Anticoagulants Resumption after Warfarin-Related Intracerebral Haemorrhage: The Multicenter Study on Cerebral Hemorrhage in Italy (MUCH-Italy).

Whether to resume antithrombotic treatment after oral anticoagulant-related intracerebral haemorrhage (OAC-ICH) is debatable. In this study, we aimed at investigating long-term outcome associated with OAC resumption after warfarin-related ICH, in comparison with secondary prevention strategies with platelet inhibitors or antithrombotic discontinuation. Participants were patients who sustained an incident ICH during warfarin treatment (2002-2014) included in the Multicenter Study on Cerebral Hemorrhage in Italy. Primary end-point was a composite of ischemic stroke/systemic embolism (SE) and all-cause mortality. Secondary end-points were ischemic stroke/SE, all-cause mortality and major recurrent bleeding. We computed individual propensity score (PS) as the probability that a patient resumes OACs or other agents given his pre-treatment variables, and performed Cox multivariable analysis using Inverse Probability of Treatment Weighting (IPTW) procedure. A total of 244 patients qualified for the analysis. Unlike antiplatelet agents, OAC resumption was associated with a lower rate of the primary end-point (weighted hazard ratio [HR], 0.21; 95% confidence interval [CI], 0.09-0.45), as well as of overall mortality (weighted HR, 0.17; 95% CI, 0.06-0.45) and ischemic stroke/SE (weighted HR, 0.19; 95% CI, 0.06-0.60) with no significant increase of major bleeding in comparison with patients receiving no antithrombotics. In the subgroup of patients with atrial fibrillation, OACs resumption was also associated with a reduction of the primary end-point (weighted HR, 0.22; 95% CI, 0.09-0.54), and the secondary end-point ischemic stroke/SE (weighted HR, 0.09; 95% CI, 0.02-0.40). In conclusion, in patients who have an ICH while receiving warfarin, resuming anticoagulation results in a favorable trade-off between bleeding susceptibility and thromboembolic risk.

Early Recurrence and Major Bleeding in Patients With Acute Ischemic Stroke and Atrial Fibrillation Treated With Non-Vitamin-K Oral Anticoagulants (RAF-NOACs) Study.

BACKGROUND: The optimal timing to administer non-vitamin K oral anticoagulants (NOACs) in patients with acute ischemic stroke and atrial fibrillation is unclear. This prospective observational multicenter study evaluated the rates of early recurrence and major bleeding (within 90 days) and their timing in patients with acute ischemic stroke and atrial fibrillation who received NOACs for secondary prevention. METHODS AND RESULTS: Recurrence was defined as the composite of ischemic stroke, transient ischemic attack, and symptomatic systemic embolism, and major bleeding was defined as symptomatic cerebral and major extracranial bleeding. For the analysis, 1127 patients were eligible: 381 (33.8%) were treated with dabigatran, 366 (32.5%) with rivaroxaban, and 380 (33.7%) with apixaban. Patients who received dabigatran were younger and had lower admission National Institutes of Health Stroke Scale score and less commonly had a CHA2DS2-VASc score >4 and less reduced renal function. Thirty-two patients (2.8%) had early recurrence, and 27 (2.4%) had major bleeding. The rates of early recurrence and major bleeding were, respectively, 1.8% and 0.5% in patients receiving dabigatran, 1.6% and 2.5% in those receiving rivaroxaban, and 4.0% and 2.9% in those receiving apixaban. Patients who initiated NOACs within 2 days after acute stroke had a composite rate of recurrence and major bleeding of 12.4%; composite rates were 2.1% for those who initiated NOACs between 3 and 14 days and 9.1% for those who initiated >14 days after acute stroke. CONCLUSIONS: In patients with acute ischemic stroke and atrial fibrillation, treatment with NOACs was associated with a combined 5% rate of ischemic embolic recurrence and severe bleeding within 90 days.

Association Between Migraine and Cervical Artery Dissection: The Italian Project on Stroke in Young Adults.

