Enhancing stroke risk prediction in patients with transient ischemic attack: insights from a prospective cohort study implementing fast-track care.

Background and aims: Fast-track care have been proved to reduce the short-term risk of stroke after transient ischemic attack (TIA). We aimed to investigate stroke risk and to characterize short- and long-term stroke predictors in a large cohort of TIA patients undergoing fast-track management. Methods: Prospective study, enrolling consecutive TIA patients admitted to a Northern Italy emergency department from August 2010 to December 2017. All patients underwent fast-track care within 24 h of admission. The primary outcome was defined as the first stroke recurrence at 90 days, 12 and 60 months after TIA. Stroke incidence with 95% confidence interval (CI) at each timepoint was calculated using Poisson regression. Predictors of stroke recurrence were evaluated with Cox regression analysis. The number needed to treat (NNT) of fast-track care in preventing 90-day stroke recurrence in respect to the estimates based on baseline ABCD2 score was also calculated. Results: We enrolled 1,035 patients (54.2% males). Stroke incidence was low throughout the follow-up with rates of 2.2% [95% CI 1.4-3.3%] at 90 days, 2.9% [95% CI 1.9-4.2%] at 12 months and 7.1% [95% CI 5.4-9.0%] at 60 months. Multiple TIA, speech disturbances and presence of ischemic lesion at neuroimaging predicted stroke recurrence at each timepoint. Male sex and increasing age predicted 90-day and 60-month stroke risk, respectively. Hypertension was associated with higher 12-month and 60-month stroke risk. No specific TIA etiology predicted higher stroke risk throughout the follow-up. The NNT for fast-track care in preventing 90-day stroke was 14.5 [95% CI 11.3-20.4] in the overall cohort and 6.8 [95% CI 4.6-13.5] in patients with baseline ABCD2 of 6 to 7. Conclusion: Our findings support the effectiveness of fast-track care in preventing both short- and long-term stroke recurrence after TIA. Particular effort should be made to identify and monitor patients with baseline predictors of higher stroke risk, which may vary according to follow-up duration.

Rapid outpatient transient ischemic attack clinic and stroke service activity during the SARS-CoV-2 pandemic: a multicenter time series analysis.

Background and aim: Rapid outpatient evaluation and treatment of TIA in structured clinics have been shown to reduce stroke recurrence. It is unclear whether short-term downtrends in TIA incidence and admissions have had enduring impact on TIA clinic activity. This study aims to measure the impact of the pandemic on hospitals with rapid TIA clinics. Methods: Relevant services were identified by literature search and contacted. Three years of monthly data were requested - a baseline pre-COVID period (April 2018 to March 2020) and an intra-COVID period (April 2020 to March 2021). TIA presentations, ischemic stroke presentations, and reperfusion trends inclusive of IV thrombolysis (IVT) and endovascular thrombectomy (EVT) were recorded. Pandemic impact was measured with interrupted time series analysis, a segmented regression approach to test an effect of an intervention on a time-dependent outcome using a defined impact model. Results: Six centers provided data for a total of 6,231 TIA and 13,191 ischemic stroke presentations from Australia (52.1%), Canada (35.0%), Italy (7.6%), and England (5.4%). TIA clinic volumes remained constant during the pandemic (2.9, 95% CI -1.8 to 7.6, p = 0.24), as did ischemic stroke (2.9, 95% CI -7.8 to 1.9, p = 0.25), IVT (-14.3, 95% CI -36.7, 6.1, p < 0.01), and EVT (0, 95% CI -16.9 to 16.9, p = 0.98) counts. Proportion of ischemic strokes requiring IVT decreased from 13.2 to 11.4% (p < 0.05), but those requiring EVT did not change (16.0 to 16.7%, p = 0.33). Conclusion: This suggests that the pandemic has not had an enduring effect on TIA clinic or stroke service activity for these centers. Furthermore, the disproportionate decrease in IVT suggests that patients may be presenting outside the IVT window during the pandemic - delays in seeking treatment in this group could be the target for public health intervention.

CAR t-cell therapy in BOlogNa-NEUrotoxicity TReatment and Assessment in Lymphoma (CARBON-NEUTRAL): proposed protocol and results from an Italian study.

