[Acute and chronic toxicities associated with the use and misuse of nitrous oxide: An update]. / Toxicités aiguës et chroniques associées à l'usage et au mésusage du protoxyde d'azote : mise au point.

Nitrous oxide (N2O) is used since the eighteenth century as an anesthetic and analgesic but also for recreational use. If the labelled uses of N2O and their modalities are nowadays perfectly framed, the misuse of N2O takes very alarming proportions among teenagers and young adults. This misuse is the cause of acute (hypoxia, barotrauma, burns, neuropsychiatric disorders) and chronic complications if repeated (myeloneuropathy, anemia, thrombosis, inhalant use disorder). The main mechanism of the latter is mainly related to a functional deficit in vitamin B12 induced by N2O. The management of acute complications is symptomatic. The management of chronic complications is based on vitamin B12 supplementation. The best biomarker of chronic N2O exposure is the elevation of the plasmatic level of methylmalonic acid. In all cases of recreational misuses, addiction treatment is necessary to prevent complications or their worsening by providing information in order to stop consumption.

Outcomes of Acute Stroke Patients Requiring Mechanical Ventilation: Study Protocol for the SPICE Multicenter Prospective Observational Study.

BACKGROUND: Care pathways and long-term outcomes of acute stroke patients requiring mechanical ventilation have not been thoroughly studied. METHODS AND RESULTS: Stroke Prognosis in Intensive Care (SPICE) is a prospective multicenter cohort study which will be conducted in 34 intensive care units (ICUs) in the Paris, France area. Patients will be eligible if they meet all of the following inclusion criteria: (1) age of 18 years or older; (2) acute stroke (i.e., ischemic stroke, intracranial hemorrhage, or subarachnoid hemorrhage) diagnosed on neuroimaging; (3) ICU admission within 7 days before or after stroke onset; and (4) need for mechanical ventilation for a duration of at least 24 h. Patients will be excluded if they meet any of the following: (1) stroke of traumatic origin; (2) refusal to participate; and (3) privation of liberty by administrative or judicial decision. The primary endpoint is poor functional outcome at 1 year, defined by a score of 4 to 6 on the modified Rankin scale (mRS), indicating severe disability or death. Main secondary endpoints will include decisions to withhold or withdraw care, mRS scores at 3 and 6 months, and health-related quality of life at 1 year. CONCLUSIONS: The SPICE multicenter study will investigate 1-year outcomes, ethical issues, as well as care pathways of acute stroke patients requiring invasive ventilation in the ICU. Gathered data will delineate human resources and facilities needs for adequate management. The identification of prognostic factors at the acute phase will help to identify patients who may benefit from prolonged intensive care and rehabilitation. TRIAL REGISTRATION: NCT03335995.

Can anticoagulation therapy in cerebral venous thrombosis associated with Behçet's disease be stopped without relapse?

There is as yet no consensus on the treatment of cerebral venous thrombosis (CVT) in Behçet's disease, and the place of anticoagulation is also still being debated. This report is of a series of seven patients with Behçet's disease (BD)-associated CVT, for which anticoagulation was stopped, and discusses the possibility of stopping anticoagulation during follow-up while receiving optimal treatment for BD. The diagnosis of BD was established during follow-up, which lasted a median of 120 [range: 60-1490] days after CVT diagnosis. The median duration of anticoagulation therapy was 29.5 months. On stopping anticoagulation, concomitant treatment then included colchicine, steroids and azathioprine, all introduced after BD was diagnosed. With a median follow-up of 25 months after anticoagulation interruption, only one relapse of CVT was observed. No relapse of CVT or other venous thrombosis was observed in the six patients treated by steroids associated with an immunosuppressant or colchicine. Our results emphasize that corticosteroids are essential for the treatment of BD-associated CVT, and that anticoagulant therapy may be safely stopped during follow-up in the presence of optimal BD treatment (steroids alone or with immunosuppressive drugs).

European Stroke Organization guideline for the diagnosis and treatment of cerebral venous thrombosis - endorsed by the European Academy of Neurology.