Importance: Although sparse observational studies have suggested a link between migraine and cervical artery dissection (CEAD), any association between the 2 disorders is still unconfirmed. This lack of a definitive conclusion might have implications in understanding the pathogenesis of both conditions and the complex relationship between migraine and ischemic stroke (IS). Objective: To investigate whether a history of migraine and its subtypes is associated with the occurrence of CEAD. Design, Setting, and Participants: A prospective cohort study of consecutive patients aged 18 to 45 years with first-ever acute ischemic stroke enrolled in the multicenter Italian Project on Stroke in Young Adults was conducted between January 1, 2000, and June 30, 2015. In a case-control design, the study assessed whether the frequency of migraine and its subtypes (presence or absence of an aura) differs between patients whose IS was due to CEAD (CEAD IS) and those whose IS was due to a cause other than CEAD (non-CEAD IS) and compared the characteristics of patients with CEAD IS with and without migraine. Main Outcomes and Measures: Frequency of migraine and its subtypes in patients with CEAD IS vs non-CEAD IS. Results: Of the 2485 patients (mean [SD] age, 36.8 [7.1] years; women, 1163 [46.8%]) included in the registry, 334 (13.4%) had CEAD IS and 2151 (86.6%) had non-CEAD IS. Migraine was more common in the CEAD IS group (103 [30.8%] vs 525 [24.4%], P = .01), and the difference was mainly due to migraine without aura (80 [24.0%] vs 335 [15.6%], P < .001). Compared with migraine with aura, migraine without aura was independently associated with CEAD IS (OR, 1.74; 95% CI, 1.30-2.33). The strength of this association was higher in men (OR, 1.99; 95% CI, 1.31-3.04) and in patients 39.0 years or younger (OR, 1.82; 95% CI, 1.22-2.71). The risk factor profile was similar in migrainous and non-migrainous patients with CEAD IS (eg, hypertension, 20 [19.4%] vs 57 [24.7%], P = .29; diabetes, 1 [1.0%] vs 3 [1.3%], P > .99). Conclusions and Relevance: In patients with IS aged 18 to 45 years, migraine, especially migraine without aura, is consistently associated with CEAD. This finding suggests common features and warrants further analyses to elucidate the underlying biologic mechanisms.

Assessment of the Incremental Diagnostic Value of Florbetapir F 18 Imaging in Patients With Cognitive Impairment: The Incremental Diagnostic Value of Amyloid PET With [18F]-Florbetapir (INDIA-FBP) Study.

IMPORTANCE: Cerebral amyloidosis is a key abnormality in Alzheimer disease (AD) and can be detected in vivo with positron emission tomography (PET) ligands. Although amyloid PET has clearly demonstrated analytical validity, its clinical utility is debated. OBJECTIVE: To evaluate the incremental diagnostic value of amyloid PET with florbetapir F 18 in addition to the routine clinical diagnostic assessment of patients evaluated for cognitive impairment. DESIGN, SETTING, AND PARTICIPANTS: The Incremental Diagnostic Value of Amyloid PET With [18F]-Florbetapir (INDIA-FBP) Study is a multicenter study involving 18 AD evaluation units from eastern Lombardy, Northern Italy, 228 consecutive adults with cognitive impairment were evaluated for AD and other causes of cognitive decline, with a prescan diagnostic confidence of AD between 15% and 85%. Participants underwent routine clinical and instrumental diagnostic assessment. A prescan diagnosis was made, diagnostic confidence was estimated, and drug treatment was provided. At the time of this workup, an amyloid PET/computed tomographic scan was performed, and the result was communicated to physicians after workup completion. Physicians were asked to review the diagnosis, diagnostic confidence, and treatment after the scan. The study was conducted from August 5, 2013, to December 31, 2014. MAIN OUTCOMES AND MEASURES: Primary outcomes were prescan to postscan changes of diagnosis, diagnostic confidence, and treatment. RESULTS: Of the 228 participants, 107 (46%) were male; mean (SD) age was 70.5 (7) years. Diagnostic change occurred in 46 patients (79%) having both a previous diagnosis of AD and an amyloid-negative scan (P < .001) and in 16 (53%) of those with non-AD diagnoses and an amyloid-positive scan (P < .001). Diagnostic confidence in AD diagnosis increased by 15.2% in amyloid-positive (P < .001; effect size Cohen d = 1.04) and decreased by 29.9% in amyloid-negative (P < .001; d = -1.19) scans. Acetylcholinesterase inhibitors and memantine hydrochloride were introduced in 61 (65.6%) patients with positive scan results who had not previously received those drugs, and the use of the drugs was discontinued in 6 (33.3%) patients with negative scan results who were receiving those drugs (P < .001). CONCLUSIONS AND RELEVANCE: Amyloid PET in addition to routine assessment in patients with cognitive impairment has a significant effect on diagnosis, diagnostic confidence, and drug treatment. The effect on health outcomes, such as morbidity and mortality, remains to be assessed.

