hospital and out-of-hospital stroke in patients with COVID-19: two different diseases?

BACKGROUND: Ischemic stroke is a known complication of COVID-19. It may have a different pathogenesis and worse outcome compared to stroke in patients without COVID-19. Furthermore, patients with COVID-19 and out-of-hospital stroke onset might have different characteristics compared to patients with COVID-19 and in-hospital stroke onset. The aim of our study was to analyze the characteristics of patients with stroke with and without COVID-19 and of patients with COVID-19 with in-hospital and out-of-hospital stroke. METHODS: We performed a retrospective study of all consecutive patients admitted to our hospital with ischemic stroke between October 2020 and February 2021. We compared functional outcome, lab test, demographic, and clinical characteristics between patients with or without COVID-19. We performed a sub-analysis comparing patients with COVID-19 and in-hospital and out-of-hospital stroke onset. RESULTS: We included in the final analysis 137 patients of whom 26 with COVID-19. Half (13) had out-of-hospital stroke and half in-hospital stroke onset. Overall, patients with COVID-19 had higher mortality compared to the control group (27% vs 9%, p: 0.02), and non-significantly lower rate of good functional outcome (50% vs 63%, p: 0.22). Patients with COVID-19 and out-of-hospital stroke had higher rate of good functional outcome (69% vs 39%, p: 0.05), higher lymphocyte count, and lower D-dimer compared with patients with in-hospital stroke onset. CONCLUSIONS: Patients with stroke and COVID-19 had higher mortality compared to patients without COVID-19. Among patients with COVID-19 those with out-of-hospital stroke had better outcome and fewer blood test abnormalities compared to patients with in-hospital stroke.

Evaluation of stroke prognostication using age and NIH Stroke Scale index (SPAN-100 index) in delayed intravenous thrombolysis patients (beyond 4.5 hours).

OBJECTIVES: the efficacy of delayed intravenous tissue plasminogen activator (tPA), beyond the 4.5 h window, is evolving. Advanced age and high admission National Institutes of Health Stroke Scale (NIHSS) score are proposed to adversely affect the outcome of delayed thrombolysis and limit the inclusion criteria. The summation of patient age and admission NIHSS score was introduced as the SPAN-100 index as a tool of prediction of the clinical outcome after acute ischemic stroke (AIS). We aimed to assess the SPAN-100 index in AIS thrombolysed patients after 4.5 h. MATERIALS AND METHODS: The SPAN-100 index was applied to AIS patients receiving delayed IV thrombolysis (IVT) after 4.5 h. Patients demographics, risk factors, clinical, laboratory and radiological data, mismatch evidence, treatment onset and modality, NIHSS score at baseline and at discharge, and 3 months follow-up modified Rankin Scale (mRS) were reviewed. SPAN-100 score ≥ 100 is classified as SPAN-100 positive while score < 100 is SPAN-100 negative. Clinical outcomes, death and intracerebral hemorrhage (ICH) incidences were compared between SPAN-100 positive and negative groups. RESULTS: SPAN-100-positive delayed IVT-patients (11/136) had a 6-fold increased risk for unfavorable outcome compared to SPAN-negative patients (OR 6.34; 95% CI 1.59-25.24 p=0.004), however there was no relation between the SPAN-100 positivity and mortality or ICH. CONCLUSION: SPAN-100-positive patients are more likely to achieve non-favorable outcome with delayed IVT in comparison to the SPAN-100-negative patients. SPAN-100 index may influence the eligibility criteria of delayed thrombolysis.

Platelet Function Monitoring Performed after Carotid Stenting during Endovascular Stroke Treatment Predicts Outcome.

OBJECTIVES: Many studies showed that platelet reactivity testing can predict ischemic events after carotid stenting or ischemic stroke. The aim of our study was to assess the role of early platelet function monitoring in predicting 90-days functional outcome, stent thrombosis and hemorrhagic transformation in patients with ischemic stroke treated with endovascular procedures requiring emergent extracranial stenting. MATERIALS AND METHODS: We performed a retrospective study on consecutive patients with acute anterior circulation stroke admitted to our hospital between January 2015 and March 2020, in whom platelet reactivity testing was performed within 10 days from stenting. Patients were divided according to validated cutoffs in acetylsalicylic acid and Clopidogrel responders and not responders. Group comparison and regression analyses were performed to identify differences between groups and outcome predictors. RESULTS: We included in the final analysis 54 patients. Acetylsalicylic acid resistance was an independent predictor of poor 90 days outcome (OR for modified Rankin scale (mRS) ≤ 2: 0.10 95% CI: 0.02 - 0.69) whereas Clopidogrel resistance was an independent predictor of good outcome (OR for mRS ≤ 2: 7.09 95%CI: 1.33 - 37.72). Acetylsalicylic acid resistance was also associated with increased 90-days mortality (OR: 18.42; 95% CI: 1.67 - 203.14). CONCLUSION: We found a significant association between resistance to acetylsalicylic acid and poor 90-days functional outcome and between resistance to Clopidogrel and good 90-days functional outcome. If confirmed, our results might improve pharmacological management after acute carotid stenting.

