Four clinical and biological phenotypes in antiphospholipid syndrome: a cluster analysis of 174 patients with antinuclear antibody tests

IntroductionAntiphospholipid syndrome (APS) is an autoimmune thrombotic disease with various systemic presentations. This study aimed to identify homogeneous groups of patients based on a non-supervised hierarchical cluster analysis and assess the rate of relapse associated with antinuclear antibodies (ANA).MethodsThis retrospective observational study enrolled patients, over a 90-month period, who had APS as defined by the 2006 Sydney classification criteria, and for whom ANA workup was performed. Agglomerative unsupervised hierarchical clustering was conducted to classify patients into subgroups using 24 variables reflecting a range of clinical and biological baseline features associated with APS.ResultsHundred and seventy-four patients were included and were categorized into four phenotypes. Cluster 1 (n=73) associated mostly middle-aged men with risk factors for cardiovascular disease. Obstetrical APS with low-risk thrombosis made up cluster 2 (n=25). Patients with venous thromboembolism (VTE), microvascular findings and double/triple positive APL antibodies (50%) were represented in cluster 3 (n=33). Whereas cluster 4 (n=43) characterized a predominantly female subpopulation with positive ANA and systemic lupus (n=23) that exhibited a high thrombotic risk and more frequent relapses (n=38) (p<0.001).ConclusionsThis study identified four homogenous groups of patients with APS listed as: i) cardiovascular and arterial risk, ii) obstetrical, iii) VTE and microvascular, and iv) ANA-positive APS. We found that ANA-positivity was associated with higher rates of relapse. Applying ANA status to classification criteria could constitute a novel approach to tailoring management for APS, based on phenotypic patterns and risk assessment

Chronic Obstructive Pulmonary Disease Is Associated with Altered Neuropsychological Performance in Young Adults

Subjects with ischemic lesions have an increased risk of dementia. In addition, Alzheimer's disease (AD) and vascular cognitive impairment share many risk factors. These observations suggest that different diseases that cause altered blood perfusion of the brain or hypoxia promote AD neurodegeneration. In this case-control, cross-sectional study, we sought to test the hypothesis that hypoxia facilitates cognitive decline. We looked for altered neuropsychological performance in subjects with chronic obstructive pulmonary disease (COPD) without apparent cardio- or cerebrovascular diseases or risk factors for atherosclerosis. A selected, homogeneous group of workers from two ceramic factories in a small town of central Italy was enrolled in this study. The COPD patients had a slightly, but significantly worse performance than controls in a number of neuropsychological tests. The findings are consistent with the working hypothesis that chronic hypoxia facilitates cognitive decline

Recanalization Therapies for Large Vessel Occlusion Due to Cervical Artery Dissection: A Cohort Study of the EVA-TRISP Collaboration

Background and Purpose: This study aimed to investigate the effect of endovascular treatment (EVT, with or without intravenous thrombolysis [IVT]) versus IVT alone on outcomes in patients with acute ischemic stroke (AIS) and intracranial large vessel occlusion (LVO) attributable to cervical artery dissection (CeAD). Methods: This multinational cohort study was conducted based on prospectively collected data from the EVA-TRISP (EndoVAscular treatment and ThRombolysis for Ischemic Stroke Patients) collaboration. Consecutive patients (2015–2019) with AIS-LVO attributable to CeAD treated with EVT and/or IVT were included. Primary outcome measures were (1) favorable 3-month outcome (modified Rankin Scale score 0–2) and (2) complete recanalization (thrombolysis in cerebral infarction scale 2b/3). Odds ratios with 95% confidence intervals (OR [95% CI]) from logistic regression models were calculated (unadjusted, adjusted). Secondary analyses were performed in the patients with LVO in the anterior circulation (LVOant) including propensity score matching. Results: Among 290 patients, 222 (76.6%) had EVT and 68 (23.4%) IVT alone. EVT-treated patients had more severe strokes (National Institutes of Health Stroke Scale score, median [interquartile range]: 14 [10–19] vs. 4 [2–7], Padjusted 0.56 [0.24–1.32]). EVT was associated with higher rates of recanalization (80.5% vs. 40.7%; ORadjusted 8.85 [4.28–18.29]) compared to IVT. All secondary analyses showed higher recanalization rates in the EVT-group, which however never translated into better functional outcome rates compared to the IVT-group. Conclusion: We observed no signal of superiority of EVT over IVT regarding functional outcome in CeAD-patients with AIS and LVO despite higher rates of complete recanalization with EVT. Whether pathophysiological CeAD-characteristics or their younger age might explain this observation deserves further research

