Carotid endarterectomy or stenting or best medical treatment alone for moderate-to-severe asymptomatic carotid artery stenosis: 5-year results of a multicentre, randomised controlled trial.

BACKGROUND: The optimal treatment for patients with asymptomatic carotid artery stenosis is under debate. Since best medical treatment (BMT) has improved over time, the benefit of carotid endarterectomy (CEA) or carotid artery stenting (CAS) is unclear. Randomised data comparing the effect of CEA and CAS versus BMT alone are absent. We aimed to directly compare CEA plus BMT with CAS plus BMT and both with BMT only. METHODS: SPACE-2 was a multicentre, randomised, controlled trial at 36 study centres in Austria, Germany, and Switzerland. We enrolled participants aged 50-85 years with asymptomatic carotid artery stenosis at the distal common carotid artery or the extracranial internal carotid artery of at least 70%, according to European Carotid Surgery Trial criteria. Initially designed as a three-arm trial including one group for BMT alone (with a randomised allocation ratio of 2·9:2·9:1), the SPACE-2 study design was amended (due to slow recruitment) to become two substudies with two arms each comparing CEA plus BMT with BMT alone (SPACE-2a) and CAS plus BMT with BMT alone (SPACE-2b); in each case in a 1:1 randomisation. Participants and clinicians were not masked to allocation. The primary efficacy endpoint was the cumulative incidence of any stroke or death from any cause within 30 days or any ipsilateral ischaemic stroke within 5 years. The primary safety endpoint was any stroke or death from any cause within 30 days after CEA or CAS. The primary analysis was by intention-to treat, which included all randomly assigned patients in SPACE-2, SPACE-2a, and SPACE-2b, analysed using meta-analysis of individual patient data. We did two-step hierarchical testing to first show superiority of CEA and CAS to BMT alone then to assess non-inferiority of CAS to CEA. Originally, we planned to recruit 3640 patients; however, the study had to be stopped prematurely due to insufficient recruitment. This report presents the primary analysis at 5-year follow-up. This trial is registered with ISRCTN, number ISRCTN78592017. FINDINGS: 513 patients across SPACE-2, SPACE-2a, and SPACE-2b were recruited and surveyed between July 9, 2009, and Dec 12, 2019, of whom 203 (40%) were allocated to CEA plus BMT, 197 (38%) to CAS plus BMT, and 113 (22%) to BMT alone. Median follow-up was 59·9 months (IQR 46·6-60·0). The cumulative incidence of any stroke or death from any cause within 30 days or any ipsilateral ischaemic stroke within 5 years (primary efficacy endpoint) was 2·5% (95% CI 1·0-5·8) with CEA plus BMT, 4·4% (2·2-8·6) with CAS plus BMT, and 3·1% (1·0-9·4) with BMT alone. Cox proportional-hazard testing showed no difference in risk for the primary efficacy endpoint for CEA plus BMT versus BMT alone (hazard ratio [HR] 0·93, 95% CI 0·22-3·91; p=0·93) or for CAS plus BMT versus BMT alone (1·55, 0·41-5·85; p=0·52). Superiority of CEA or CAS to BMT was not shown, therefore non-inferiority testing was not done. In both the CEA group and the CAS group, five strokes and no deaths occurred in the 30-day period after the procedure. During the 5-year follow-up period, three ipsilateral strokes occurred in both the CAS plus BMT and BMT alone group, with none in the CEA plus BMT group. INTERPRETATION: CEA plus BMT or CAS plus BMT were not found to be superior to BMT alone regarding risk of any stroke or death within 30 days or ipsilateral stroke during the 5-year observation period. Because of the small sample size, results should be interpreted with caution. FUNDING: German Federal Ministry of Education and Research (BMBF) and German Research Foundation (DFG).

Reversible Edema in the Penumbra Correlates With Severity of Hypoperfusion.

