Thierry Moulin

Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): a randomised placebo-controlled trial

BACKGROUND Hemiplegia and hemiparesis are the most common deficits caused by stroke. A few small clinical trials suggest that fluoxetine enhances motor recovery but its clinical efficacy is unknown. We therefore aimed to investigate whether fluoxetine would enhance motor recovery if given soon after an ischaemic stroke to patients who have motor deficits. METHODS In this double-blind, placebo-controlled trial, patients from nine stroke centres in France who had ischaemic stroke and hemiplegia or hemiparesis, had Fugl-Meyer motor scale (FMMS) scores of 55 or less, and were aged between 18 years and 85 years were eligible for inclusion. Patients were randomly assigned, using a computer random-number generator, in a 1:1 ratio to fluoxetine (20 mg once per day, orally) or placebo for 3 months starting 5-10 days after the onset of stroke. All patients had physiotherapy. The primary outcome measure was the change on the FMMS between day 0 and day 90 after the start of the study drug. Participants, carers, and physicians assessing the outcome were masked to group assignment. Analysis was of all patients for whom data were available (full analysis set). This trial is registered with ClinicalTrials.gov, number NCT00657163. FINDINGS 118 patients were randomly assigned to fluoxetine (n=59) or placebo (n=59), and 113 were included in the analysis (57 in the fluoxetine group and 56 in the placebo group). Two patients died before day 90 and three withdrew from the study. FMMS improvement at day 90 was significantly greater in the fluoxetine group (adjusted mean 34·0 points [95% CI 29·7-38·4]) than in the placebo group (24·3 points [19·9-28·7]; p=0·003). The main adverse events in the fluoxetine and placebo groups were hyponatraemia (two [4%] vs two [4%]), transient digestive disorders including nausea, diarrhoea, and abdominal pain (14 [25%] vs six [11%]), hepatic enzyme disorders (five [9%] vs ten [18%]), psychiatric disorders (three [5%] vs four [7%]), insomnia (19 [33%] vs 20 [36%]), and partial seizure (one [<1%] vs 0). INTERPRETATION In patients with ischaemic stroke and moderate to severe motor deficit, the early prescription of fluoxetine with physiotherapy enhanced motor recovery after 3 months. Modulation of spontaneous brain plasticity by drugs is a promising pathway for treatment of patients with ischaemic stroke and moderate to severe motor deficit. FUNDING Public French National Programme for Clinical Research.

Arterial territories of the human brain : Cerebral hemispheres

The development of neuroimaging has allowed clinicians to improve clinicoanatomic correlations in patients with stroke. Anatomic structures are well delineated on MRI, but there is a lack of standardization in their arterial supply. As in our previous study depicting the arterial supply of the brainstem and cerebellum, we present a system of 12 axial sections of the hemispheres depicting the dominant arterial territories, the most important anatomic structures, and Brodmanns areas. The area of variation of the cortical territory of the anterior, middle, and posterior cerebral arteries is also represented. These sections may be used as a practical tool to determine arterial territories on CT or MRI, and may help establish consistent clinicoanatomic correlations in patients with supratentorial stroke.

Arterial territories of human brain Brainstem and cerebellum

The development of neuroimaging has allowed clinicians to improve clinicoanatomic correlations in patients with strokes.Brainstem and cerebellum structures are well delineated on MRI, but there is a lack of standardization in their arterial supply. We present a system of 12 brainstem and cerebellum axial sections, depicting the dominant arterial territories and the most important anatomic structures. These sections may be used as a practical tool to determine arterial territories on MRI, and may help establish consistent clinicoanatomic correlations in patients with brainstem and cerebellar ischemic strokes. NEUROLOGY 1996;47: 1125-1135