The Boston criteria version 2.0 for cerebral amyloid angiopathy:a multicentre, retrospective, MRI–neuropathology diagnostic accuracy study

BACKGROUND: Cerebral amyloid angiopathy (CAA) is an age-related small vessel disease, characterised pathologically by progressive deposition of amyloid β in the cerebrovascular wall. The Boston criteria are used worldwide for the in-vivo diagnosis of CAA but have not been updated since 2010, before the emergence of additional MRI markers. We report an international collaborative study aiming to update and externally validate the Boston diagnostic criteria across the full spectrum of clinical CAA presentations. METHODS: In this multicentre, hospital-based, retrospective, MRI and neuropathology diagnostic accuracy study, we did a retrospective analysis of clinical, radiological, and histopathological data available to sites participating in the International CAA Association to formulate updated Boston criteria and establish their diagnostic accuracy across different populations and clinical presentations. Ten North American and European academic medical centres identified patients aged 50 years and older with potential CAA-related clinical presentations (ie, spontaneous intracerebral haemorrhage, cognitive impairment, or transient focal neurological episodes), available brain MRI, and histopathological assessment for CAA diagnosis. MRI scans were centrally rated at Massachusetts General Hospital (Boston, MA, USA) for haemorrhagic and non-haemorrhagic CAA markers, and brain tissue samples were rated by neuropathologists at the contributing sites. We derived the Boston criteria version 2.0 (v2.0) by selecting MRI features to optimise diagnostic specificity and sensitivity in a prespecified derivation cohort (Boston cases 1994-2012, n=159), then externally validated the criteria in a prespecified temporal validation cohort (Boston cases 2012-18, n=59) and a geographical validation cohort (non-Boston cases 2004-18; n=123), comparing accuracy of the new criteria to the currently used modified Boston criteria with histopathological assessment of CAA as the diagnostic standard. We also assessed performance of the v2.0 criteria in patients across all cohorts who had the diagnostic gold standard of brain autopsy. FINDINGS: The study protocol was finalised on Jan 15, 2017, patient identification was completed on Dec 31, 2018, and imaging analyses were completed on Sept 30, 2019. Of 401 potentially eligible patients presenting to Massachusetts General Hospital, 218 were eligible to be included in the analysis; of 160 patient datasets from other centres, 123 were included. Using the derivation cohort, we derived provisional criteria for probable CAA requiring the presence of at least two strictly lobar haemorrhagic lesions (ie, intracerebral haemorrhages, cerebral microbleeds, or foci of cortical superficial siderosis) or at least one strictly lobar haemorrhagic lesion and at least one white matter characteristic (ie, severe visible perivascular spaces in centrum semiovale or white matter hyperintensities in a multispot pattern). The sensitivity and specificity of these criteria were 74·8% (95% CI 65·4-82·7) and 84·6% (71·9-93·1) in the derivation cohort, 92·5% (79·6-98·4) and 89·5% (66·9-98·7) in the temporal validation cohort, 80·2% (70·8-87·6) and 81·5% (61·9-93·7) in the geographical validation cohort, and 74·5% (65·4-82·4) and 95·0% (83·1-99·4) in all patients who had autopsy as the diagnostic standard. The area under the receiver operating characteristic curve (AUC) was 0·797 (0·732-0·861) in the derivation cohort, 0·910 (0·828-0·992) in the temporal validation cohort, 0·808 (0·724-0·893) in the geographical validation cohort, and 0·848 (0·794-0·901) in patients who had autopsy as the diagnostic standard. The v2.0 Boston criteria for probable CAA had superior accuracy to the current Boston criteria (sensitivity 64·5% [54·9-73·4]; specificity 95·0% [83·1-99·4]; AUC 0·798 [0·741-0854]; p=0·0005 for comparison of AUC) across all individuals who had autopsy as the diagnostic standard. INTERPRETATION: The Boston criteria v2.0 incorporate emerging MRI markers of CAA to enhance sensitivity without compromising their specificity in our cohorts of patients aged 50 years and older presenting with spontaneous intracerebral haemorrhage, cognitive impairment, or transient focal neurological episodes. Future studies will be needed to determine generalisability of the v.2.0 criteria across the full range of patients and clinical presentations. FUNDING: US National Institutes of Health (R01 AG26484)

Cerebral venous sinus thrombosis due to vaccine-induced immune thrombotic thrombocytopenia in middle-income countries