Middle cerebral artery ischemic stroke and COVID-19: a case report.

We present a clinical case of a patient with SARS-CoV-2 infection and respiratory symptoms, complicated with a pro-thrombotic state involving multiple vascular territories and concomitant interleukin-6 increase. This case underlines the possibility to develop a COVID-19-related coagulopathy.

The Relation Between Aortic Arch Branching Types and the Laterality of Cardio-Embolic Stroke.

BACKGROUND AND PURPOSE: The trajectory of cardiogenic emboli could be affected by anatomical and flow characteristics of the aortic arch. We aimed to study the relation between the different aortic arch patterns and the laterality of cardiogenic emboli. METHODS: 192 cardioembolic strokes were classified into 3 groups according to the type of the aortic arch; type 1 (n = 69), type 2 (n = 49), type 3 (n = 74). The side and site of the cerebral vessels occlusion were divided into anterior and posterior circulation strokes, and anterior strokes were further subdivided into right or left internal carotid, middle or anterior cerebral arteries occlusion. RESULTS: Overall, the anterior circulation embolic occlusions were more common than the posterior, and middle cerebral artery more commonly affected than internal carotid artery. The left side propensity was higher either in the total patients' pool or after segregation into atrial fibrillation (AF) and non AF cardio-embolic cases in all types of aortic arch except for type 1 aortic arch in the non AF cases. This propensity tended to get higher with advancement of the aortic arch types but failed to show statistically significant difference between the 3 arch types, however combination of type 2 and 3 arches into a single group showed statistically significant rise in the left side propensity in the total cardioembolic cases (P = 0.039) and in the non AF cardioembolic cases (P = 0.029). The bovine arch also showed increased left side propensity. CONCLUSION: Cardioemboli tends to have left anterior cerebrovascular predilection especially with AF. Different geometrical patterns of aortic arch branching seem to affect the laterality of cardioemboli and increase its left side predilection.

Vascular Remodeling in Moyamoya Angiopathy: From Peripheral Blood Mononuclear Cells to Endothelial Cells.

The pathophysiological mechanisms of Moyamoya angiopathy (MA), which is a rare cerebrovascular condition characterized by recurrent ischemic/hemorrhagic strokes, are still largely unknown. An imbalance of vasculogenic/angiogenic mechanisms has been proposed as one possible disease aspect. Circulating endothelial progenitor cells (cEPCs) have been hypothesized to contribute to vascular remodeling of MA, but it remains unclear whether they might be considered a disease effect or have a role in disease pathogenesis. The aim of the present study was to provide a morphological, phenotypical, and functional characterization of the cEPCs from MA patients to uncover their role in the disease pathophysiology. cEPCs were identified from whole blood as CD45dimCD34+CD133+ mononuclear cells. Morphological, biochemical, and functional assays were performed to characterize cEPCs. A significant reduced level of cEPCs was found in blood samples collected from a homogeneous group of adult (mean age 46.86 ± 11.7; 86.36% females), Caucasian, non-operated MA patients with respect to healthy donors (HD; p = 0.032). Since no difference in cEPC characteristics and functionality was observed between MA patients and HD, a defective recruitment mechanism could be involved in the disease pathophysiology. Collectively, our results suggest that cEPC level more than endothelial progenitor cell (EPC) functionality seems to be a potential marker of MA. The validation of our results on a larger population and the correlation with clinical data as well as the use of more complex cellular model could help our understanding of EPC role in MA pathophysiology.

GEN-O-MA project: an Italian network studying clinical course and pathogenic pathways of moyamoya disease-study protocol and preliminary results.