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.

Serum cholesterol levels, HMG-CoA reductase inhibitors and the risk of intracerebral haemorrhage. The Multicenter Study on Cerebral Haemorrhage in Italy (MUCH-Italy).

OBJECTIVE: Although a concern exists that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) might increase the risk of intracerebral haemorrhage (ICH), the contribution of these agents to the relationship between serum cholesterol and disease occurrence has been poorly investigated. METHODS: We compared consecutive patients having ICH with age and sex-matched stroke-free control subjects in a case-control analysis, as part of the Multicenter Study on Cerebral Haemorrhage in Italy (MUCH-Italy), and tested the presence of interaction effects between total serum cholesterol levels and statins on the risk of ICH. RESULTS: A total of 3492 cases (mean age, 73.0±12.7 years; males, 56.6%) and 3492 control subjects were enrolled. Increasing total serum cholesterol levels were confirmed to be inversely associated with ICH. We observed a statistical interaction between total serum cholesterol levels and statin use for the risk of haemorrhage (Interaction OR (IOR), 1.09; 95% CI 1.05 to 1.12). Increasing levels of total serum cholesterol were associated with a decreased risk of ICH within statin strata (average OR, 0.87; 95% CI 0.86 to 0.88 for every increase of 0.26 mmol/l of total serum cholesterol concentrations), while statin use was associated with an increased risk (OR, 1.54; 95% CI 1.31 to 1.81 of the average level of total serum cholesterol). The protective effect of serum cholesterol against ICH was reduced by statins in strictly lobar brain regions more than in non-lobar ones. CONCLUSIONS: Statin therapy and total serum cholesterol levels exhibit interaction effects towards the risk of ICH. The magnitude of such effects appears higher in lobar brain regions.

Intravenous thrombolysis or endovascular therapy for acute ischemic stroke associated with cervical internal carotid artery occlusion: the ICARO-3 study.

The aim of the ICARO-3 study was to evaluate whether intra-arterial treatment, compared to intravenous thrombolysis, increases the rate of favourable functional outcome at 3 months in acute ischemic stroke and extracranial ICA occlusion. ICARO-3 was a non-randomized therapeutic trial that performed a non-blind assessment of outcomes using retrospective data collected prospectively from 37 centres in 7 countries. Patients treated with endovascular treatment within 6 h from stroke onset (cases) were matched with patients treated with intravenous thrombolysis within 4.5 h from symptom onset (controls). Patients receiving either intravenous or endovascular therapy were included among the cases. The efficacy outcome was disability at 90 days assessed by the modified Rankin Scale (mRS), dichotomized as favourable (score of 0-2) or unfavourable (score of 3-6). Safety outcomes were death and any intracranial bleeding. Included in the analysis were 324 cases and 324 controls: 105 cases (32.4 %) had a favourable outcome as compared with 89 controls (27.4 %) [adjusted odds ratio (OR) 1.25, 95 % confidence interval (CI) 0.88-1.79, p = 0.1]. In the adjusted analysis, treatment with intra-arterial procedures was significantly associated with a reduction of mortality (OR 0.61, 95 % CI 0.40-0.93, p = 0.022). The rates of patients with severe disability or death (mRS 5-6) were similar in cases and controls (30.5 versus 32.4 %, p = 0.67). For the ordinal analysis, adjusted for age, sex, NIHSS, presence of diabetes mellitus and atrial fibrillation, the common odds ratio was 1.15 (95 % IC 0.86-1.54), p = 0.33. There were more cases of intracranial bleeding (37.0 versus 17.3 %, p = 0.0001) in the intra-arterial procedure group than in the intravenous group. After the exclusion of the 135 cases treated with the combination of I.V. thrombolysis and I.A. procedures, 67/189 of those treated with I.A. procedures (35.3 %) had a favourable outcome, compared to 89/324 of those treated with I.V. thrombolysis (27.4 %) (adjusted OR 1.75, 95 % CI 1.00-3.03, p = 0.05). Endovascular treatment of patients with acute ICA occlusion did not result in a better functional outcome than treatment with intravenous thrombolysis, but was associated with a higher rate of intracranial bleeding. Overall mortality was significantly reduced in patients treated with endovascular treatment but the rates of patients with severe disability or death were similar. When excluding all patients treated with the combination of I.V. thrombolysis and I.A. procedures, a potential benefit of I.A. treatment alone compared to I.V. thrombolysis was observed.