Background: Adenovirus-based COVID-19 vaccines are extensively used in low- and middle-income countries (LMICs). Remarkably, cases of cerebral venous sinus thrombosis due to vaccine-induced immune thrombotic thrombocytopenia (CVST-VITT) have rarely been reported from LMICs. Aims: We studied the frequency, manifestations, treatment, and outcomes of CVST-VITT in LMICs. Methods: We report data from an international registry on CVST after COVID-19 vaccination. VITT was classified according to the Pavord criteria. We compared CVST-VITT cases from LMICs to cases from high-income countries (HICs). Results: Until August 2022, 228 CVST cases were reported, of which 63 were from LMICs (all middle-income countries [MICs]: Brazil, China, India, Iran, Mexico, Pakistan, Turkey). Of these 63, 32 (51%) met the VITT criteria, compared to 103 of 165 (62%) from HICs. Only 5 of the 32 (16%) CVST-VITT cases from MICs had definite VITT, mostly because anti-platelet factor 4 antibodies were often not tested. The median age was 26 (interquartile range [IQR] 20–37) versus 47 (IQR 32–58) years, and the proportion of women was 25 of 32 (78%) versus 77 of 103 (75%) in MICs versus HICs, respectively. Patients from MICs were diagnosed later than patients from HICs (1/32 [3%] vs. 65/103 [63%] diagnosed before May 2021). Clinical manifestations, including intracranial hemorrhage, were largely similar as was intravenous immunoglobulin use. In-hospital mortality was lower in MICs (7/31 [23%, 95% confidence interval (CI) 11–40]) than in HICs (44/102 [43%, 95% CI 34–53], p = 0.039). Conclusions: The number of CVST-VITT cases reported from LMICs was small despite the widespread use of adenoviral vaccines. Clinical manifestations and treatment of CVST-VITT cases were largely similar in MICs and HICs, while mortality was lower in patients from MICs.</p

Sex differences in cerebral venous sinus thrombosis after adenoviral vaccination against COVID-19

Introduction: Cerebral venous sinus thrombosis associated with vaccine-induced immune thrombotic thrombocytopenia (CVST-VITT) is a severe disease with high mortality. There are few data on sex differences in CVST-VITT. The aim of our study was to investigate the differences in presentation, treatment, clinical course, complications, and outcome of CVST-VITT between women and men. Patients and methods: We used data from an ongoing international registry on CVST-VITT. VITT was diagnosed according to the Pavord criteria. We compared the characteristics of CVST-VITT in women and men. Results: Of 133 patients with possible, probable, or definite CVST-VITT, 102 (77%) were women. Women were slightly younger [median age 42 (IQR 28–54) vs 45 (28–56)], presented more often with coma (26% vs 10%) and had a lower platelet count at presentation [median (IQR) 50x109/L (28–79) vs 68 (30–125)] than men. The nadir platelet count was lower in women [median (IQR) 34 (19–62) vs 53 (20–92)]. More women received endovascular treatment than men (15% vs 6%). Rates of treatment with intravenous immunoglobulins were similar (63% vs 66%), as were new venous thromboembolic events (14% vs 14%) and major bleeding complications (30% vs 20%). Rates of good functional outcome (modified Rankin Scale 0-2, 42% vs 45%) and in-hospital death (39% vs 41%) did not differ. Discussion and conclusions: Three quarters of CVST-VITT patients in this study were women. Women were more severely affected at presentation, but clinical course and outcome did not differ between women and men. VITT-specific treatments were overall similar, but more women received endovascular treatment.</p

Sex differences in cerebral venous sinus thrombosis after adenoviral vaccination against COVID-19

Introduction: Cerebral venous sinus thrombosis associated with vaccine-induced immune thrombotic thrombocytopenia (CVST-VITT) is a severe disease with high mortality. There are few data on sex differences in CVST-VITT. The aim of our study was to investigate the differences in presentation, treatment, clinical course, complications, and outcome of CVST-VITT between women and men. Patients and methods: We used data from an ongoing international registry on CVST-VITT. VITT was diagnosed according to the Pavord criteria. We compared the characteristics of CVST-VITT in women and men. Results: Of 133 patients with possible, probable, or definite CVST-VITT, 102 (77%) were women. Women were slightly younger [median age 42 (IQR 28–54) vs 45 (28–56)], presented more often with coma (26% vs 10%) and had a lower platelet count at presentation [median (IQR) 50x109/L (28–79) vs 68 (30–125)] than men. The nadir platelet count was lower in women [median (IQR) 34 (19–62) vs 53 (20–92)]. More women received endovascular treatment than men (15% vs 6%). Rates of treatment with intravenous immunoglobulins were similar (63% vs 66%), as were new venous thromboembolic events (14% vs 14%) and major bleeding complications (30% vs 20%). Rates of good functional outcome (modified Rankin Scale 0-2, 42% vs 45%) and in-hospital death (39% vs 41%) did not differ. Discussion and conclusions: Three quarters of CVST-VITT patients in this study were women. Women were more severely affected at presentation, but clinical course and outcome did not differ between women and men. VITT-specific treatments were overall similar, but more women received endovascular treatment.</p