Stroke Patterns of Internal Carotid Artery Dissection in 40 Patients

BACKGROUND AND PURPOSE Internal carotid artery dissection (ICAD) is a frequent cause of ischemic stroke in young patients. Whether cerebral ischemia is of embolic or hemodynamic origin remains to be determined. Heparin is often administered in ICAD; however, a drug trial can hardly be conducted because of the low recurrence rate after the acute stage. Therefore, the best therapeutic approach should be determined on the basis of the presumed mechanism of cerebral ischemia. One way to approach the mechanism of stroke in ICAD is to determine stroke patterns. We postulated that most cortical and large subcortical infarcts (>/=15 mm) are of embolic origin and that small subcortical infarcts (<15 mm) and junctional infarcts are not. The aim of our study was to determine the stroke patterns in 40 consecutive patients with ICAD. METHODS The patients (26 women and 14 men; mean age, 42.8 years) had a total of 65 ICADs. Seventeen patients were free of any vascular risk factor. CT scans, MRI scans, and angiographic features were analyzed by observers who were blinded to the clinical findings. RESULTS We found 34 cortical infarcts, 25 large subcortical infarcts, 1 small subcortical infarct, and 5 junctional infarcts. CONCLUSIONS Most infarcts related to ICAD are cortical infarcts or large subcortical infarcts; small subcortical infarcts and junctional infarcts are infrequent. Therefore, these findings suggest that most infarcts occurring in carotid artery dissection (CAD) are probably embolic rather than hemodynamic in origin. According to this presumed mechanism, anticoagulation seems a logical treatment at the early stage of CAD.

Early CT signs in acute middle cerebral artery infarction Predictive value for subsequent infarct locations and outcome

During the first hours after acute ischemic stroke, the CT usually shows no abnormalities.Therapeutic trials of ischemia in the middle cerebral artery (MCA) territory involves decision-making when the CT may not show obvious ischemic changes. We reviewed 100 consecutive patients, admitted within 14 hours after a first stroke. Selective criteria were clinical presentation with MCA ischemia and at least two CTs (1 initial and 1 control). All CTs were retrospectively analyzed by at least two physicians blinded to the patients status. On the first CT, early signs were hyperdense MCA sign (HMCAS), early parenchymatous signs (attenuation of the lentiform nucleus [ALN], loss of the insular ribbon [LIR], and hemispheric sulcus effacement [HSE]), midline shift, and early infarction. Subsequent infarct locations were classified according to total, partial superficial (superior or inferior), deep, or multiple MCA territories. Clinical features, etiology, and Rankin scale were collected. There were 52 women (mean age 70.8). The CTs were performed at mean 6.4 hours (1 to 14 hours) and before the sixth hour in 62% of the patients. Early CT was abnormal in 94% of the cases, and the abnormalities found were an HMCAS in 22 patients, ALN in 48, LIR in 59, HSE in 69, midline shift in 5, and early infarct in 7. CT was normal in six patients where it was performed earliest (mean 4.5 hours) and in the oldest patients (mean age 80.1). Early parenchymatous CT signs were significantly associated with subsequent MCA infarct location and extension: ALN and deep infarct, HSE and superficial infarct, LIR and large infarct. HMCAS was never found in isolation and was always associated with the three other signs in extended MCA infarct. The presence of two or three signs (ALN, LIR, or HSE) was associated with extended MCA infarct (p < 0.001) and poor outcome (p < 0.001). Our findings suggest that CT frequently discloses parenchymal abnormalities during the first hours of ischemic stroke. Early signs allow the prediction of subsequent infarct locations; CT may provide a simple tool in evaluating the early prognosis of MCA infarction and thus may be useful in selecting better treatments. NEUROLOGY 1996;47: 366-375

Risk of stroke and recurrent dissection after a cervical artery dissection: A multicenter study

Objective: To assess the risk of stroke, TIA, or dissection recurrence after a first event of cervical artery dissection (CAD). Methods: The authors undertook a historical cohort study of consecutive patients with a first event of CAD who were admitted in 24 departments of neurology within a period of at least 1 year. Patients were retrospectively selected from a stroke data bank or from the local administrative data bank using the 10th revision of the International Statistical Classification of Diseases. A neurologist and a radiologist reviewed all charts to validate diagnosis and collect data. In 2002, patients were interviewed by phone or during a visit by the local investigators. Results: Four hundred fifty-nine patients (mean age 44.0 ± 9.7 years) were included in the study. Among the 457 survivors, 25 (5.5%) could not be contacted in 2002 because they had moved. After a mean follow-up of 31 months, four (0.9%) patients presented a recurrent ischemic stroke attributable to either not yet completely recovered initial CAD (n = 2) or a recurrent CAD (n = 2). Eight (1.8%) patients had a TIA without CAD recurrence. Two TIA occurred at the acute stage of CAD. Of the six remaining TIA, only one was associated with chronic arterial stenosis. In addition, two patients had recurrent CAD without stroke, giving a total of four (0.9%) CAD recurrences. Conclusions: Patients with a first event of CAD have a very low risk of ischemic events or dissection recurrences. Ischemic events seem rarely to be in relation with chronic arterial lesions.