BACKGROUND AND PURPOSE: Current guidelines on cerebral venous thrombosis (CVT) diagnosis and management were issued by the European Federation of Neurological Societies in 2010. We aimed to update the previous European Federation of Neurological Societies guidelines using a clearer and evidence-based methodology. METHOD: We followed the Grading of Recommendations, Assessment, Development and Evaluation system, formulating relevant diagnostic and treatment questions, performing systematic reviews and writing recommendations based on the quality of available scientific evidence. RESULTS: We suggest using magnetic resonance or computed tomographic angiography for confirming the diagnosis of CVT and not routinely screening patients with CVT for thrombophilia or cancer. We recommend parenteral anticoagulation in acute CVT and decompressive surgery to prevent death due to brain herniation. We suggest preferentially using low-molecular-weight heparin in the acute phase and not direct oral anticoagulants. We suggest not using steroids and acetazolamide to reduce death or dependency. We suggest using antiepileptics in patients with an early seizure and supratentorial lesions to prevent further early seizures. We could not make recommendations concerning duration of anticoagulation after the acute phase, thrombolysis and/or thrombectomy, therapeutic lumbar puncture, and prevention of remote seizures with antiepileptic drugs. We suggest that, in women who have suffered a previous CVT, contraceptives containing oestrogens should be avoided. We suggest that subsequent pregnancies are safe, but use of prophylactic low-molecular-weight heparin should be considered throughout pregnancy and puerperium. CONCLUSIONS: Multicentre observational and experimental studies are needed to increase the level of evidence supporting recommendations on the diagnosis and management of CVT.

Effect of the thromboxane prostaglandin receptor antagonist terutroban on arterial thrombogenesis after repeated administration in patients treated for the prevention of ischemic stroke.

BACKGROUND: The antithrombotic, antiplatelet and endothelial activity of terutroban, a specific thromboxane prostaglandin receptor antagonist, was assessed in patients previously treated with aspirin for the prevention of ischemic stroke. METHODS: This double-blind, parallel-group, 10-day study included 48 patients (age = 70.5 +/- 9.5 years) with cerebral ischemic event and/or carotid stenosis in 4 groups: terutroban 10 mg/day (n = 13), aspirin 300 mg/day (n = 12), terutroban 10 mg/day + aspirin 300 mg/day (n = 11) or clopidogrel 75 mg/day + aspirin 300 mg/day (n = 12). The measurements included parameters from an ex vivo model of thrombosis, platelet aggregation in platelet-rich plasma and plasma biomarkers of endothelial/platelet activation. RESULTS: Between days 0 and 10, the mean cross-sectional surface of dense thrombus significantly decreased with terutroban (58%, p = 0.001), terutroban + aspirin (63%, p = 0.005) and clopidogrel + aspirin (61%, p < 0.05). On day 10, the value for terutroban was significantly lower than that for aspirin (p < 0.01) and was comparable to the dual therapy terutroban + aspirin or clopidogrel + aspirin. Similar results were found for total thrombus surface and platelet adhesion. Platelet aggregation induced by the specific thromboxane prostaglandin receptor agonist U46619 was almost completely inhibited on day 10 in both terutroban groups but not in the others. As regards markers of endothelial/platelet activation or lesions, thrombomodulin significantly increased and plasma soluble P selectin significantly decreased by day 10 in both terutroban groups, whereas the von Willebrand factor did not change significantly. Terutroban was found to be safe and well TOLERATED. CONCLUSIONS: Terutroban has demonstrated an antithrombotic activity that is superior to aspirin and similar to clopidogrel + aspirin; it induces a significant in vivo reduction in endothelial/platelet activation.

Vascular risk factors and morphometric data in cervical artery dissection: a case-control study.

BACKGROUND: Limited knowledge exists on vascular risk factors, body height and weight in patients with spontaneous cervical artery dissection (sCAD). PATIENTS AND METHODS: In this case-control study, major vascular risk factors, body weight, body height and body mass index (BMI) of 239 patients obtained from a prospective hospital-based sCAD registry were compared with 516 age- and sex-matched healthy controls undergoing systematic health examinations in the Clinical and Preventive Investigations Center, Paris. Gender-specific analyses were performed. RESULTS: The mean body height was higher in sCAD patients than in controls (171.3 cm (SD 8.6) vs 167.7 cm (8.9); p<0.0001) and sCAD patients had a significantly lower mean body weight (67.5 (12.2) kg vs 69.3 (14.6) kg; p<0.001) and mean BMI (22.9 (3.3) kg/m2 vs 24.5 (4.2) kg/m2; p<0.0001) than controls. The overall frequency of hypertension, diabetes, current smoking, past smoking and hypercholesterolaemia did not differ significantly between sCAD patients and controls. The mean total plasma cholesterol level was identical in both groups (5.5 mmol/l, SD 1.1). Gender specific subgroup analyses showed similar results for men and women. CONCLUSION: Patients with sCAD had a higher body height and a lower body weight and BMI than controls, while major vascular risk factors were similar in sCAD patients and controls.