BACKGROUND: GENetics of mOyaMoyA (GEN-O-MA) project is a multicenter observational study implemented in Italy aimed at creating a network of centers involved in moyamoya angiopathy (MA) care and research and at collecting a large series and bio-repository of MA patients, finally aimed at describing the disease phenotype and clinical course as well as at identifying biological or cellular markers for disease progression. The present paper resumes the most important study methodological issues and preliminary results. METHODS: Nineteen centers are participating to the study. Patients with both bilateral and unilateral radiologically defined MA are included in the study. For each patient, detailed demographic and clinical as well as neuroimaging data are being collected. When available, biological samples (blood, DNA, CSF, middle cerebral artery samples) are being also collected for biological and cellular studies. RESULTS: Ninety-eight patients (age of onset mean ± SD 35.5 ± 19.6 years; 68.4% females) have been collected so far. 65.3% of patients presented ischemic (50%) and haemorrhagic (15.3%) stroke. A higher female predominance concomitantly with a similar age of onset and clinical features to what was reported in previous studies on Western patients has been confirmed. CONCLUSION: An accurate and detailed clinical and neuroimaging classification represents the best strategy to provide the characterization of the disease phenotype and clinical course. The collection of a large number of biological samples will permit the identification of biological markers and genetic factors associated with the disease susceptibility in Italy.

Usefulness of Thromboelastography in the Detection and Management of Tissue Plasminogen Activator-Associated Hyperfibrinolysis.

Rotation thromboelastometry is a viscoelastometric method that provides a rapid assessment of a patient's hemostatic processes in emergency settings, allowing prompt identification of specific coagulation abnormalities. Its results thus might guide targeted replacement therapy in hemorrhagic conditions, in case of platelet or coagulation factor deficiency, or hyperfibrinolysis, which is difficult to identify otherwise. Although currently used in emergency and traumatic surgery, there are limited data about thromboelastometry in ischemic stroke, particularly in monitoring the coagulative response to recombinant tissue plasminogen activator after intravenous thrombolysis (IVT). Here we report a case of ischemic stroke complicated by a remote asymptomatic intracranial hemorrhage after IVT and additional endovascular therapy that has been successfully treated with intravenous infusion of tranexamic acid after the detection of the status of hyperfibrinolysis provided by thromboelastometry. Further studies are needed to provide the potential usefulness of thromboelastometry and tranexamic acid in ischemic stroke complicated by intracranial bleeding.

Platelet Function Testing in Patients with Acute Ischemic Stroke: An Observational Study.

BACKGROUND: The measurement of platelet reactivity in patients with stroke undergoing antiplatelet therapies is not commonly performed in clinical practice. We assessed the prevalence of therapy responsiveness in patients with stroke and further investigated differences between patients on prevention therapy at stroke onset and patients naive to antiplatelet medications. We also sought differences in responsiveness between etiological subtypes and correlations between Clopidogrel responsiveness and genetic polymorphisms. METHODS: A total of 624 stroke patients on antiplatelet therapy were included. Two different groups were identified: "non-naive patients", and "naive patients". Platelet function was measured with multiple electrode aggregometry, and genotyping assays were used to determine CYP2C19 polymorphisms. RESULTS: Aspirin (ASA) responsiveness was significantly more frequent in naive patients compared with non-naive patients (94.9% versus 82.6%, P < .0010). A better responsiveness to ASA compared with Clopidogrel or combination therapy was found in the entire population (P < .0010), in non-naive patients (P < .0253), and in naive patients (P < .0010). Multivariate analysis revealed a strong effect of Clopidogrel as a possible "risk factor" for unresponsiveness (odds ratio 3.652, P < .0001). No difference between etiological subgroups and no correlations between responsiveness and CYP2C19 polymorphisms were found. CONCLUSION: In our opinion, platelet function testing could be potentially useful in monitoring the biological effect of antiplatelet agents. A substantial proportion of patients with stroke on ASA were "resistant", and the treatment with Clopidogrel was accompanied by even higher rates of unresponsiveness. Longitudinal studies are needed to assess whether aggregometry might supply individualized prognostic information and whether it can be considered a valid tool for future prevention strategies.

