Hereditary transthyretin amyloidosis: a comprehensive review with a focus on peripheral neuropathy.

Amyloidoses represent a group of diseases characterized by the pathological accumulation in the extracellular area of insoluble misfolded protein material called "amyloid". The damage to the tissue organization and the direct toxicity of the amyloidogenic substrates induce progressive dysfunctions in the organs involved. They are usually multisystem diseases involving several vital organs, such as the peripheral nerves, heart, kidneys, gastrointestinal tract, liver, skin, and eyes. Transthyretin amyloidosis (ATTR) is related to abnormalities of transthyretin (TTR), a protein that acts as a transporter of thyroxine and retinol and is produced predominantly in the liver. ATTR is classified as hereditary (ATTRv) and wild type (ATTRwt). ATTRv is a severe systemic disease of adults caused by mutations in the TTR gene and transmitted in an autosomal dominant manner with incomplete penetrance. Some pathogenic variants in TTR are preferentially associated with a neurological phenotype (progressive peripheral sensorimotor polyneuropathy); others are more frequently associated with restrictive heart failure. However, many mutations express a mixed phenotype with neurological and cardiological involvement. ATTRv is now a treatable disease. A timely and definite diagnosis is essential in view of the availability of effective therapies that have revolutionized the management of affected patients. The purpose of this review is to familiarize the clinician with the disease and with the correct diagnostic pathways in order to obtain an early diagnosis and, consequently, the possibility of an adequate treatment.

A Comprehensive Update on Late-Onset Pompe Disease.

Pompe disease (PD) is an autosomal recessive disorder caused by mutations in the GAA gene that lead to a deficiency in the acid alpha-glucosidase enzyme. Two clinical presentations are usually considered, named infantile-onset Pompe disease (IOPD) and late-onset Pompe disease (LOPD), which differ in age of onset, organ involvement, and severity of disease. Assessment of acid alpha-glucosidase activity on a dried blood spot is the first-line screening test, which needs to be confirmed by genetic analysis in case of suspected deficiency. LOPD is a multi-system disease, thus requiring a multidisciplinary approach for efficacious management. Enzyme replacement therapy (ERT), which was introduced over 15 years ago, changes the natural progression of the disease. However, it has limitations, including a reduction in efficacy over time and heterogeneous therapeutic responses among patients. Novel therapeutic approaches, such as gene therapy, are currently under study. We provide a comprehensive review of diagnostic advances in LOPD and a critical discussion about the advantages and limitations of current and future treatments.

Leprosy Neuropathy in a Non-Endemic Area: A Clinical and Pathological Study.

The extent of nerve involvement in leprosy is highly variable in distribution and clinical presentation. Mononeuropathies, multiple mononeuropathies, and polyneuropathies can present both in the context of a cutaneous and/or systemic picture and in the form of pure neuritic leprosy (PNL). The differential diagnosis of leprosy neuropathy remains challenging because it is a very rare condition and, especially in Western countries, is often overlooked. We report one case of the polyneuropathic form of PNL (P-PNL) and one case of multiple mononeuropathy in paucibacillary leprosy. In both cases, the diagnosis was achieved by performing a sural nerve biopsy, which showed subverted structure, severe infiltration of inflammatory cells in nerve fascicles, granulomatous abnormalities, and the presence of alcohol-acid-resistant, Ziehl-Neelsen-positive bacilli inside the nerve bundles. Leprosy remains an endemic disease in many areas of the world, and globalization has led to the spread of cases in previously disease-free countries. In this perspective, our report emphasizes that the diagnostic possibility of leprosy neuropathy should always be taken into account, even in Western countries, in the differential diagnostic process of an acquired sensory polyneuropathy or multineuropathy and confirms that nerve biopsy remains a useful procedure in working up neuropathies with unknown etiology.

Juvenile-Onset Recurrent Rhabdomyolysis Due to Compound Heterozygote Variants in the ACADVL Gene.

Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is a rare autosomal recessive long-chain fatty acid oxidation disorder caused by mutations in the ACADVL gene. The myopathic form presents with exercise intolerance, exercise-related rhabdomyolysis, and muscle pain, usually starting during adolescence or adulthood. We report on a 17-year-old boy who has presented with exercise-induced muscle pain and fatigue since childhood. In recent clinical history, episodes of exercise-related severe hyperCKemia and myoglobinuria were reported. Electromyography was normal, and a muscle biopsy showed only "moth-eaten" fibers, and a mild increase in lipid storage in muscle fibers. NGS analysis displayed the already known heterozygote c.1769G>A variant and the unreported heterozygote c.523G>C change in ACADVL both having disease-causing predictions. Plasma acylcarnitine profiles revealed high long-chain acylcarnitine species levels, especially C14:1. Clinical, histopathological, biochemical, and genetic tests supported the diagnosis of VLCAD deficiency. Our report of a novel pathogenic missense variant in ACADVL expands the allelic heterogeneity of the disease. Since dietary treatment is the only therapy available for treating VLCAD deficiency and it is more useful the earlier it is started, prompt diagnosis is essential in order to minimize muscle damage and slow the disease progression.

Prognostic Usefulness of Motor Unit Number Index (MUNIX) in Patients Newly Diagnosed with Amyotrophic Lateral Sclerosis.

The MUNIX technique allows us to estimate the number and size of surviving motor units (MUs). Previous studies on ALS found correlations between MUNIX and several clinical measures, but its potential role as a predictor of disease progression rate (DPR) has not been thoroughly evaluated to date. We aimed to investigate MUNIX's ability to predict DPR at a six-month follow up. METHODS: 24 ALS patients with short disease duration (<24 months from symptoms' onset) were enrolled and divided according to their baseline DPR into two groups (normal [DPR-N] and fast [DPR-F] progressors). MUNIX values were obtained from five muscles (TA, APB, ADM, FDI, Trapezius) and averaged for each subject. RESULTS: MUNIX was found to predict DPR at follow up in a multivariable linear regression model; namely, patients with lower MUNIX values were at risk of showing greater DPR scores at follow up. The result was replicated in a simple logistic regression analysis, with the dichotomic category "MUNIX-Low" as the independent variable and the outcome "DPR-F" as the dependent variable. CONCLUSIONS: our results pave the way for the use of the MUNIX method as a prognostic tool in early ALS, enabling patients' stratification according to their rates of future decline.

Timely Leukapheresis May Interfere with the "Fitness" of Lymphocytes Collected for CAR-T Treatment in High Risk DLBCL Patients.

The development of chimeric antigen receptor (CAR)-T cell therapy has revolutionized the treatment of hematological diseases. However, approximately 60% of patients relapse after CAR-T cell therapy, and no clear cause for this failure has been identified. The objective of the Bio-CAR-T BS study (ClinicalTrials.gov: NCT05366569) is to improve our understanding of the lymphocyte harvest to maximize the quality of the CAR-T cell product. Of the 14 patients enrolled, 11 were diagnosed with DLBCL, 2 with PMBCL, and 1 with ALL. Five of 11 DLBCL patients met the criteria for "pre-emptive" Lymphocytes-apheresis (being at high risk of second relapse), and 6 were included in the standard-of-care Lymphocytes-apheresis group. Previous autologous stem cell transplantation (ASCT) and age were significantly different between the two groups. At the time of Lymphocyte-apheresis, patients in the "pre-emptive" group had more "fit" lymphocytes (higher CD4+/CD8+ ratio; higher naïve T cells levels) compared with standard group, probably due to the impact of ASCT. At the same time, also being older than 60 years results in a more "exhausted" lymphocyte profile. Overall, "pre-emptive" Ly-apheresis in DLBCL patients at high risk of relapse appears to be feasible and may allow the timely collection of "fit" lymphocytes for CAR-T cell manufacturing.

Association of Microglial Activation With Spontaneous ARIA-E and CSF Levels of Anti-Aß Autoantibodies.