Antithrombotic medications and the etiology of intracerebral hemorrhage: MUCH-Italy.

OBJECTIVE: To test the hypothesis that the effect of antithrombotic medications on the risk of intracerebral hemorrhage (ICH) varies according to the location of the hematoma. METHODS: Consecutive patients with ICH were enrolled as part of the Multicenter Study on Cerebral Hemorrhage in Italy (MUCH-Italy). Multivariable logistic regression models served to examine whether risk factors for ICH and location of the hematoma (deep vs lobar) predict treatment-specific ICH subgroups (antiplatelets-related ICH and oral anticoagulants [OACs]-related ICH). RESULTS: A total of 870 (313 lobar ICH, 557 deep ICH) subjects were included. Of these, 223 (25.6%) were taking antiplatelets and 77 (8.8%) OACs at the time of stroke. The odds of antiplatelet-related ICH increased with aging (odds ratio [OR] 1.05; 95% confidence interval [CI] 1.03-1.07) and hypertension (OR 1.86; 95% CI 1.22-2.85) but had no relation with the anatomical location of ICH. Conversely, lobar location of the hematoma was associated with the subgroup of OAC-related ICH (OR 1.70; 95% CI 1.03-2.81) when compared to the subgroup of patients taking no antithrombotic medications. Within the subgroup of patients taking OACs, international normalized ratio (INR) values were higher in those with lobar ICH as compared to those with deep ICH (2.8 ± 1.1 vs 2.2 ± 0.8; p = 0.011). The proportion of patients with lobar hematoma increased with increasing intensity of anticoagulation, with a ~2-fold increased odds of lobar compared to deep ICH (odds 2.17; p = 0.03) in those exposed to overanticoagulation (INR values >3.0). CONCLUSIONS: OACs, as opposed to antiplatelets, predispose to lobar location of brain hematomas according to a dose-response relationship.

Obesity and the risk of intracerebral hemorrhage: the multicenter study on cerebral hemorrhage in Italy.

BACKGROUND AND PURPOSE: The effect of obesity on the risk of intracerebral hemorrhage (ICH) may depend on the pathophysiology of vessel damage. To further address this issue, we investigated and quantified the correlations between obesity and obesity-related conditions in the causal pathways leading to ICH. METHODS: A total of 777 ICH cases ≥ 55 years of age (287 lobar ICH and 490 deep ICH) were consecutively enrolled as part of the Multicenter Study on Cerebral Hemorrhage in Italy and compared with 2083 control subjects by a multivariate path analysis model. Separate analyses were conducted for deep and lobar ICH. RESULTS: Obesity was not independently associated with an increased risk of lobar ICH (odds ratio [OR], 0.76; 95% confidence interval [CI], 0.58-1.01) or deep ICH (OR, 1.18; 95% CI, 0.95-1.45) when compared with control subjects. The path analysis confirmed the nonsignificant total effect of obesity on the risk of lobar ICH (OR, 0.77; 95% CI, 0.58-1.02) but demonstrated a significant indirect effect on the risk of deep ICH (OR, 1.28; 95% CI, 1.03-1.57), mostly determined by hypertension (OR, 1.07; 95% CI, 1.04-1.11) and diabetes mellitus (OR, 1.04; 95% CI, 1.01-1.07). Obesity was also associated with an increased risk of deep ICH when compared with lobar ICH (OR, 1.62; 95% CI, 1.14-2.31). CONCLUSIONS: Obesity increases the risk of deep ICH, mostly through an indirect effect on hypertension and other intermediate obesity-related comorbidities, but has no major influence on the risk of lobar ICH. This supports the hypothesis of different, vessel-specific, biological mechanisms underlying the relationship between obesity and cerebral hemorrhage.

Severity of acute intracerebral haemorrhage, elderly age and atrial fibrillation: independent predictors of poor outcome at three months.