Risk Profile of Symptomatic Lacunar Stroke Versus Nonlobar Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: Although lacunar stroke (LS) and deep intracerebral hemorrhage (dICH) represent acute manifestations of the same pathological process involving cerebral small vessels (small vessel disease), it remains unclear what factors predispose to one phenotype rather than the other at individual level. METHODS: Consecutive patients with either acute symptomatic LS or dICH were prospectively enrolled as part of a multicenter Italian study. We compared the risk factor profile of the 2 subgroups using multivariable logistic regression. RESULTS: During a time course of 9.5 years, 1931 subjects (1434 LS and 497 dICH; mean age, 71.3±13.3 years; males, 55.5%) qualified for the analysis. Current smoking was associated with LS (odds ratio [OR], 2.17; P<0.001). Conversely, dICH cases were more likely to be hypertensive (OR, 1.87; P<0.001), excessive alcohol consumers (OR, 1.70; P=0.001), and more frequently under treatment with warfarin (OR, 2.05; P=0.010) and statins (OR, 3.10; P<0.001). Hypercholesterolemia, diabetes mellitus, and antiplatelet treatment were not associated with a specific small vessel disease manifestation. CONCLUSIONS: The risk factor profile of dICH differs from that associated with LS. This might be used for disease risk stratification at individual level.

"Opening the Unopenable": Endovascular Treatment in a Patient with Three Months' Internal Carotid Artery Occlusion and Hemispheric Symptomatic Hypoperfusion.

BACKGROUND: Internal carotid artery occlusion (ICAO) is defined as "untouchable" by all specialists; no treatment is indicated because intervention risks (carotid endarterectomy (CEA) or endovascular treatment) are usually much more than benefits.(1,2) We report the case of a patient admitted to our hospital with an atherothrombotic ischemic stroke due to symptomatic acute ICAO, who developed a recurrent stroke with hemispheric hypoperfusion and was treated in the emergency department with ICAO revascularization after 60 days of occlusion finding. CASE DESCRIPTION: D.G., a 62-year-old man, came to our attention for a transient episode of left weakness and hypoesthesia. The electrocardiogram revealed a new diagnosis of atrial fibrillation. CT angiography showed right ICAO; computed tomography and magnetic resonance imaging studies with perfusion imaging revealed a severe hemispheric hypoperfusion. Full anticoagulation therapy was started, and antihypertensive therapy was reduced to help collateral circulation. Some weeks later, the patient was readmitted to the stroke unit for 2 episodes of left-hand weakness. Cerebral angiography confirmed right ICAO from the proximal tract to the siphon. After some days, the patient suffered a femoral hemorrhagic lesion, with active bleeding, and was treated with surgical intervention. On the following day, the patient presented with left hemiplegia with hemianesthesia (National Institutes of Health Stroke Scale score = 14). The patient was treated in the emergency department with a complex endovascular treatment with complete recanalization of ICAO by positioning 3 stents through the intravenous infusion of abciximab. After intensive rehabilitation, at the 3- and 6-month follow-up evaluations, the patient regained autonomy. CONCLUSION: In literature, treatment of chronic ICAO is not indicated. Endovascular recanalization may be beneficial to patients with chronic cerebral hypoperfusion due to ICAO, when all conservative medical therapies have failed.

The role of automated computed topography perfusion in prediction of hemorrhagic transformation after acute ischemic stroke.

INTRODUCTION: The role of computed tomography perfusion (CTP) in prediction of hemorrhagic transformation (HT) has been evolving. We aimed to study the role of automated perfusion post-processing software in prediction of HT using the commercially available RAPID software. METHODS: Two hundred eighty-two patients with anterior circulation ischemic stroke, who underwent CTP with RAPID automated post-processing, were retrospectively enrolled and divided into HT (n = 91) and non-HT groups (n = 191). The automated RAPID-generated perfusion maps were reviewed. Mismatch volume and ratio, time to maximum (Tmax) > 4-10s volumes, hypoperfusion index, cerebral blood flow (CBF) < 20-38% volumes, cerebral blood volume (CBV) < 34%-42% volumes, and CBV index were recorded and analyzed. RESULTS: The volumes of brain tissues suffering from reduction of cerebral blood flow (CBF < 20%-38%), reduction in cerebral blood volumes (CBV < 34-42%), and delayed contrast arrival times (Tmax > 4-10s) were significantly higher in the HT group. The mismatch volumes were also higher in the HT group (p = .001). Among these parameters, the Tmax > 6s volume was the most reliable and sensitive predictor of HT (p = .001, AUC = 0.667). However, the combination of the perfusion parameters can slightly improve the diagnostic efficiency (AUC = 0.703). There was no statistically significant difference between the non-HT group and either the parenchymal or the symptomatic subtypes. CONCLUSION: The RAPID automated CTP parameters can provide a reliable predictor of HT overall but not the parenchymal or the symptomatic subtypes. The infarct area involving the penumbra and core represented by the Tmax > 6s threshold is the most sensitive predictor; however, the combination of the perfusion parameters can slightly improve the diagnostic efficiency.