BACKGROUND AND OBJECTIVES: Amyloid-related imaging abnormalities suggestive of vasogenic edema or sulcal effusion (ARIA-E) are the most common adverse events complicating Alzheimer disease (AD) immunotherapy with anti-ß-amyloid (Aß) monoclonal antibodies. ARIA-E can also occur spontaneously in cerebral amyloid angiopathy-related inflammation (CAA-ri), a rare autoimmune encephalopathy associated with increased CSF levels of anti-Aß autoantibodies. Although the pathophysiologic mechanisms of ARIA-E remain to be fully elucidated, experimental evidence from ex vivo studies suggests that gantenerumab and aducanumab enable microglial activation. However, the in vivo evidence for a direct association between neuroinflammation and ARIA-E in patients with high CSF anti-Aß (auto)antibody levels has never been demonstrated. METHODS: The spatial distribution and temporal variations of microglial activation associated with levels of anti-Aß autoantibodies at (sub)acute presentation of ARIA-E and after corticosteroid therapy were evaluated in a longitudinal case series of patients with CAA-ri, the spontaneous variant of the iatrogenic ARIA-E reported in Aß-lowering immunotherapy with monoclonal antibodies. Multimodal and multiparametric MRI was used for CAA and ARIA-E severity quantification, according to validated scoring system; CSF testing for anti-Aß autoantibodies and AD biomarkers; 11C-PK11195 PET for activated microglia. RESULTS: At (sub)acute presentation, we found focal peaks of microglial activation having a greater spatial colocalization with ARIA-E compared with chronic age-related white matter change imaging abnormalities. The severity of ARIA-E and the magnitude of the associated microglial activation were greater in patients having AD and severe CAA concomitant disease compared with patients having CAA only. CSF anti-Aß autoantibodies at presentation were high in all patients and markedly decreased at posttreatment follow-up, in parallel with clinical resolution of acute symptoms, reduced ARIA-E severity, and reduced microglial activation. DISCUSSION: Our findings extend the current notion of ARIA-E by providing the first in vivo 11C-PK11195 PET evidence for an association between microglial activation and the magnitude and severity of ARIA-E in patients with increased CSF concentration of anti-Aß autoantibodies and comorbid AD and CAA disease. Our results highlight CSF testing for anti-Aß autoantibodies as a promising diagnostic, prognostic, and therapy response biomarker to help guide future treatment and management decisions in real clinical practice and clinical trials.

Guillain-Barré syndrome and COVID-19: A 1-year observational multicenter study.

BACKGROUND AND PURPOSE: Many single cases and small series of Guillain-Barré syndrome (GBS) associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were reported during the coronavirus disease 19 (COVID-19) outbreak worldwide. However, the debate regarding the possible role of infection in causing GBS is still ongoing. This multicenter study aimed to evaluate epidemiological and clinical findings of GBS diagnosed during the COVID-19 pandemic in northeastern Italy in order to further investigate the possible association between GBS and COVID-19. METHODS: Guillain-Barré syndrome cases diagnosed in 14 referral hospitals from northern Italy between March 2020 and March 2021 were collected and divided into COVID-19-positive and COVID-19-negative. As a control population, GBS patients diagnosed in the same hospitals from January 2019 to February 2020 were considered. RESULTS: The estimated incidence of GBS in 2020 was 1.41 cases per 100,000 persons/year (95% confidence interval 1.18-1.68) versus 0.89 cases per 100,000 persons/year (95% confidence interval 0.71-1.11) in 2019. The cumulative incidence of GBS increased by 59% in the period March 2020-March 2021 and, most importantly, COVID-19-positive GBS patients represented about 50% of the total GBS cases with most of them occurring during the two first pandemic waves in spring and autumn 2020. COVID-19-negative GBS cases from March 2020 to March 2021 declined by 22% compared to February 2019-February 2020. CONCLUSIONS: Other than showing an increase of GBS in northern Italy in the "COVID-19 era" compared to the previous year, this study emphasizes how GBS cases related to COVID-19 represent a significant part of the total, thus suggesting a relation between COVID-19 and GBS.

Italian Real-Life Experience of Patients with Hereditary Transthyretin Amyloidosis Treated with Patisiran.

Hereditary transthyretin amyloidosis (ATTRv) is a multisystemic, rare, inherited, progressive and adult-onset disease, affecting the sensorimotor nerves, heart, autonomic function and other organs. The actual scenario of pharmaceutical approaches for ATTRv amyloidosis includes five main groups: TTR stabilizers, TTR mRNA silencers, TTR fibril disruptors, inhibitor of TTR fibril seeding and gene therapy. Patisiran is a small, double-stranded interfering RNA encapsulated in a lipid nanoparticle, able to penetrate into hepatocytes, where it selectively targets TTR mRNA, reducing TTR production. We report and discuss 9 cases of different patients with ATTRv amyloidosis successfully managed with patisiran in the real clinical practice. Literature data, as well as the above presented case reports, show that this drug is effective and safe in improving both neurological and cardiovascular symptoms of ATTRv amyloidosis, and to maintain a good QoL, independently form the stage of the disease and the involved mutation. Recent studies correlated improved functional and biochemical outcomes with a regression of amyloid burden, especially at the cardiac level. Today, patisiran can be considered a valid therapeutic option for the management of patients with ATTRv amyloidosis and polyneuropathy and cardiovascular symptoms.