Long term vascular prognosis after intracerebral haemorrhage

Contexte : Les hémorragies intracérébrales spontanées (HIC) présentent une mortalité élevée et un pronostic fonctionnel sombre. Les survivants sont à haut risque d’évènements vasculaires majeurs mais les données concernant le pronostic au long terme des HIC sont limitées. L’objectif principal de ce travail était d’étudier le pronostic vasculaire cérébral et extra-cérébral au long cours.Méthodes : Nous avons inclus les patients de la cohorte prospective et observationnelle PITCH (Prognosis of Intra Cerebral Haemorrhage), qui a recruté de façon consécutive tous les patients admis au CHU de Lille pour une HIC spontanée entre 2004 et 2009.Nous avons étudié (i) l’incidence des évènements vasculaires majeurs, ischémiques ethémorragiques, ainsi que leurs facteurs prédictifs cliniques et neuroradiologiques ; (ii)la prévalence de la sidérose superficielle corticale (SSc) et les facteurs cliniques et radiologiques associés ; (iii) l’impact des micro hémorragies cérébrales sur le risque de récidive hémorragique.Résultats : Nous avons mis en évidence qu’il existait un risque élevé d’évènements vasculaires majeurs, cérébraux et extra-cérébraux, chez les patients ayant souffert d’une HIC. Au long cours, le risque d’évènements ischémiques dépasse le risque hémorragique, en particulier chez les patients avec une hémorragie profonde.Concernant le risque hémorragique cérébral, nous avons montré qu’au sein de notre cohorte, un patient sur cinq avait de la SSc sur l’IRM cérébrale réalisée à l’admission et que la présence de SSc est un facteur neuroradiologique prédictif majeur de récidive hémorragique, suggérant l’implication de l’angiopathie amyloïde cérébrale. Un nombre élevé de microhémorragies cérébrales est par ailleurs associé à un risque de récidive hémorragique plus importante.Conclusion : Les résultats de ce travail ont un impact clinique important, ils suggèrent l’indication d’un suivi au long cours et multidisciplinaire des patients ayant présenté une HIC. Ils apportent des informations nouvelles sur le risque extra-cérébral et sur les prédicteurs de récidive hémorragique.Background: Spontaneous (non-traumatic) intracerebral hemorrhage (ICH) is the mostdramatic type of stroke being responsible for the majority of mortality and stroke related disability. Survivors are at high risk of major vascular events, nevertheless, data on long-term prognosis after ICH are scarce. The main objective was to study long term cerebral and extra-cerebral vascular prognosis after ICH.Methods: We included patients from the PITCH (Prognosis of Intra Cerebral Haemorrhage) cohort which is a prospective and observational study that included consecutive adults admitted at the Lille University Hospital for spontaneous ICH between 2004 and 2009. We aimed to determine (i) cumulative incidence of major ischemic and hemorrhagic vascular events and their clinical and radiological predictors;(ii) the prevalence of cortical superficial siderosis (cSS) and its associated factors; (iii) the impact of cerebral microbleeds on ICH recurrence.Results: We showed that ICH survivors are at high risk of major cerebral and extracerebralvascular events. Ischemic risk overwhelmed the hemorrhagic one on long term,particularly in deep index ICH. Concerning recurrent ICH, we found that in our cohort,one out of five patients had cSS on baseline MRI and its presence was a strong predictorof recurrent ICH, suggesting the implication of underlying cerebral amyloid angiopathy.Global burden of microbleeds was also associated with higher rate of ICH recurrence.Conclusion: These findings have immediate clinical relevance and suggest that ICH survivors should benefit of a long-term and multidisciplinary follow-up. These results may also provide additional information on the risk of major ischemic and hemorrhagicevents after ICH and on radiological predictors of recurrence risk

Pronostic vasculaire au long cours des patients après une hémorragie intracérébrale