BACKGROUND AND PURPOSE: Prognostic risk factors of haemorrhagic stroke are not yet fully identified. This study investigated clinical factors leading to poor outcome at three months in patients with intracerebral haemorrhage (ICH) in order to better understand the role of clinical features in prognostic evaluation. SUBJECTS AND METHODS: This was a prospective cohort study on patients having ICH admitted to two Italian hospitals (the Stroke Units at "Ospedale Santa Maria della Misericordia", Perugia and "Ospedale C. Poma", Mantua) between January 1, 2006 and June 30, 2010. RESULTS: A total of 470 consecutive ICH patients (mean age 73.89±13.02 years) were included and of these, 241 (51.1%) were males. At three months, 293 (62.3%) patients had poor outcome including 133 (27.6%) deaths. The resulting significant predictors of poor outcome from univariate analysis included: age, NIH Stroke Scale Score (NIHSSS) at admission, hyperglycaemia and the presence of atrial fibrillation (AF). These variables were confirmed in logistic regression analyses as being independent predictors of disability: age (OR 1.04 95% CI, 1.02-1.07, p=0.0001), AF (OR 3.18 95% CI, 1.12-9.05 p=0.03) and NIHSSS (OR 1.38 95% CI, 1.28-1.48, p=0.0001), while elderly age (OR 1.10 95% CI, 1.06-1.14, p≤0.0001) and high NIHSSS (OR 1.25 95% CI, 1.19-1.31, p≤0.0001) resulted being independent predictors of mortality. CONCLUSIONS: This study found that severity of ICH, elderly age and AF were independent predictors of poor outcome in ICH patients at three months. Thereby, this highlights the importance of understanding the roles of clinical features in ICH prognostic evaluation.

Intravenous thrombolysis for acute ischemic stroke associated to extracranial internal carotid artery occlusion: the ICARO-2 study.

BACKGROUND AND PURPOSES: In a case-control study in patients with acute ischemic stroke and extracranial internal carotid artery (eICA) occlusion, thrombolytic treatment was associated with increased mortality. The aim of this cohort study was to assess the efficacy and safety of thrombolysis in patients with eICA occlusion compared to those without eICA occlusion. METHODS: Consecutive patients treated with intravenous tissue-type plasminogen activator within 4.5 h from symptom onset included in the Safe Implementation of Thrombolysis in Stroke - International Stroke Thrombolysis Registry (SITS-ISTR) in 20 Italian centres were analyzed. Acute carotid occlusion was diagnosed using ultrasound examination, angio-CT scan or angio-MRI. Since the SITS-ISTR database did not plan to report the site of vessel occlusion, each participating center provided the code of the patient with eICA occlusion. Patients were divided into 2 groups, those with and those without eICA occlusion. Main outcome measures were: death, disability (modified Rankin Scale, mRS, 3-6) and any intracranial bleeding at 3 months. Multiple logistic regression analysis was performed to reveal predictors for main outcomes. The following variables of interest were included in the analysis: presence of eICA occlusion, age, gender, diabetes mellitus, hyperlipidemia, atrial fibrillation, congestive heart failure, previous stroke, current smoking, antiplatelet treatment at stroke onset, baseline NIHSS score, baseline blood glucose, cholesterol and blood pressure, history of hypertension and stroke onset to treatment time. RESULTS: A total of 1,761 patients without eICA occlusion and 137 with eICA occlusion were included in the study. At 3 months, 42 patients were lost to follow-up (3 with eICA occlusion). Death occurred in 30 (22.4%) patients with eICA occlusion and in 175 (10.2%) patients without (p < 0.0001). Death or disability at 3 months occurred in 91 of 134 patients with eICA occlusion (67.9%) compared with 654 of 1,722 patients without eICA occlusion (37.9%, p < 0.0001). No or minimal disability at 3 months (mRS 0-1) was reported in 25 (18.7%) patients with eICA occlusion and in 829 (48.2%) patients without (p < 0.0001). Any intracranial bleeding detected by CT or MRI at posttreatment imaging was seen in 16 (11.7%) patients with eICA occlusion and in 314 (17.8%) of those without (p = 0.09). The proportion of symptomatic intracerebral hemorrhage was 5.8% for patients with eICA occlusion and 8.0% for patients without (p = 0.16). At logistic regression analysis, eICA occlusion was associated with mortality (odds ratio, OR 5.7; 95% confidence interval, CI 2.9-11.1) and mortality or disability (OR 5.0; 95% CI 2.9-8.7) at 90 days. CONCLUSIONS: This cohort study in patients with acute ischemic stroke treated with thrombolysis showed an association between eICA occlusion and adverse outcome.

Ventilatory disorders.