MR imaging features of isolated cortical vein thrombosis: diagnosis and follow-up.

BACKGROUND AND PURPOSE: To our knowledge, very few MR imaging data have been reported in isolated cortical venous thrombosis (ICoVT). The purpose of this study was to describe MR imaging features, including T2*gradient-echo (GE) sequence, in presumed ICoVT. MATERIALS AND METHODS: MR imaging examinations were performed in 8 patients with ICoVT (MR venography was performed in all patients and digital substraction angiography in 4) at the time of diagnosis and during the follow-up at 15 days (4 patients) and at 3 (8 patients), 6 (6 patients), 12 (3 patients), and 18 months (1 patient). We assessed the presence of a magnetic susceptibility effect (MSE) on T2*GE imaging at each site of cerebral venous thrombosis and the presence or absence of a normal flow void and iso-, hypo-, or hyperintense signal intensity on T1, T2, diffusion-weighted imaging (DWI), and fluid-attenuated inversion recovery (FLAIR) images. Parenchymal signal-intensity changes were also assessed on the same sequences. RESULTS: MSE was detected on T2*GE imaging at the site of a cortical vein in all subjects at the first MR imaging examination. The occluded vein appeared as hyperintense in 3 patients, iso- to slightly hyperintense in 1 on T1, hypointense in 6 on FLAIR images, and as signal-intensity loss on DWI in 3. At follow-up, persisting signal-intensity abnormalities on T2*GE imaging were detected at the venous sites in all patients, whereas signal-intensity changes on T1- and T2-weighted images were no longer present. Parenchymal hyperintensities on FLAIR and DWI (increased apparent diffusion coefficient [ADC]) were observed in close vicinity to the thrombosis in 6/8 patients. Petechial hemorrhages (n = 3) or hematoma (n = 2) was present on T2*GE imaging in 5/8 patients. During the follow-up, all cerebral tissue signal-intensity changes on T1, T2, and FLAIR images decreased both in volume and intensity. ADC values normalized within the tissue after 3 months in all patients. CONCLUSIONS: On T2*GE imaging, MSE of hemoglobin products within the thrombus was observed both at the early and late phases of ICoVT and appears to be of high diagnostic value compared with the other signal intensity changes detected on standard MR imaging.

[Cerebral venous thrombosis]. / Thromboses veineuses cérébrales: mise au point.

INTRODUCTION: Although more rare than arterial thrombosis, cerebral venous thrombosis are a non-negligible cause of stroke. Characterised by the large diversity of clinical presentations and etiologies, they have a much better prognosis than arterial stroke. The evolution remains unforeseeable, with a non-negligible proportion of worsening at the acute phase and diagnosis must be early to begin as soon as possible the treatment, which is at present based on heparin therapeutics. CURRENT KNOWLEDGE AND KEY POINTS: Neuroimaging examinations are essential for diagnosis of CVT. MR Imaging with MR venography is the key procedure. New sequences are on evaluation in CVT bringing some physiopathogical arguments (Diffusion weighted imaging) or help for diagnosis (with T2* MRI sequence). If D-dimers dosage is helpful for diagnosis of deep venous thrombosis, its interest remains to be determined during CVT. CONCLUSION: CVT diagnosis is a challenge for the clinician. Because of the multiple causes and favorising factors, CVT are at the convergence of many specialties and could thus benefit of each one contribution for better understanding the physiopathology, improving earlier diagnosis or identifying the severe forms that could require right away more aggressive treatments than heparin. The interest of local thrombolysis or thrombectomy remains to be determined in an international randomised study.

[Headache in patients with cerebral venous thrombosis]. / Céphalées au cours des thromboses veineuses cérébrales.

Headache is the most frequent symptom of cerebral venous thrombosis. They do not have particular characteristics and can mimic other numerous varieties of headache. Frequently associated with other neurological symptoms, such as intracranial hypertension, seizures, focal deficits or disorders of consciousness, they are sometimes isolated, which stresses the need for investigations in all recent and unusual headache.