Imaging markers of intracerebral hemorrhage expansion in patients with unclear symptom onset.

BACKGROUND: Hematoma expansion (HE) is common and associated with poor outcome in intracerebral hemorrhage (ICH) with unclear symptom onset (USO). AIMS: We tested the association between non-contrast computed tomography (NCCT) markers and HE in this population. METHODS: Retrospective analysis of patients with primary spontaneous ICH admitted at five centers in the United States and Italy. Baseline NCCT was analyzed for presence of the following markers: intrahematoma hypodensities, heterogeneous density, blend sign, and irregular shape. Variables associated with HE (hematoma growth > 6 mL and/or > 33% from baseline to follow-up imaging) were explored with multivariable logistic regression. RESULTS: Of 2074 patients screened, we included 646 subjects (median age = 75, 53.9% males), of whom 178 (27.6%) had HE. Hypodensities (odds ratio (OR) = 2.67, 95% confidence interval (CI) = 1.79-3.98), heterogeneous density (OR = 2.16, 95% CI = 1.46-3.21), blend sign (OR = 2.28, 95% CI = 1.38-3.75) and irregular shape (OR = 1.82, 95% CI = 1.21-2.75) were independently associated with a higher risk of HE, after adjustment for confounders (ICH volume, anticoagulation, and time from last seen well (LSW) to NCCT). Hypodensities had the highest sensitivity for HE (0.69), whereas blend sign was the most specific marker (0.90). All NCCT markers were more frequent in early presenters (time from LSW to NCCT ⩽ 6 h, n = 189, 29.3%), and more sensitive in this population as well (hypodensities had 0.77 sensitivity). CONCLUSION: NCCT markers are associated with HE in ICH with USO. These findings require prospective replication and suggest that NCCT features may help the stratification of HE in future studies on USO patients.

Imaging features and ultraearly hematoma growth in intracerebral hemorrhage associated with COVID-19.

PURPOSE: Intracerebral hemorrhage (ICH) is an uncommon but deadly event in patients with COVID-19 and its imaging features remain poorly characterized. We aimed to describe the clinical and imaging features of COVID-19-associated ICH. METHODS: Multicenter, retrospective, case-control analysis comparing ICH in COVID-19 patients (COV19 +) versus controls without COVID-19 (COV19 -). Clinical presentation, laboratory markers, and severity of COVID-19 disease were recorded. Non-contrast computed tomography (NCCT) markers (intrahematoma hypodensity, heterogeneous density, blend sign, irregular shape fluid level), ICH location, and hematoma volume (ABC/2 method) were analyzed. The outcome of interest was ultraearly hematoma growth (uHG) (defined as NCCT baseline ICH volume/onset-to-imaging time), whose predictors were explored with multivariable linear regression. RESULTS: A total of 33 COV19 + patients and 321 COV19 - controls with ICH were included. Demographic characteristics and vascular risk factors were similar in the two groups. Multifocal ICH and NCCT markers were significantly more common in the COV19 + population. uHG was significantly higher among COV19 + patients (median 6.2 mL/h vs 3.1 mL/h, p = 0.027), and this finding remained significant after adjustment for confounding factors (systolic blood pressure, antiplatelet and anticoagulant therapy), in linear regression (B(SE) = 0.31 (0.11), p = 0.005). This association remained consistent also after the exclusion of patients under anticoagulant treatment (B(SE) = 0.29 (0.13), p = 0.026). CONCLUSIONS: ICH in COV19 + patients has distinct NCCT imaging features and a higher speed of bleeding. This association is not mediated by antithrombotic therapy and deserves further research to characterize the underlying biological mechanisms.

Hematoma Expansion in Intracerebral Hemorrhage With Unclear Onset.