Breathing is a primal homeostatic neural process, regulating levels of oxygen and carbon dioxide in blood and tissues, which are crucial for life. Rhythmic respiratory movements must occur continuously throughout life and originate from neural activity generated by specially organized macro- and microcircuits in the brainstem. In the respiratory network there is a spatial and dynamic hierarchy of interacting circuits, each of which controls different aspects of respiratory rhythm generation and pattern formation, which can be revealed as the network is progressively reduced. The motor pattern during normal breathing is considered to consist of three phases: inspiration, post-inspiration and expiration. The expression of each rhythmogenic mechanism is state-dependent and produces specific motor patterns likely to underpin distinct motor behaviors. Vascular neurological disorders affecting these areas or the respiratory motor unit may lead to impaired respiratory activity. Manifestations associated with disorders of this network include sleep apnea and dysrhythmic breathing frequently associated with disturbances of cardiovagal and sympathetic vasomotor control. Respiratory dysfunction constitutes an early and relatively major manifestation of vascular neurologic disorders; ventilation control and breathing behavior correction are necessary to improve stroke management.

Acute and chronic carotid occlusion syndromes.

Clinical manifestations of acute internal carotid artery (ICA) occlusion are the most variable among all cerebrovascular syndromes. This extreme variability is related essentially to three variables: collateral circulation, cerebral vasoreactivity with hemodynamic factors, and the characteristics of occlusion. Intracranial circulation is represented by a mirabilis network connecting both anterior-posterior and deep-shallow circulation systems. The compensation mechanisms in ICA occlusion can be influenced by preexisting risk factors. Moreover, an alteration in cerebral hemodynamic function related to previous stroke, chronic hypoperfusion and vascular risk factors play a relevant role in the clinical features of ICA occlusion. On the other hand, also after an acute event, the clinical evolution in a patient with ICA occlusion, which is defined here as chronic occlusion, is extremely variable: some patients remain asymptomatic, while others suffer recurrent TIA or minor/major stroke. The factors set forth above associated with other underlying conditions also affect clinical development. However, a fundamental role is played by the proper management of vascular risk factors whether in acute or chronic ICA occlusion.

Systemic thrombolysis in patients with acute ischemic stroke and Internal Carotid ARtery Occlusion: the ICARO study.

BACKGROUND AND PURPOSE: The beneficial effect of intravenous thrombolytic therapy in patients with acute ischemic stroke attributable to internal carotid artery (ICA) occlusion remains unclear. The aim of this study was to evaluate the efficacy and safety of intravenous recombinant tissue-type plasminogen activator in these patients. METHODS: ICARO was a case-control multicenter study on prospectively collected data. Patients with acute ischemic stroke and ICA occlusion treated with intravenous recombinant tissue-type plasminogen activator within 4.5 hours from symptom onset (cases) were compared to matched patients with acute stroke and ICA occlusion not treated with recombinant tissue-type plasminogen activator (controls). Cases and controls were matched for age, gender, and stroke severity. The efficacy outcome was disability at 90 days assessed by the modified Rankin Scale, dichotomized as favorable (score of 0-2) or unfavorable (score of 3-6). Safety outcomes were death and any intracranial bleeding. RESULTS: Included in the analysis were 253 cases and 253 controls. Seventy-three cases (28.9%) had a favorable outcome as compared with 52 controls (20.6%; adjusted odds ratio (OR), 1.80; 95% confidence interval [CI], 1.03-3.15; P=0.037). A total of 104 patients died, 65 cases (25.7%) and 39 controls (15.4%; adjusted OR, 2.28; 95% CI, 1.36-3.22; P=0.001). There were more fatal bleedings (2.8% versus 0.4%; OR, 7.17; 95% CI, 0.87-58.71; P=0.068) in the cases than in the controls. CONCLUSIONS: In patients with stroke attributable to ICA occlusion, thrombolytic therapy results in a significant reduction in the proportion of patients dependent in activities of daily living. Increases in death and any intracranial bleeding were the trade-offs for this clinical benefit.

CSF Alzheimer's disease-like pattern in corticobasal syndrome: evidence for a distinct disorder.