OBJECTIVE: To investigate neurotoxicity clinical and instrumental features, incidence, risk factors, and early and long-term prognosis in lymphoma patients who received CAR T-cell therapy. METHODS: In this prospective study, consecutive refractory B-cell non-Hodgkin lymphoma patients who received CAR T-cell therapy were included. Patients were comprehensively evaluated (neurological examination, EEG, brain MRI, and neuropsychological test) before and after (two and twelve months) CAR T-cells. From the day of CAR T-cells infusion, patients underwent daily neurological examinations to monitor the development of neurotoxicity. RESULTS: Forty-six patients were included in the study. The median age was 56.5 years, and 13 (28%) were females. Seventeen patients (37%) developed neurotoxicity, characterized by encephalopathy frequently associated with language disturbances (65%) and frontal lobe dysfunction (65%). EEG and brain FDG-PET findings also supported a predominant frontal lobe involvement. The median time at onset and duration were five and eight days, respectively. Baseline EEG abnormalities predicted ICANS development in the multivariable analysis (OR 4.771; CI 1.081-21.048; p = 0.039). Notably, CRS was invariably present before or concomitant with neurotoxicity, and all patients who exhibited severe CRS (grade ≥ 3) developed neurotoxicity. Serum inflammatory markers were significantly higher in patients who developed neurotoxicity. A complete neurological resolution following corticosteroids and anti-cytokines monoclonal antibodies was reached in all patients treated, except for one patient developing a fatal fulminant cerebral edema. All surviving patients completed the 1-year follow-up, and no long-term neurotoxicity was observed. CONCLUSIONS: In the first prospective Italian real-life study, we presented novel clinical and investigative insights into ICANS diagnosis, predictive factors, and prognosis.

Capsular Warning Syndrome: Features, Risk Profile, and Prognosis in a Large Prospective TIA Cohort.

INTRODUCTION: Features and prognosis of capsular warning syndrome (CWS) have been poorly investigated prospectively. AIMS: The study aimed to characterize CWS clinical features, risk profile, short- and long-term prognosis, among a large TIA cohort. METHODS: Prospective cohort study of consecutive TIAs was conducted from August 1, 2010, to December 31, 2017. Demographic and clinical characteristics, risk profile, primary (stroke and composite outcome) and secondary (TIA recurrence, cerebral hemorrhage, new onset atrial fibrillation) outcomes were compared between CWS, lacunar (L), and nonlacunar (NL) TIAs. RESULTS: 1,035 patients (33 CWS, 189 L-TIAs, 813 NL-TIAs) were enrolled. Newly diagnosed (ND) hypertension, hypercholesterolemia, cigarette smoking, and leukoaraiosis were independent risk factors of CWS (p < 0.05). CWS showed the highest stroke (30.3% vs. 0.5% and 1.5% for L-TIAs and NL-TIAs, respectively) and composite outcome risk at follow-up (p < 0.001), but better 3-month post-stroke prognosis (mRS 0-2 90.0% vs. 36.8%; p = 0.002). CWS-related stroke mostly occurred <48 h (80.0%) and had a small vessel occlusion etiology (100%), affecting more often the internal capsule (60.0%). Dual antiplatelet therapy (DAPT) versus single antiplatelet therapy was associated with lower 3-month cumulative stroke incidence (12.5% vs. 57.1%; p = 0.010). Intravenous thrombolysis (IVT) showed similar 3-month efficacy and safety in strokes after TIAs groups (median mRS 0, IQR 0-1; p = 0.323). CONCLUSIONS: CWS is associated with higher stroke risk and better functional prognosis than L- and NL-TIAs. CWS risk profile is consistent with severe small vessel disease, and ND hypertension could represent a major risk factor. DAPT and IVT seem effective and safe in preventing and treating stroke following CWS.

Frontal predominant encephalopathy with early paligraphia as a distinctive signature of CAR T-cell therapy-related neurotoxicity.

Chimeric antigen receptor (CAR) T-cell therapy is an emerging highly effective treatment for refractory haematological malignancies. Unfortunately, its therapeutic benefit may be hampered by treatment-related toxicities, including neurotoxicity. Early aggressive treatment is paramount to prevent neurological sequelae, yet it potentially interferes with the anti-cancer action of CAR T-cells. We describe four CAR T-cells infused patients who presented with reiterative writing behaviours, namely paligraphia, as an early manifestation of neurotoxicity, and eventually developed frontal predominant encephalopathy (one mild, three severe). Paligraphia may represent an early, specific, and easily detectable clinical finding of CAR T-cell therapy-related neurotoxicity, potentially informing its management.

Clinicoradiological Profile and Functional Outcome of Acute Cerebral Venous Thrombosis: A Hospital-Based Cohort Study.