Background and Purpose: We aimed to investigate fluid-attenuated inversion recovery changes in the penumbra. Methods: We determined core and perfusion lesions in subjects from the WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke) and AXIS 2 trial (Granulocyte Colony-Stimulating Factor in Patients With Acute Ischemic Stroke) with perfusion- and diffusion-weighted imaging at baseline. Only subjects with a mismatch volume >15 mL and ratio >1.2 were included. We created voxel-based relative fluid-attenuated inversion recovery signal intensity (rFLAIR SI) maps at baseline and follow-up. We studied rFLAIR SI in 2 regions of interest: baseline penumbra (baseline perfusion lesion−[core lesion+voxels with apparent diffusion coefficient <620 10−6 mm2/s]) and noninfarcted penumbra (baseline perfusion lesion−follow-up fluid-attenuated inversion recovery lesion) at 24 hours (WAKE-UP) or 30 days (AXIS 2). We analyzed the association between rFLAIR SI and severity of hypoperfusion, defined as time to maximum of the residue function. Results: In the baseline penumbra, rFLAIR SI was elevated (ratio, 1.04; P=1.7×10−13; n=126) and correlated with severity of hypoperfusion (Pearson r, 0.03; P<1.0×10−4; n=126). In WAKE-UP, imaging at 24 hours revealed a further increase of rFLAIR SI in the noninfarcted penumbra (ratio, 1.05 at 24 hours versus 1.03 at baseline; P=7.1×10−3; n=43). In AXIS 2, imaging at 30 days identified reversibility of the rFLAIR SI (ratio, 1.02 at 30 days versus 1.04 at baseline; P=1.5×10−3; n=26) since it was no longer different from 1 (ratio, 1.01 at 30 days; P=0.099; n=26). Conclusions: Penumbral rFLAIR SI increases appear early after stroke onset, correlate with severity of hypoperfusion, further increase at 24 hours, and are reversible by 30 days. Registration: URL: https://clinicaltrials.gov; Unique identifier: NCT01525290. URL: https://clinicaltrials.gov; Unique identifier: NCT00927836.

CT versus MR Techniques in the Detection of Cervical Artery Dissection.

BACKGROUND: Spontaneous cervical artery dissection (sCAD) is an important etiology of juvenile stroke. The gold standard for the diagnosis of sCAD is convential angiography. However, magnetic resonance imaging (MRI)/MR angiography (MRA) and computed tomography (CT)/CT angiography (CTA) are frequently used alternatives. New developments such as multislice CT/CTA have enabled routine acquisition of thinner sections with rapid imaging times. The goal of this study was to compare the capability of recent developed 128-slice CT/CTA to MRI/MRA to detect radiologic features of sCAD. METHODS: Retrospective review of patients with suspected sCAD (n = 188) in a database of our Stroke center (2008-2014), who underwent CT/CTA and MRI/MRA on initial clinical work-up. A control group of 26 patients was added. All Images were evaluated concerning specific and sensitive radiological features for dissection by two experienced neuroradiologists. Imaging features were compared between the two modalities. RESULTS: Forty patients with 43 dissected arteries received both modalities (29 internal carotid arteries [ICAs] and 14 vertebral arteries [VAs]). All CADs were identified in CT/CTA and MRI/MRA. The features intimal flap, stenosis, and lumen irregularity appeared in both modalities. One high-grade stenosis was identified by CT/CTA that was expected occluded on MRI/MRA. Two MRI/MRA-confirmed pseudoaneurysms were missed by CT/CTA. None of the controls evidenced specific imaging signs for dissection. CONCLUSIONS: CT/CTA is a reliable and better available alternative to MRI/MRA for diagnosis of sCAD. CT/CTA should be used to complement MRI/MRA in cases where MRI/MRA suggests occlusion.

Deficits in tongue motor control are linked to microstructural brain damage in multiple sclerosis: a pilot study.

BACKGROUND: Deterioration of fine motor control of the tongue is common in Multiple Sclerosis (MS) and has a major impact on quality of life. However, the underlying neuronal substrate is largely unknown. Here, we aimed to explore the association of tongue motor dysfunction in MS patients with overall clinical disability and structural brain damage. METHODS: We employed a force transducer based quantitative-motor system (Q-Motor) to objectively assess tongue function in 33 patients with MS. The variability of tongue force output (TFV) and the mean applied tongue force (TF) were measured during an isometric tongue protrusion task. Twenty-three age and gender matched healthy volunteers served as controls. Correlation analyses of motor performance in MS patients with individual disease burden as expressed by the Expanded Disability Status Scale (EDSS) and with microstructural brain damage as measured by the fractional anisotropy (FA) on Diffusion Tensor Imaging were performed. RESULTS: MS patients showed significantly increased TFV and decreased TF compared to controls (p < 0.02). TFV but not TF was correlated with the EDSS (p < 0.04). TFV was inversely correlated with FA in the bilateral posterior limb of the internal capsule expanding to the brain stem (p < 0.001), a region critical to tongue function. TF showed a weaker, positive and unilateral correlation with FA in the same region (p < 0.001). CONCLUSIONS: Changes in TFV were more robust and correlated better with disease phenotype and FA changes than TF. TFV might serve as an objective and non-invasive outcome measure to augment the quantitative assessment of motor dysfunction in MS.

Association between the perfusion/diffusion and diffusion/FLAIR mismatch: data from the AXIS2 trial.