BACKGROUND: Corticobasal syndrome (CBS) has a heterogeneous neuropathological spectrum, ranging from the classical corticobasal degeneration to Alzheimer's disease (AD). The neuropathology of CBS is still unpredictable. CSF tau/abeta ratio is a reliable marker of AD. OBJECTIVE: To evaluate the presence of a distinct clinical and neuroimaging CBS phenotype according to CSF pattern. METHODS: 30 patients fulfilling current clinical criteria for CBS entered the study. Each patient underwent a clinical and standardised neuropsychological assessment, and CSF analysis (total tau and abeta42 dosages). CSF AD-like pattern and CSF non-AD like pattern (nAD-like) were identified. In 23 CBS cases, (99m)Tc-ECD single photon emission computed tomography (SPECT) scan was performed and analysed by statistical parametric mapping. RESULTS: CSF AD-like pattern was reported in six cases (20%). The two subgroups did not differ in demographic characteristics or global cognitive impairment. The AD-like group showed greater impairment of memory performances, language and psychomotor speed while the nAD-like group had more severe extrapyramidal syndrome with comparable apraxia scores. Voxel by voxel analysis on SPECT images demonstrated that CBS AD-like patients had greater hypoperfusion in the brain areas typically affected by AD-namely, precuneus, posterior cingulate and hippocampus, bilaterally-compared with nAD-like patients (p<0.001). No clusters above the pre-established threshold were detected when nAD-like were compared with AD-like patients. CONCLUSIONS: CSF AD-like profile in CBS is associated with earlier memory impairment and brain abnormalities typically found in classical AD. These findings argue for the usefulness of CSF testing to identify AD in CBS, and might suggest a different pharmacological approach on the basis of biological data.

Risk of recurrent cerebrovascular events in patients with cryptogenic stroke or transient ischemic attack and patent foramen ovale: the FORI (Foramen Ovale Registro Italiano) study.

BACKGROUND: The optimal management of patients with cryptogenic ischemic stroke found to have a patent foramen ovale (PFO) at diagnostic workup remains unclear. The aims of this observational multicenter study were to evaluate: (1) the risk of recurrent cerebrovascular events in patients with cryptogenic minor ischemic stroke or transient ischemic attack (TIA) and PFO who either underwent percutaneous PFO closure or received only medical treatment, and (2) the risk factors associated with recurrent events. METHODS: Consecutive patients (aged 55 years or less) with first-ever cryptogenic minor ischemic stroke or TIA and PFO were recruited in 13 Italian hospitals between January 2006 and September 2007 and followed up for 2 years. RESULTS: 238 patients were included in the study (mean age 42.2 ± 10.0 years; 118 males); 117 patients (49.2%) received only antithrombotic therapy while 121 patients underwent percutaneous PFO closure (50.8%). Stroke as the qualifying event was more common in the medical treatment group (p = 0.01). The presence of atrial septal aneurysm and evidence of 20 bubbles or more on transcranial Doppler were more common in the PFO closure group (p = 0.002 and 0.02). Eight patients (6.6%) experienced a nonfatal complication during PFO closure. At the 2-year follow-up, 17 recurrent events (TIA or stroke; 3.6% per year) were observed; 7 of these events (2.9% per year) occurred in the percutaneous PFO closure group and 10 events (4.2% per year) in the medical treatment group. The rate of recurrent stroke was 0.4% per year in patients who underwent percutaneous closure (1 event) and 3.4% per year in patients who received medical treatment (8 events). On multivariate analysis, percutaneous closure was not protective in preventing recurrent TIA or stroke (OR = 0.1, 95% CI = 0.02-1.5, p = 0.1), while it was barely protective in preventing recurrent stroke (OR = 0.1, 95% CI = 0.0-1.0, p = 0.053). CONCLUSIONS: The results of this observational, nonrandomized study suggest that PFO closure might be superior to medical therapy for the prevention of recurrent stroke. Periprocedural complications were the trade-off for this clinical benefit. Controlled randomized clinical trials comparing percutaneous closure with medical management are required.

Risk factors for cerebral ischemic events in patients with atrial fibrillation on warfarin for stroke prevention.