Headache as the only neurological sign of cerebral venous thrombosis: a series of 17 cases.

BACKGROUND: Headache is the most frequent symptom in cerebral venous thrombosis (CVT), and usually the first. However, it has rarely been reported as the only symptom of CVT. OBJECTIVES: To study the characteristics of patients in whom headache was the only presentation of CVT in the absence of intracranial hypertension, subarachnoid haemorrhage (SAH), meningitis, or other intracranial lesion. METHODS: From a prospective study of 123 consecutive patients with CVT only those with isolated headache and normal brain computed tomography (CT) scan and cerebrospinal fluid (CSF) examination were included in the present study. All patients underwent an extensive systematic aetiological work-up and were given intravenous heparin followed by oral anticoagulants. A detailed description of the headache was obtained. RESULTS: Headache was only sign of CVT in 17 patients. The lateral sinus was the most frequently involved sinus (n = 15). Onset of headache was progressive in 11, acute in 3, and thunderclap in 3 patients. Once established, the headache was continuous in 15, diffuse in four and unilateral in 13, usually ipsilateral to the occluded lateral sinus. No specific risk factor or cause was found. All had a favourable evolution. CONCLUSION: The pathogenesis of isolated headache in CVT in the absence of intracranial hypertension, SAH, meningitis or intracerebral lesion is unknown but may involve changes in the walls of the occluded sinus. Hence MRI/MRV should be used to look for signs of CVT in all patients with recent headache (progressive or thunderclap) even when the CT scan and CSF examination are normal.

Migraine and haemostasis.

Migraine is a risk factor for cerebral infarction in young women. The nature of the connection between these diseases remains however essentially unknown. Abnormalities of haemostasis leading to an increased thrombotic risk would provide a logical link. Platelets, antiphospholipid antibodies and more recently congenital thrombophilia have thus successively been implicated. The different studies concerning these topics have been reviewed. Because of the conflicting results obtained and because of the numerous methodological shortcomings of many of these studies, no definite conclusion can be reached. It is possible that these 3 factors play a role in the ischemic risk of migraine, but it is as likely or even more likely that other factors (inside or outside the hemostatic system) play a more important role. Further studies are thus deeply needed.

[Aspirin and cerebral ischemic accidents]. / Aspirine et accidents ischémiques cérébraux.

At the acute phase of cerebral infarction, two recent large studies found that the use of aspirin reduces both mortality and the risk of the recurrence of stroke. In primary prevention, aspirin nearly halves the risk of myocardial infarction but does not reduce that of stroke. Concerning the secondary prevention of atherothrombotic brain infarcts, aspirin has been the most extensively studied drug, and is efficient between 50 mg and 1.3 g. In spite of the efficacy of other antiplatelets in this indication--ticlopidine (500 mg), clopidogrel (75 mg) and dipyridamole (400 mg)--aspirin remains the most cost-effective, doses between 100 and 300 mg being the most widely used. Cardiac diseases with a high embolic risk require the use of oral anticoagulation. In nonvalvular atrial fibrillation, the choice of antithrombotic drugs depends on risk stratification: oral anticoagulants are indicated in high-risk subjects, whereas aspirin is recommended in low-risk subjects and when oral anticoagulants are contraindicated. Studies with associations of aspirin and other antiplatelets are required to increase the yield of this medication in high-risk subjects, in parallel with efforts to detect and to treat the vascular risk factors.

Poly(ADP-ribose) polymerase alleles in French Caucasians are associated neither with lupus nor with primary antiphospholipid syndrome. GRAID Research Group. Group for Research on Auto-Immune Disorders.

OBJECTIVE: To investigate the putative involvement of poly(ADP-ribose) polymerase (PARP) alleles in systemic lupus erythematosus (SLE) and primary antiphospholipid syndrome (APS). METHODS: This study of French Caucasians included 171 unrelated patients with SLE, 88 unrelated patients with primary APS, and 193 ethnically matched healthy controls. The SLE group comprised 89 patients with sporadic SLE and 82 patients with familial SLE. Patients' and controls' DNA were genotyped for the various alleles of a polymorphic CA dinucleotide repeat located within the promoter region of PARP. RESULTS: No statistically significant difference was observed for the distribution of PARP alleles between the healthy control group and each patient group or the pooled SLE patient group. CONCLUSION: The study findings strongly suggest that these alleles do not influence susceptibility to SLE or primary APS in French Caucasians.