Introduction Acute cerebral venous thrombosis (CVT) may result in a variety of clinical presentations, with headache being the most common. The relationship between clinical and neuroradiological characteristics in acute CVT patients is still not univocally characterized. Materials and methods We enrolled 32 consecutive acute CVT patients admitted to our emergency department from January 1, 2012, to June 30, 2019. Clinicoradiological associations and their relationship with the functional outcome at the discharge were tested. Results Headache was the presenting symptom in 85% of patients, more frequently subacute (82%), new-onset (67%), with unusual features in respect to prior headache episodes (100%), and associated with concomitant neurological symptoms/signs (74%). Patients with holocranial headache showed more frequent venous ischemia (VI) compared to those with bilateral and unilateral headache (50% vs. 20% vs. 0%, respectively; p=0.027). Patients with concomitant neurological defects had a higher prevalence of VI (50.0% vs. 15.0%; p=0.049) and superior sagittal sinus thrombosis (67% vs. 30%; p=0.043) than those without. Vomit was more frequently observed in patients with straight sinus thrombosis (67% vs. 8%; p=0.005). Increasing age and VI were independently associated with poor (modified Rankin scale (mRS) 2-5) functional outcome (odds ratio (OR) = 1.081, 95% confidence interval (CI) 1.004-1.165; p=0.038 and OR = 12.089, 95% CI 1.141-128.104; p=0.039, respectively). Conclusions Our study confirms and enriches available data on the clinicoradiological profile of patients with acute CVT and suggests that increasing age and venous ischemia are independently associated with poor outcomes.

Prospective observational cohort study of early recurrent TIA: Features, frequency, and outcome.

OBJECTIVES: To evaluate the frequency, clinical and etiologic features, and short- and long-term outcomes of early recurrent TIA. METHODS: This prospective observational cohort study enrolled all consecutive patients with TIA referred to our emergency department and diagnosed by a vascular neurologist. Expedited assessment and best secondary prevention were performed within 24 hours. Primary endpoints were stroke and a composite outcome including stroke, acute coronary syndrome, and vascular death at 3, 12, and, for a subset of patients, 60 months; secondary outcomes were TIA relapse, cerebral hemorrhage, new-onset atrial fibrillation, and death resulting from other causes. Concordance between index TIA and subsequent stroke etiologies was also evaluated. RESULTS: A total of 1,035 patients (822 with a single TIA, 213 with recurrent TIA = 21%) were enrolled from August 2010 to December 2017. Capsular warning syndrome and large artery atherosclerosis showed the strongest relationship with early recurrent TIA. The risk of stroke was significantly higher in the early recurrent TIA subgroup at each follow-up, and most stroke episodes occurred within 48 hours of index TIA. TIAs with lesion, dysarthria, and leukoaraiosis were the 3- and 12-month independent predictors of stroke incidence after early recurrent TIA subgroup. Index TIA and subsequent stroke etiologies showed substantial concordance. An ABCD3 score >6 predicted a higher risk of stroke recurrence over the entire follow-up. CONCLUSIONS: Our study evaluated long-term outcome after early recurrent TIA. Our observations support the importance of promptly detecting and treating patients with early recurrent TIAs to reduce the high early and long-term risk of poor clinical outcomes.

Echocardiographic characteristics of hypertensive patients affected by transient ischemic attack: a cross-sectional study.

Atrial septal aneurysm (ASA), common finding in normal echocardiographies, has been described in association with transient ischemic attacks (TIAs)/strokes, as well as hypertensive end-organ damage such as left ventricular (LV) hypertrophy. Aim of this study was to assess if a cluster of echocardiographic aspects could characterize TIA hypertensive patients. A cross-sectional study on patients with history of TIA, referring to a Hypertension Center echolab, has been performed. A total of 5223 patients received transthoracic echocardiography. TIA patients were 292 (5.6%). A total of 102 age/sex-matched patients without TIA have been collected as controls. The main characteristic of TIA patients resulted ASA/bulging (B) (TIA 61%, controls 6%, P = .0001). Other aspect was LV concentric remodeling (TIA 32.3%, controls 20.8%, P = .029) and mitral flow aspects of diastolic dysfunction. After adjustment for age and hypertension, ASA/B (odds ratio [OR] = 62.4, 95% confidence interval [CI]: 13.6-73.9, P < .001), followed by LV concentric hypertrophy (OR = 2.1, 95% CI: 1.1-4.3, P = .043), was associated with a positive TIA history. A binary logistic regression performed in ASA/B patients, identified relative wall thickness as the strongest TIA-associated aspect (OR = 53.4, 95% CI: 11.9-74.18, P = .001). ASA/B, common finds in general population, could carry a significant incremental possibility of association with TIA when concentric geometry, frequent hypertensive aspect, is present as well.

Thrombin generation and intracranial atherosclerotic disease in patients with a transient ischaemic attack.