Background: Spontaneous (non-traumatic) intracerebral hemorrhage (ICH) is the mostdramatic type of stroke being responsible for the majority of mortality and stroke related disability. Survivors are at high risk of major vascular events, nevertheless, data on long-term prognosis after ICH are scarce. The main objective was to study long term cerebral and extra-cerebral vascular prognosis after ICH.Methods: We included patients from the PITCH (Prognosis of Intra Cerebral Haemorrhage) cohort which is a prospective and observational study that included consecutive adults admitted at the Lille University Hospital for spontaneous ICH between 2004 and 2009. We aimed to determine (i) cumulative incidence of major ischemic and hemorrhagic vascular events and their clinical and radiological predictors;(ii) the prevalence of cortical superficial siderosis (cSS) and its associated factors; (iii) the impact of cerebral microbleeds on ICH recurrence.Results: We showed that ICH survivors are at high risk of major cerebral and extracerebralvascular events. Ischemic risk overwhelmed the hemorrhagic one on long term,particularly in deep index ICH. Concerning recurrent ICH, we found that in our cohort,one out of five patients had cSS on baseline MRI and its presence was a strong predictorof recurrent ICH, suggesting the implication of underlying cerebral amyloid angiopathy.Global burden of microbleeds was also associated with higher rate of ICH recurrence.Conclusion: These findings have immediate clinical relevance and suggest that ICH survivors should benefit of a long-term and multidisciplinary follow-up. These results may also provide additional information on the risk of major ischemic and hemorrhagicevents after ICH and on radiological predictors of recurrence risk.Contexte : Les hémorragies intracérébrales spontanées (HIC) présentent une mortalité élevée et un pronostic fonctionnel sombre. Les survivants sont à haut risque d’évènements vasculaires majeurs mais les données concernant le pronostic au long terme des HIC sont limitées. L’objectif principal de ce travail était d’étudier le pronostic vasculaire cérébral et extra-cérébral au long cours.Méthodes : Nous avons inclus les patients de la cohorte prospective et observationnelle PITCH (Prognosis of Intra Cerebral Haemorrhage), qui a recruté de façon consécutive tous les patients admis au CHU de Lille pour une HIC spontanée entre 2004 et 2009.Nous avons étudié (i) l’incidence des évènements vasculaires majeurs, ischémiques ethémorragiques, ainsi que leurs facteurs prédictifs cliniques et neuroradiologiques ; (ii)la prévalence de la sidérose superficielle corticale (SSc) et les facteurs cliniques et radiologiques associés ; (iii) l’impact des micro hémorragies cérébrales sur le risque de récidive hémorragique.Résultats : Nous avons mis en évidence qu’il existait un risque élevé d’évènements vasculaires majeurs, cérébraux et extra-cérébraux, chez les patients ayant souffert d’une HIC. Au long cours, le risque d’évènements ischémiques dépasse le risque hémorragique, en particulier chez les patients avec une hémorragie profonde.Concernant le risque hémorragique cérébral, nous avons montré qu’au sein de notre cohorte, un patient sur cinq avait de la SSc sur l’IRM cérébrale réalisée à l’admission et que la présence de SSc est un facteur neuroradiologique prédictif majeur de récidive hémorragique, suggérant l’implication de l’angiopathie amyloïde cérébrale. Un nombre élevé de microhémorragies cérébrales est par ailleurs associé à un risque de récidive hémorragique plus importante.Conclusion : Les résultats de ce travail ont un impact clinique important, ils suggèrent l’indication d’un suivi au long cours et multidisciplinaire des patients ayant présenté une HIC. Ils apportent des informations nouvelles sur le risque extra-cérébral et sur les prédicteurs de récidive hémorragique

Sumatriptan succinate. pharmacokinetics of different formulations in clinical practice

Introduction: Migraine is a common neurovascular disorder characterized by recurrent episodes of disabling headache, autonomic nervous system dysfunction, and in some patients, neurological aura symptoms. Triptans are frequently prescribed drugs for the treatment of the acute migraine attack, considering their capability to provide wide efficacy and tolerability. Areas covered: This review discusses pharmacodynamics and pharmacokinetics of sumatriptan succinate, considering the clinical impact of new drug formulations in the treatment of acute migraine and cluster headache. The data were obtained by searching the following keywords in MEDLINE: sumatriptan succinate, pharmacokinetics, pharmacodynamics, triptans, migraine, new delivery systems, relative to the period 1989 - 2012. Expert opinion: Subcutaneous sumatriptan has been considered as the most efficacious treatment in the acute phase of migraine both on pain alone as well as on associated autonomic symptoms. Pharmacologically, pharmacokinetic parameters, in particular bioavailability, T-max and C-max are responsible for the wide efficacy of the compound and the limited adverse effect (AE) profile. The new drug formulations that are the most similar to the pharmacokinetics parameters of the subcutaneous one are promising because they both improve pharmacokinetic bioavailability bypassing the first-pass metabolism and increase patient compliance