OBJECTIVE: To investigate the prevalence, predictors, and prognostic effect of hematoma expansion (HE) in patients with intracerebral hemorrhage (ICH) with unclear symptom onset (USO). METHODS: We performed a retrospective analysis of patients with primary spontaneous ICH admitted at 5 academic medical centers in the United States and Italy. HE (volume increase >6 mL or >33% from baseline to follow-up noncontrast CT [NCCT]) and mortality at 30 days were the outcomes of interest. Baseline NCCT was also analyzed for presence of hypodensities (any hypodense region within the hematoma margins). Predictors of HE and mortality were explored with multivariable logistic regression. RESULTS: We enrolled 2,165 participants, 1,022 in the development cohort and 1,143 in the replication cohort, of whom 352 (34.4%) and 407 (35.6%) had ICH with USO, respectively. When compared with participants having a clear symptom onset, patients with USO had a similar frequency of HE (25.0% vs 21.9%, p = 0.269 and 29.9% vs 31.5%, p = 0.423). Among patients with USO, HE was independently associated with mortality after adjustment for confounders (odds ratio [OR] 2.64, 95% confidence interval [CI] 1.43-4.89, p = 0.002). This finding was similar in the replication cohort (OR 3.46, 95% CI 1.86-6.44, p < 0.001). The presence of NCCT hypodensities in patients with USO was an independent predictor of HE in the development (OR 2.59, 95% CI 1.27-5.28, p = 0.009) and replication (OR 2.43, 95% CI 1.42-4.17, p = 0.001) population. CONCLUSION: HE is common in patients with USO and independently associated with worse outcome. These findings suggest that patients with USO may be enrolled in clinical trials of medical treatments targeting HE.

Guillain-Barré syndrome and COVID-19: an observational multicentre study from two Italian hotspot regions.

OBJECTIVE: Single cases and small series of Guillain-Barré syndrome (GBS) have been reported during the SARS-CoV-2 outbreak worldwide. We evaluated incidence and clinical features of GBS in a cohort of patients from two regions of northern Italy with the highest number of patients with COVID-19. METHODS: GBS cases diagnosed in 12 referral hospitals from Lombardy and Veneto in March and April 2020 were retrospectively collected. As a control population, GBS diagnosed in March and April 2019 in the same hospitals were considered. RESULTS: Incidence of GBS in March and April 2020 was 0.202/100 000/month (estimated rate 2.43/100 000/year) vs 0.077/100 000/month (estimated rate 0.93/100 000/year) in the same months of 2019 with a 2.6-fold increase. Estimated incidence of GBS in COVID-19-positive patients was 47.9/100 000 and in the COVID-19-positive hospitalised patients was 236/100 000. COVID-19-positive patients with GBS, when compared with COVID-19-negative subjects, showed lower MRC sum score (26.3±18.3 vs 41.4±14.8, p=0.006), higher frequency of demyelinating subtype (76.6% vs 35.3%, p=0.011), more frequent low blood pressure (50% vs 11.8%, p=0.017) and higher rate of admission to intensive care unit (66.6% vs 17.6%, p=0.002). CONCLUSIONS: This study shows an increased incidence of GBS during the COVID-19 outbreak in northern Italy, supporting a pathogenic link. COVID-19-associated GBS is predominantly demyelinating and seems to be more severe than non-COVID-19 GBS, although it is likely that in some patients the systemic impairment due to COVID-19 might have contributed to the severity of the whole clinical picture.

Safety of Anticoagulation in Patients Treated With Urgent Reperfusion for Ischemic Stroke Related to Atrial Fibrillation.

BACKGROUND AND PURPOSE: The optimal timing for starting oral anticoagulant after an ischemic stroke related to atrial fibrillation remains a challenge, mainly in patients treated with systemic thrombolysis or mechanical thrombectomy. We aimed at assessing the incidence of early recurrence and major bleeding in patients with acute ischemic stroke and atrial fibrillation treated with thrombolytic therapy and/or thrombectomy, who then received oral anticoagulants for secondary prevention. METHODS: We combined the dataset of the RAF and the RAF-NOACs (Early Recurrence and Major Bleeding in Patients With Acute Ischemic Stroke and Atrial Fibrillation Treated With Non-Vitamin K Oral Anticoagulants) studies, which were prospective observational studies carried out from January 2012 to March 2014 and April 2014 to June 2016, respectively. We included consecutive patients with acute ischemic stroke and atrial fibrillation treated with either vitamin K antagonists or nonvitamin K oral anticoagulants. Primary outcome was the composite of stroke, transient ischemic attack, symptomatic systemic embolism, symptomatic cerebral bleeding, and major extracerebral bleeding within 90 days from the inclusion. Treated-patients were propensity matched to untreated-patients in a 1:1 ratio after stratification by baseline clinical features. RESULTS: A total of 2159 patients were included, 564 (26%) patients received acute reperfusion therapies. After the index event, 505 (90%) patients treated with acute reperfusion therapies and 1287 of 1595 (81%) patients untreated started oral anticoagulation. Timing of starting oral anticoagulant was similar in reperfusion-treated and untreated patients (median 7.5 versus 7.0 days, respectively). At 90 days, the primary study outcome occurred in 37 (7%) patients treated with reperfusion and in 146 (9%) untreated patients (odds ratio, 0.74 [95% CI, 0.50-1.07]). After propensity score matching, risk of primary outcome was comparable between the 2 groups (odds ratio, 1.06 [95% CI, 0.53-2.02]). CONCLUSIONS: Acute reperfusion treatment did not influence the risk of early recurrence and major bleeding in patients with atrial fibrillation-related acute ischemic stroke, who started on oral anticoagulant.