Proposal of multimodal computed tomography-based scoring system in prediction of hemorrhagic transformation in acute ischemic stroke.

INTRODUCTION: The routinely used computed tomography (CT)-based workup in the setting of acute ischemic stroke (AIS) includes non-contrast brain CT, CT angiography (CTA), and CT perfusion. Several CT, CTA, CTP-based radiological biomarkers of hemorrhagic transformation (HT) were reported. AIM OF THE STUDY: To assess the predictive value of the combined multimodal CT parameters for HT after AIS and proposal of predictive scoring scale. METHODS: The source images of the NCCT, CTA and CTP of 282 AIS patients involving the anterior circulation (HT = 91, non-HT = 191) were retrospectively reviewed and the following biomarkers were recorded and analyzed: Early subtle ischemic signs, hyperdense middle cerebral artery sign (HMCAS) and Alberta Stroke Program Early CT Score (ASPECTS) < 7 in NCCT, large-vessel occlusion (LVO), clot burden score (CBS) < 6, large-vessel occlusion, poor collateral score (CS) and Tmax > 6 s ≥ 56.5 ml. A scoring system to predict HT based on these biomarkers was developed. Each biomarker counts for a single point with the total score ranging from 0 to 7. RESULTS: All the aforementioned multimodal CT biomarkers and the selected cut offs were significantly associated with higher HT risk. The calculated scores were statistically significant different between the HT and the non-HT groups with AUC 0.761 (95% CI 0.703-0.819, P < 0.0000001). Rates of HT were approximately five times higher in patients with score ≥ 3. CONCLUSION: Multimodal CT-based scoring system may provide highly reliable predictive model of hemorrhagic transformation in acute ischemic stroke.

Intracranial Stenosis Treated with Stenting in Patients with Suspected Cerebral Vasculitis: Two Case Reports.

Central nervous system vasculitis (CNSV) is an uncommon and poorly understood form of vasculitis. Early recognition is important because medical treatment might improve the outcome. However, randomized clinical trials on CNSV treatment do not exist. Endovascular treatment has been reported in few cases, but no data exist for intracranial stenting. We report 2 cases of patients with suspected CNSV and recurrent clinical episodes, treated with intracranial stenting. A 48-year-old man had relapsing episodes of right hemiparesis. Neuroradiological exams showed severe left carotid terminus stenosis. Despite immunosuppressive therapy, neuroradiological follow-up exams showed a worsening of the aforementioned stenosis with many transient episodes of weakness in the right limbs and aphasia. A 64-year-old woman had a sudden onset of dysarthria and transient aphasia. Neuroradiological exams showed a severe arterial stenosis involving the origin of left anterior cerebral artery and middle cerebral artery (MCA). Despite dual antiplatelet therapy, she presented an acute onset of severe aphasia, due to an occlusion of the left carotid terminus and proximal MCA. In both cases, endovascular procedure and intracranial stenting was performed, with marked improvement of cerebral blood flow. No more clinical episodes were reported. Intracranial stenting may be a valid therapeutic option in selected patients with CNSV and involvement of medium or large size vessels with clinical worsening despite best medical treatment.

Thalamocortical sensorimotor circuit in multiple sclerosis: an integrated structural and electrophysiological assessment.

Demyelination and axonal damage are pathologic hallmarks of multiple sclerosis (MS), leading to loss of neuronal synchronization, functional disconnection amongst brain relays, and clinical sequelae. To investigate these properties, the primary component of the sensorimotor network was analyzed in mildly disabled Relapsing-Remitting MS patients without sensory symptoms at the time of the investigation. By magnetoencephalography (MEG), the recruitment pattern within the primary sensory (S1) and motor (M1) areas was estimated through the morphology of the early components of somatosensory evoked magnetic fields (SEFs), after evaluating the S1 responsiveness to sensory inputs from the contralateral arm. In each hemisphere, network recruitment properties were correlated with ispilateral thalamus volume, estimated by morphometric techniques upon high-resolution 3D structural magnetic resonance images (MRI). S1 activation was preserved, whereas SEF morphology was strikingly distorted in MS patients, marking a disruption of primary somatosensory network patterning. An unbalance of S1-M1 dynamic recruitment was documented and correlated with the thalamic volume reduction in the left hemisphere. These findings support the model of MS as a disconnection syndrome, with major susceptibility to damage experienced by nodes belonging to more frequently recruited and highly specialized networks.