Mechanical thrombectomy after intravenous alteplase versus alteplase alone after stroke (THRACE): a randomised controlled trial

BACKGROUND Intravenous thrombolysis with alteplase alone cannot reperfuse most large-artery strokes. We aimed to determine whether mechanical thrombectomy in addition to intravenous thrombolysis improves clinical outcome in patients with acute ischaemic stroke. METHODS THRACE is a randomised controlled trial done in 26 centres in France. Patients aged 18-80 years with acute ischaemic stroke and proximal cerebral artery occlusion were randomly assigned to receive either intravenous thrombolysis alone (IVT group) or intravenous thrombolysis plus mechanical thrombectomy (IVTMT group). Intravenous thrombolysis (alteplase 0·9 mg/kg [maximum 90 mg], with an initial bolus of 10% of the total dose followed by infusion of the remaining dose over 60 min) had to be started within 4 h and thrombectomy within 5 h of symptom onset. Occlusions had to be confirmed by CT or magnetic resonance angiography. Randomisation was done centrally with a computer-generated sequential minimisation method and was stratified by centre. The primary outcome was the proportion of patients achieving functional independence at 3 months, defined by a score of 0-2 on the modified Rankin scale, assessed in the modified intention-to-treat population (ie, patients lost to follow-up and those with missing data were excluded). Safety outcomes were analysed in the per-protocol population (ie, all patients who did not follow the protocol of their randomisation group precisely were excluded from the analysis). THRACE is registered with ClinicalTrials.gov, NCT01062698. FINDINGS Between June 1, 2010, and Feb 22, 2015, 414 patients were randomly assigned to the IVT group (n=208) or the IVTMT group (n=204). Four patients (two in each group) lost to follow-up and six (four in the IVT group and two in the IVTMT group) with missing data were excluded. 85 (42%) of 202 patients in the IVT group and 106 (53%) of 200 patients in the IVTMT group achieved functional independence at 3 months (odds ratio 1·55, 95% CI 1·05-2·30; p=0·028). The two groups had no significant differences in mortality at 3 months (24 [12%] deaths of 202 patients vs 27 [13%] of 206; p=0·70) or symptomatic intracranial haemorrhage at 24 h (four [2%] of 185 vs three [2%] of 192; p=0·71). Common adverse events related to thrombectomy were vasospasm (33 [23%] patients) and embolisation in a new territory (nine [6%]). INTERPRETATION Mechanical thrombectomy combined with standard intravenous thrombolysis improves functional independence in patients with acute cerebral ischaemia, with no evidence of increased mortality. Bridging therapy should be considered for patients with large-vessel occlusions of the anterior circulation. FUNDING French Ministry for Health.

Hemorrhagic Transformation in Acute Ischemic Stroke The MAST-E Study

BACKGROUND AND PURPOSE Hemorrhagic transformation (HT) is the most critical complication of thrombolytics in clinical trials in acute stroke. The aim of this study was to determine the rates and the predictors of HT in the Multicenter Acute Stroke Trial-Europe (MAST-E) study. METHODS We performed a post hoc analysis of MAST-E data designed to assess the safety and efficacy of streptokinase administered intravenously within 6 hours of stroke onset. HT included all intracerebral hemorrhages and symptomatic hemorrhages (SHT) associated with clinical worsening. The predictors of HT and SHT were determined using multivariate modeling. RESULTS Among the 310 patients included, 159 patients had HT and 37 SHT (97 and 33 in the streptokinase group and 62 and 4 in the placebo group, respectively). Patients with SHT had significantly more atrial fibrillation, diabetes mellitus, no heparin use, streptokinase treatment, and early CT signs. In the multivariate analysis, HT was predicted by early CT signs and streptokinase treatment. SHT was predicted by diabetes mellitus, early CT signs, streptokinase treatment, and the interaction between streptokinase treatment and decreased level of consciousness. Among the streptokinase-treated patients, the same predictors remained. CONCLUSIONS The relative risks of HT after streptokinase were in the same range in MAST-E as in other streptokinase and tPA trials. Early CT signs were strong predictors of both HT and SHT, stressing that these patients are at high risk of bleeding. In our study, the predictors of HT and SHT were similar to those of tPA trials in acute stroke.