BACKGROUND: Intracranial atherosclerotic disease (ICAD) is responsible for at least 10% of transient ischaemic attacks (TIA). Thrombin generation has been shown to be associated with several atherosclerotic conditions and may be relevant in the pathogenesis of TIA from ICAD. OBJECTIVE: To evaluate the association between thrombin generation and ICAD in patients with TIA. MATERIALS AND METHODS: Consecutive patients with confirmed diagnosis of TIA by vascular neurologist were enrolled. Within 24h from diagnosis, all the patients underwent: blood samples including thrombin generation search, electrocardiography, brain CT scan, blood pressure (BP) measurement, supra-aortic echo-Doppler, transcranial Doppler (TCD) and standard echocardiogram. Thrombin generation was measured as endogenous thrombin potential (ETP) in platelet-rich plasma (PRP) and in platelet-poor plasma (PPP), in the presence and in the absence of thrombomodulin (TM). RESULTS: 120 patients (male 52.5%), aged 69±16years were enrolled. Ten patients on warfarin treatment had significantly lower ETP than the others. Among the remaining, ETP in the presence or absence of TM did not differ according to TOAST classification aetiology (large vessel vs. cardioembolic vs. lacunar vs. others). In PRP, ETP was similar in patients with ICAD and in those without (1748±160 vs. 1851±36nM·min, p=0.393), whereas, ETP measured in presence of thrombomodulin was higher in patients with than in those without ICAD (2045±99 vs. 1715±41nM·min, p=0.011). In PPP, ETP was similar in patients with ICAD and in those without, whereas thrombin peak was higher in patients with ICAD than in those without both in the presence (165±17 vs. 130±5nM, p=0.036) and in the absence of TM (178±19 vs. 142±5nM, p=0.037). CONCLUSION: ETP measured in presence of TM is enhanced in patients with ICAD, supporting that thrombomodulin-protein C pathways is relevant in TIA from ICAD. These hypothesis-generating data suggest that thrombin generation may be relevant in cerebral ischaemia from intracranial disease, and justify larger studies.

Short- and Long-Term Stroke Risk after Urgent Management of Transient Ischaemic Attack: The Bologna TIA Clinical Pathway.

BACKGROUND: Rapid management can reduce the short stroke risk after transient ischaemic attack (TIA), but the long-term effect is still little known. We evaluated 3-year vascular outcomes in patients with TIA after urgent care. METHODS: We prospectively enrolled all consecutive patients with TIA diagnosed by a vascular neurologist and referred to our emergency department (ED). Expedited assessment and best secondary prevention was within 24 h. Endpoints were stroke within 90 days, and stroke, myocardial infarction, and vascular death at 12, 24 and 36 months. RESULTS: Between August 2010 and July 2013, we evaluated 686 patients with suspected TIA; 433 (63%) patients had confirmed TIA. Stroke at 90 days was 2.07% (95% confidence interval (CI), 1.1-3.9) compared with the ABCD2-predicted risk of 9.1%. The long-term stroke risk was 2.6% (95% CI, 1.1-4.2), 3.7% (95% CI, 1.6-5.9) and 4.4% (95% CI, 1.9-6.8) at 12, 24 and 36 months, respectively. The composite outcome of stroke, myocardial infarction, and vascular death was 3.5% (95% CI, 1.7-5.1), 4.9% (95% CI, 2.5-7.4), and 5.6% (95% CI, 2.8-8.3) at 12, 24, and 36 months, respectively. CONCLUSIONS: TIA expedited management driven by vascular neurologists was associated with a marked reduction in the expected early stroke risk and low long-term risk of stroke and other vascular events.

Seizures in acute stroke: incidence, risk factors and prognosis.

BACKGROUND AND PURPOSE: Studies on post-stroke seizures have produced conflicting results. Our study aim was to further elucidate the incidence and predictive factors of early post-stroke seizures (ES) and their relationship with outcome. METHODS: relevant clinical data were prospectively collected in 2,053 patients with acute stroke admitted to the Stroke Unit from 2004 to 2008. RESULTS: Sixty-six patients (8 hemorrhagic and 58 ischemic strokes) aged 73-88 years (mean age 82 years) presented seizures in the first week after stroke onset. The type of ischemic stroke was atherothrombotic in 10 patients, cardioembolic in 21, lacunar in 4, undetermined in 19, and of other etiology in 4. Twenty-seven patients had generalized convulsive, 6 had complex partial, and 33 had simple partial seizures. Status epilepticus was observed in 13 patients. The severity of strokes in patients with ES was greater than in those without (National Institutes of Health Stroke Scale >14 in 50 vs. 25%), so mortality (30 days) was higher (29 vs. 14%). Independent seizure predictors were: total anterior circulation infarct, hemorrhagic transformation, hyperglycemia, and the interaction term diabetes × hyperglycemia. CONCLUSIONS: ES may be considered a marker of stroke severity. Cortical location of the lesion, hemorrhagic transformation, and hyperglycemia in patients without diabetes are important predictors of ES.