Clinical characteristics and outcomes of inpatients with neurologic disease and COVID-19 in Brescia, Lombardy, Italy.

OBJECTIVE: To report clinical and laboratory characteristics, treatment, and clinical outcomes of patients admitted for neurologic diseases with and without coronavirus disease 2019 (COVID-19). METHODS: In this retrospective, single-center cohort study, we included all adult inpatients with confirmed COVID-19 admitted to a neuro-COVID unit beginning February 21, 2020, who had been discharged or died by April 5, 2020. Demographic, clinical, treatment, and laboratory data were extracted from medical records and compared (false discovery rate corrected) to those of neurologic patients without COVID-19 admitted in the same period. RESULTS: One hundred seventy-three patients were included in this study, of whom 56 were positive and 117 were negative for COVID-19. Patients with COVID-19 were older (77.0 years, interquartile range [IQR] 67.0-83.8 years vs 70.1 years, IQR 52.9-78.6 years, p = 0.006), had a different distribution regarding admission diagnoses, including cerebrovascular disorders (n = 43, 76.8% vs n = 68, 58.1%), and had a higher quick Sequential Organ Failure Assessment (qSOFA) score on admission (0.9, IQR 0.7-1.1 vs 0.5, IQR 0.4-0.6, p = 0.006). In-hospital mortality rates (n = 21, 37.5% vs n = 5, 4.3%, p < 0.001) and incident delirium (n = 15, 26.8% vs n = 9, 7.7%, p = 0.003) were significantly higher in the COVID-19 group. Patients with COVID-19 and without COVID with stroke had similar baseline characteristics, but patients with COVID-19 had higher modified Rankin Scale scores at discharge (5.0, IQR 2.0-6.0 vs 2.0, IQR 1.0-3.0, p < 0.001), with a significantly lower number of patients with a good outcome (n = 11, 25.6% vs n = 48, 70.6%, p < 0.001). In patients with COVID-19, multivariable regressions showed increasing odds of in-hospital death associated with higher qSOFA scores (odds ratio [OR] 4.47, 95% confidence interval [CI] 1.21-16.5, p = 0.025), lower platelet count (OR 0.98, 95% CI 0.97-0.99, p = 0.005), and higher lactate dehydrogenase (OR 1.01, 95% CI 1.00-1.03, p = 0.009) on admission. CONCLUSIONS: Patients with COVID-19 admitted with neurologic disease, including stroke, have a significantly higher in-hospital mortality and incident delirium and higher disability than patients without COVID-19.

Subarachnoid Extension Predicts Lobar Intracerebral Hemorrhage Expansion.