Patent Foramen Ovale Closure or Anticoagulation vs. Antiplatelets after Stroke

BACKGROUND Trials of patent foramen ovale (PFO) closure to prevent recurrent stroke have been inconclusive. We investigated whether patients with cryptogenic stroke and echocardiographic features representing risk of stroke would benefit from PFO closure or anticoagulation, as compared with antiplatelet therapy. METHODS In a multicenter, randomized, open‐label trial, we assigned, in a 1:1:1 ratio, patients 16 to 60 years of age who had had a recent stroke attributed to PFO, with an associated atrial septal aneurysm or large interatrial shunt, to transcatheter PFO closure plus long‐term antiplatelet therapy (PFO closure group), antiplatelet therapy alone (antiplatelet‐only group), or oral anticoagulation (anticoagulation group) (randomization group 1). Patients with contraindications to anticoagulants or to PFO closure were randomly assigned to the alternative noncontraindicated treatment or to antiplatelet therapy (randomization groups 2 and 3). The primary outcome was occurrence of stroke. The comparison of PFO closure plus antiplatelet therapy with antiplatelet therapy alone was performed with combined data from randomization groups 1 and 2, and the comparison of oral anticoagulation with antiplatelet therapy alone was performed with combined data from randomization groups 1 and 3. RESULTS A total of 663 patients underwent randomization and were followed for a mean (±SD) of 5.3±2.0 years. In the analysis of randomization groups 1 and 2, no stroke occurred among the 238 patients in the PFO closure group, whereas stroke occurred in 14 of the 235 patients in the antiplatelet‐only group (hazard ratio, 0.03; 95% confidence interval, 0 to 0.26; P<0.001). Procedural complications from PFO closure occurred in 14 patients (5.9%). The rate of atrial fibrillation was higher in the PFO closure group than in the antiplatelet‐only group (4.6% vs. 0.9%, P=0.02). The number of serious adverse events did not differ significantly between the treatment groups (P=0.56). In the analysis of randomization groups 1 and 3, stroke occurred in 3 of 187 patients assigned to oral anticoagulants and in 7 of 174 patients assigned to antiplatelet therapy alone. CONCLUSIONS Among patients who had had a recent cryptogenic stroke attributed to PFO with an associated atrial septal aneurysm or large interatrial shunt, the rate of stroke recurrence was lower among those assigned to PFO closure combined with antiplatelet therapy than among those assigned to antiplatelet therapy alone. PFO closure was associated with an increased risk of atrial fibrillation. (Funded by the French Ministry of Health; CLOSE ClinicalTrials.gov number, NCT00562289.)

The Besançon Stroke Registry : An acute stroke registry of 2,500 consecutive patients

The purpose of this study was to estimate the frequency of various risk factors, courses and outcome of stroke subtypes in a large hospital-based stroke registry. The Centre Hospitalier Universitaire of Besançon is the only public hospital with a neurological department in the county to admit any unselected patient with an acute stroke. A prospective hospital-based registry using systematic computer coding of data was conducted. All patients were evaluated by standard testing (neuroimaging, Doppler ultrasonography and cardiac investigations). From 1987 to 1994, 2,500 stroke patients with a first-ever stroke were included in the Besançon Stroke Registry. There were 1,425 men (mean age 66.1 years) and 1,075 women (mean age 70.6 years). Ischemic stroke was present in 84% of the patients (cerebral infarction in 84.5% and transient ischemic attacks in 15.5%), primary intracerebral hemorrhage (PIH) in 14.2% and cerebral venous thrombosis in 1.8%. On the 1st day of the stroke 79.9% of the patients were admitted, 47.1% within 6 h. In addition, stroke severity was well correlated with the time of the patients admission. Past medical history of hypertension was the major risk factor occurring in 55.8% of all patients, followed by smoking, atrial fibrillation, ischemic heart disease, hypercholesterolemia and diabetes mellitus. Clinical presentation was distributed according to classical patterns. The in-hospital mortality rate was 13.6% and was higher in patients with infarcts (13.7%) or PIH (25.6%). Logistic regression analysis determined independent predictive factors for death: deterioration at 48 h [odds ratio (OR) 10.1, 95% confidence interval (CI) 7.0-14.5], initial loss of consciousness (OR 4.5, 95% CI 3.1-6.4), age > 70 (OR 2.6, 95% CI 1.8-3.8), complete motor deficit (OR 1.9, 95% CI 1.3-2.8), major cognitive syndrome (OR 1.5, 95% CI 1.1-2.3), hyperglycemia at admission (OR 1.007, 95% CI 1.004-1.01), female gender (OR 0.7, 95% CI 0.5-0.9) and regressive stroke onset (OR 0.2, 95% CI 0.1-0.5). The Besançon Stroke Registry is a useful tool for the study of the risk factors, clinical features, and the course of strokes in an early phase.