BACKGROUND AND PURPOSES: Patients with atrial fibrillation (AF) on treatment with oral anticoagulants may still suffer ischemic cerebrovascular events. The aim of this study was to evaluate the risk factors for cerebral ischemic events in warfarin-treated AF patients with an International Normalized Ratios (INR) above 1.8 on admission. METHODS: In a case-control study, cases were consecutive patients with AF who were on warfarin and who were admitted to four Italian hospitals after an acute cerebrovascular ischemic event (ischemic stroke or transient ischemic attack) with an INR above 1.8. Controls were selected from a single anticoagulation clinic and were patients with AF on adequate warfarin treatment who did not suffer cerebrovascular events. RESULTS: Cases were identified among 4785 consecutive patients with an ischemic cerebral event. 148 cases (3.1%, 21 with transient ischemic events and 127 with ischemic strokes) had AF and were taking warfarin with an INR above 1.8 on admission. On multivariate analysis, diabetes (OR 3.8; 95% CI 1.09-13.82, p=0.025), hyperlipidemia (OR 4.5; 95% CI 1.11-18.23, p=0.035) and carotid/vertebral atherosclerosis on ultrasound (OR 3.0; 95% CI 1.13-8.41, p=0.028) were independent predictors for ischemic cerebral events. The use of statins was inversely correlated with an ischemic event (OR 0.1; 95% CI 0.06-0.47. p=0.001). CONCLUSIONS: Carotid/vertebral atherosclerosis, diabetes and hyperlipidemia are associated with an increased risk for ischemic events in patients with AF on adequate warfarin treatment. Statins significantly reduce the risk of ischemic events.

Gender differences in patients with acute ischemic stroke.

Stroke has a greater effect on women than men owing to the fact that women have more stroke events and are less likely to recover. Age-specific stroke rates are higher in men; however, because of women's longer life expectancy and the much higher incidence of stroke at older ages, women have more stroke events than men overall. The aims of this prospective study in consecutive patients were to assess whether there are gender differences in stroke risk factors, treatment or outcome. Consecutive patients with ischemic stroke were included in this prospective study at four study centers. Disability was assessed using a modified Rankin Scale score (>or=3 indicating disabling stroke) in both genders at 90 days. Outcomes and risk factors in both genders were compared using the chi(2) test. Multiple logistic regression analysis was used to identify any independent predictors of outcome. A total of 1136 patients were included in this study; of these, 494 (46%) were female. Women were statistically older compared with men: 76.02 (+/- 12.93) and 72.68 (+/- 13.27) median years of age, respectively. At admission, females had higher NIH Stroke Scale scores compared with males (9.4 [+/- 6.94] vs 7.6 [+/- 6.28] for men; p = 0.0018). Furthermore, females tended to have more cardioembolic strokes (153 [30%] vs 147 [23%] for men; p = 0.004). Males had lacunar and atherosclerotic strokes more often (146 [29%] vs 249 [39%] for men; p = 0.002, and 68 [13%] vs 123 [19%] for men; p = 0.01, respectively). The mean modified Rankin Scale score at 3 months was also significantly different between genders, at 2.5 (+/- 2.05) for women and 2.1 (+/- 2.02) for men (p = 0.003). However, at multivariate analysis, female gender was not an indicator for negative outcome. It was concluded that female gender was not an independent factor for negative outcome. In addition, both genders demonstrated different stroke pathophysiologies. These findings should be taken into account when diagnostic workup and treatment are being planned.

Cerebrospinal fluid biomarkers and prediction of conversion in patients with mild cognitive impairment: 4-year follow-up in a routine clinical setting.

Mild cognitive impairment (MCI) is a very common syndrome in elderly people, with a high risk of conversion to dementia. Several investigations have shown the usefulness of cerebrospinal fluid (CSF) biomarkers (Abeta42, total tau [T-tau], and phosphorylated tau [P-tau]) in predicting the progression to Alzheimer's disease (AD). We report a 4-year follow-up of MCI patients who underwent CSF evaluation for biomarker assessment, in order to further evaluate the usefulness of CSF analysis in predicting the conversion to dementia in a routine clinical setting. We identified 55 patients with MCI among the consecutive patients, referred from 2001 to 2003 to our Memory Clinic for cognitive disorders, who underwent a complete diagnostic assessment, including lumbar puncture (n = 273). At the end of the follow-up, 31 MCI patients (56%) did not progress to dementia (stable MCI), while 24 (44%) developed a dementia condition. At baseline, the mean levels of CSF Abeta42, T-tau, and P-tau were significantly altered in MCI patients who were converting to dementia with respect to those with stable MCI. All MCI patients with the three altered CSF biomarkers developed dementia within 1 year. Among the stable MCI patients, none showed all three pathological values and only one subject had the pathological value of P-tau. Early diagnosis of dementia and, specifically, a correct prediction of MCI outcome represent a primary goal. To this respect, the role of CSF biomarkers seems to be crucial in a routine clinical setting.