[Antiplatelet drugs for prevention of cerebral ischemic accidents]. / Les antiplaquettaires dans la prévention des accidents ischémiques cérébraux.

Antiplatelet (AP) drugs play a major role in stroke prevention. Aspirin (50-1300 mg), ticlopidine (500 mg), clopidogrel (75 mg) and dipyridamole (400 mg) are effective in secondary prevention of atherothrombotic brain infarcts. Aspirin has been the most extensively studied drug and remains the most cost-effective one. The optimal dose is still debated; doses between 100 and 300 mg are the most widely used. The preventive efficacy of aspirin is already present at the acute phase of cerebral infarct. In primary prevention, aspirin nearly halves the risk of myocardial infarction but does not reduce that of stroke. Cardiac diseases with a high embolic risk require the use of oral anticoagulation. In non valvular atrial fibrillation, the choice of antithrombotic drugs depends on risk stratification: oral anticoagulants are indicated in high risk subjects whereas aspirin is recommended in low risk subjects and when oral anticoagulants are contraindicated. Studies with new associations of AP and with new drugs are required to increase the yield of the antiplatelet approach in high risk subjects; this should be done in parallel with efforts to detect and to treat the vascular risk factors associated with the development of a mass approach for stroke primary prevention.

[Mechanisms and causes of cerebral ischemic accidents]. / Mécanismes et causes des accidents ischémiques cérébraux.

The treatment of an ischaemic stroke requires the understanding of its mechanism and the diagnosis of its cause. Two main pathophysiologic mechanisms are implicated: thromboembolic occlusion and hemodynamic failure. The knowledge of the pathophysiology is crucial to the therapeutic options particularly as regards anti-thrombotic treatments and strict bed rest. As regards etiology, most ischaemic strokes are due to 3 conditions: large artery atheroma, cardiac diseases and small perforating arteries diseases. There are numerous other causes (arterial, toxic, metabolic...) which are rare but must be looked for particularly in young subjects devoid of cardiac diseases. The discovery of a cause is important for the acute treatment of an ischaemic stroke and for the choice of secondary prevention measures.

Mitral valve strands and the risk of ischemic stroke in elderly patients. The French Study of Aortic Plaques in Stroke (FAPS) Investigators.

BACKGROUND AND PURPOSE: Strands are thin and filamentous attachments on the cardiac valves shown by transesophageal echocardiography. Their nature and their potential for embolization are largely unknown. The objective was to estimate the risk of brain infarction in patients with mitral valve strands. METHODS: Using transesophageal echocardiography, we compared the frequency of strands on native mitral valves in 284 consecutive patients admitted with brain infarction and 276 control patients, all older than 60 years. In a second part, case subjects were followed up over a 2- to 4-year period, and the risk of recurrence of brain infarction was estimated in patients with and without strands. RESULTS: In the case-control study, mitral valve strands were found in 22.5% of the case patients and in 12.1% of the control subjects. In case subjects, mitral valve strands were more frequent in those with mitral valve dystrophy (52.4% versus 37.4%; P = .03). Strands were not associated with mitral valve prolapse, annular calcifications, or left atrial spontaneous echocardiographic contrast. After adjustment for age, sex, and mitral valve dystrophy, the odds ratio for ischemic stroke among patients with mitral strands was 2.2 (95% confidence interval, 1.4 to 3.6; P = .005). The frequency of strands was not different in patients with a known cause of brain infarction (24.4%) from that in patients with no other apparent cause (20.9%). During 646 per 100 person-years of follow-up, the incidence of recurrent brain infarction was 6.0 person-years in patients with strands and 4.2 in those without. In the Cox analysis, including potential confounders and poststroke treatment, mitral valve strands did not appear as independent predictors of recurrent brain infarction (relative risk, 1.3; 95% confidence interval, 0.5 to 3.0; P = .54). CONCLUSIONS: The present study shows an independent association between mitral valve strands and the risk of brain infarction. However, the lack of an increased relative risk of recurrence raises doubts about the potential causal relation with brain infarction in patients aged 60 years or older.