Intra-cortical connectivity in multiple sclerosis: a neurophysiological approach.

Multiple sclerosis is an autoimmune disease predominantly affecting the white matter of the CNS, causing--among functional sequelae-cortico--cortical partial or total disconnection. Since functional connectivity linking cerebral regions is reliably reflected by synchronization of their neuronal firing, in this study an electrophysiological parameter measured by magnetoencephalography was used to quantify an intra-cortical connectivity (ICC) index focused on the primary somatosensory cortical areas (S1). Twenty-one patients affected by mild (Extended Disability Scale Score, median 1,5) relapsing-remitting (RR) multiple sclerosis in the remitting phase without clinically evident sensory impairment were evaluated. Three dimensional MRI was used to quantify the lesion load, discriminating black hole and non-black hole portions, normalized by individual brain volumes. When matched with a control population, multiple sclerosis patients showed a reduced ICC combined with the complete loss of the finger-dependent functional specialization in S1 cortex of the dominant hemisphere. No association was found between ICC impairment and disease duration, or prolongation of the central sensory conduction time, presence of spinal cord lesions and ongoing disease modifying therapy. The ICC index slightly correlated with the lesion load. A local index of ICC in a circumscribed brain primary area was altered in mildly disabled RR-multiple sclerosis patients, also in absence of any impairment of central sensory conduction. In conclusion, the diffuse damage influencing the multi-nodal network subtending complex cerebral functions also affects intrinsic cortical connectivity. The S1 ICC index is proposed as a highly sensitive and simple-to-test functional measure for the evaluation of intra-cortical synchronization mechanisms in RR-multiple sclerosis.

Fibrinogen concentrate replacement in ischemic stroke patients after recombinant tissue plasminogen activator treatment.

BACKGROUND: Post-thrombotic intracerebral hemorrhage (ICH) is experienced by 6-8% of stroke patients and is associated with multiple factors, including acquired coagulopathy induced by the thrombolytic drug. OBJECTIVES: The objective of this study was to assess the outcome of the intravenous (IV) administration of fibrinogen concentrate in a series of acute stroke patients who developed iatrogenic fibrinogen critical depletion after IV thrombolysis. MATERIAL AND METHODS: Of the 39 ischemic stroke patients treated with IV thrombolysis with a severe hypofibrinogenemia requiring infusion with IV fibrinogen concentrate, 30 patients were treated with 2 g of IV recombinant tissue plasminogen activator (rt-PA), followed by further doses until the fibrinogen level reached 200 mg/dL in hemorrhagic patients or 100 mg/dL in non-hemorrhagic patients, and 9 were treated with IV rt-PA followed by endovascular thrombectomy. RESULTS: Preand post-thrombolysis National Institutes of Health Stroke Scale (NIHSS) scores were statistically different for the Cochran-Mantel-Haenszel test overall (p = 0.0002), at 24-hour evaluation (p = 0.0455) and at 7-day assessment (p = 0.0006). Within the first 7 days post-thrombolysis, the brain computed tomography (CT) scans showed that 20/39 (51.28%) patients had ICH. Of the whole sample, 25.6% of the ICH patients had symptomatic intracerebral hemorrhage (SICH), according to National Institute of Neurological Disorders and Stroke (NINDS) classification. After rt-PA treatment, the median pre-thrombolysis fibrinogenemia of 332 mg/dL significantly dropped to 133 mg/dL (p < 0.0001). After the fibrinogen concentrate infusion, the median level of fibrinogenemia rose to 160 mg/dL, which was significantly higher than the median postthrombolysis levels (p < 0.0001). Recanalization was observed in 25/28 patients (89.29%): complete in 18 and partial in 7 patients. After fibrinogen IV infusion, no thrombotic complications were seen in 37 out of 39 patients (94.77%); 2/39 (0.05%) patients experienced a pulmonary embolism, 1 of them a segmental one. CONCLUSIONS: This study showed the clinical safety of administering IV fibrinogen concentrate in order to increase plasma fibrinogen levels in a series of acute stroke patients with iatrogenic fibrinogen depletion after IV thrombolysis.