Background and Purpose- We investigated whether subarachnoid extension (SAHE) of intracerebral hemorrhage (ICH) is associated with hematoma expansion (HE). Methods- Retrospective analysis of patients with primary spontaneous ICH admitted at 3 academic hospitals in Italy. The study population was divided into a development and a replication cohort. SAHE was rated on baseline noncontrast computed tomography by investigators blinded to clinical data. The main outcome of interest was HE, defined as ICH growth >33% mL and/or >6 mL. Predictors of HE were explored with multivariable logistic regression stratified by ICH location (lobar versus nonlobar). Results- A total of 360 and 192 patients were included in the development and replication cohort, respectively. SAHE was identified with good interrater reliability (K=0.82), and its frequency was 27.8% in the development and 24.5% in the replication cohort. In univariate analysis, HE was more common in patients with SAHE (52.0% versus 27.3%; P<0.001). When controlling for confounders in logistic regression, SAHE was an independent predictor of lobar HE (odds ratio, 6.00 [95% CI, 2.16-16.64]; P=0.001) whereas there was no association with HE in nonlobar ICH (odds ratio, 0.55 [95% CI, 0.17-1.84]; P=0.334). The increased risk of HE in lobar ICH with SAHE was confirmed in the replication cohort (odds ratio, 3.46 [95% CI, 1.07-11.20]; P=0.038). Conclusions- SAHE predicts HE in lobar ICH. This may improve the stratification of HE risk in clinical practice or future trials targeting HE. Further research is needed to confirm our findings and characterize the underlying biological mechanisms.

Timing of initiation of oral anticoagulants in patients with acute ischemic stroke and atrial fibrillation comparing posterior and anterior circulation strokes.

INTRODUCTION: The aim of this study in patients with acute posterior ischaemic stroke (PS) and atrial fibrillation (AF) was to evaluate (1) the risks of recurrent ischaemic event and severe bleeding and (2) these risks in relation with oral anticoagulant therapy (OAT) and its timing. MATERIALS AND METHODS: Patients with PS were prospectively included; the outcome events of these patients were compared with those of patients with anterior stroke (AS) which were taken from previous registries. The primary outcome was the composite of stroke recurrence, transient ischaemic attack, symptomatic systemic embolism, symptomatic cerebral bleeding and major extracranial bleeding occurring within 90 days from acute stroke. RESULTS: A total of 2470 patients were available for the analysis: 473 (19.1%) with PS and 1997 (80.9%) with AS. Over 90 days, 213 (8.6%) primary outcome events were recorded: 175 (8.7%) in patients with AS and 38 (8.0%) in those with PS. In patients who initiated OAT within 2 days, the primary outcome occurred in 5 out of 95 patients (5.3%) with PS compared to 21 out of 373 patients (4.3%) with AS (OR 1.07; 95% CI 0.39-2.94). In patients who initiated OAT between days 3 and 7, the primary outcome occurred in 3 out of 103 patients (2.9%) with PS compared to 26 out of 490 patients (5.3%) with AS (OR 0.54; 95% CI 0.16-1.80). DISCUSSION: our findings suggest that, when deciding the time to initiate oral anticoagulation, the location of stroke, either anterior or posterior, does not predict the risk of outcome events. CONCLUSIONS: Patients with PS or AS and AF appear to have similar risks of ischaemic or haemorrhagic events at 90 days with no difference concerning the timing of initiation of OAT.

Validation and Comparison of Noncontrast CT Scores to Predict Intracerebral Hemorrhage Expansion.

BACKGROUND AND PURPOSE: The BAT, BRAIN, and HEP scores have been proposed to predict hematoma expansion (HE) with noncontrast computed tomography (NCCT). We sought to validate these tools and compare their diagnostic performance. METHODS: We retrospectively analyzed two cohorts of patients with primary intracerebral hemorrhage. HE expansion was defined as volume growth > 33% or > 6 mL. Two raters analyzed NCCT scans and calculated the scores, blinded to clinical and imaging data. The inter-rater reliability was assessed with the interclass correlation statistic. Discrimination and calibration were calculated with area under the curve (AUC) and Hosmer-Lemeshow χ2 statistic, respectively. AUC comparison between different scores was explored with DeLong test. We also calculated the sensitivity, specificity, positive, and negative predictive values of the dichotomized scores with cutoffs identified with the Youden's index. RESULTS: A total of 230 subjects were included, of whom 86 (37.4%) experienced HE. The observed AUC for HE were 0.696 for BAT, 0.700 for BRAIN, and 0.648 for HEP. None of the scores had a significantly superior AUC compared with the others (all p > 0.4). All the scores had good calibration (all p > 0.3) and good-to-excellent inter-rater reliability (interclass correlation > 0.8). BAT ≥ 3 showed the highest specificity (0.81), whereas BRAIN ≥ 6 had the highest sensitivity (0.76). CONCLUSIONS: The BAT, BRAIN, and HEP scores can predict HE with acceptable discrimination and require just a baseline NCCT scan. These tools may be used to stratify the risk of HE in clinical practice or randomized controlled trials.