The perfusion-/diffusion-weighted imaging (PWI/DWI) mismatch and the diffusion/fluid attenuated inversion recovery (DWI/FLAIR) mismatch are magnetic resonance imaging (MRI) markers of evolving brain ischemia. We examined whether the DWI/FLAIR mismatch was independently associated with the PWI/DWI mismatch. Furthermore, we determined whether the presence of the DWI/FLAIR mismatch in patients with the PWI/DWI mismatch would provide additional information regarding last seen normal time (LTM). We used data from the 'AX200 for ischemic stroke' trial (AXIS 2 study NCT00927836). We studied the association between the presence of the DWI/FLAIR and PWI/DWI mismatch, baseline National Institute of Health Stroke Scale (NIHSS), age, ischemic-core volume, gender, intravenous (IV) tissue plasminogen activator (tPA), and perfusion-mismatch volume in univariate analysis. Significant variables (P<0.05) were added into the final multivariate model. We analyzed 197 patients. Seventy-two (37%) had both the PWI/DWI and the DWI/FLAIR mismatch. Patients with the double mismatch pattern had a shorter LTM than patients with the PWI/DWI mismatch alone (Median difference 90 minutes, P<0.01). Multivariate analysis confirmed the independent association between the two mismatch patterns (odds ratio (OR) 2.6, 95% confidence interval (CI) 1.2 to 5.4). Our study implies that the DWI/FLAIR mismatch and PWI/DWI mismatch are strongly associated, independent from LTM. Furthermore, in the presence of the PWI/DWI mismatch, the DWI/FLAIR pattern indicates a shorter LTM. This could have implications in selecting patients for reperfusion therapy.

Clinical, paraclinical and serological findings in Susac syndrome: an international multicenter study.

BACKGROUND: Susac syndrome (SuS) is a rare disorder thought to be caused by autoimmune-mediated occlusions of microvessels in the brain, retina and inner ear leading to central nervous system (CNS) dysfunction, visual disturbances due to branch retinal artery occlusions (BRAO), and hearing deficits. Recently, a role for anti-endothelial cell antibodies (AECA) in SuS has been proposed. OBJECTIVES: To report the clinical and paraclinical findings in the largest single series of patients so far and to investigate the frequency, titers, and clinical relevance of AECA in SuS. PATIENTS AND METHODS: A total of 107 serum samples from 20 patients with definite SuS, 5 with abortive forms of SuS (all with BRAO), and 70 controls were tested for AECA by immunohistochemistry employing primate brain tissue sections. RESULTS: IgG-AECA >1:100 were detected in 25% (5/20) of patients with definite SuS and in 4.3% (3/70) of the controls. Median titers were significantly higher in SuS (1:3200, range 1:100 to 1:17500) than in controls (1:100, range 1:10 to 1:320); IgG-AECA titers >1:320 were exclusively present in patients with SuS; three controls had very low titers (1:10). Follow-up samples (n = 4) from a seropositive SuS patient obtained over a period of 29 months remained positive at high titers. In all seropositive cases, AECA belonged to the complement-activating IgG1 subclass. All but one of the IgG-AECA-positive samples were positive also for IgA-AECA and 45% for IgM-AECA. SuS took a severe and relapsing course in most patients and was associated with bilateral visual and hearing impairment, a broad panel of neurological and neuropsychological symptoms, and brain atrophy in the majority of cases. Seropositive and seronegative patients did not differ with regard to any of the clinical or paraclinical parameters analyzed. CONCLUSIONS: SuS took a severe and protracted course in the present cohort, resulting in significant impairment. Our finding of high-titer IgG1 and IgM AECA in some patients suggest that humoral autoimmunity targeting the microvasculature may play a role in the pathogenesis of SuS, at least in a subset of patients. Further studies are warranted to define the exact target structures of AECA in SuS.

Huntington's disease: objective assessment of posture--a link between motor and functional deficits.

BACKGROUND: Postural deficits in Huntington's disease are linked to functional impairment. We investigated whether assessment of center-of-mass variability using posturography provides objective and quantitative measures that correlate to the severity of motor phenotype, functional measures, and genotype as assessed by a disease burden score (based on repeat length and age). In addition, we investigated whether withdrawing visual feedback facilitates the detection of postural deficits. METHODS: Using a force plate, the ability of symptomatic Huntington's disease patients (n = 34) and controls (n = 20) to stand as stably as possible was assessed in eyes-open and eyes-closed conditions. RESULTS: All posturographic measures (DISTANCE, VELOCITY, and SURFACE of centre-of-mass mobility) were increased in patients and correlated to (1) the UHDRS Total Motor Score, (2) the UHDRS Total Functional Capacity, (3) the UHDRS Functional Assessment Score, and (4) the disease burden score. Correlations to motor and functional measures were stronger when visual feedback was provided. CONCLUSIONS: Posturography may provide useful objective and quantitative measures of postural motor dysfunction in Huntington's disease.

Grasping premanifest Huntington's disease - shaping new endpoints for new trials.

Future clinical trials in subjects with premanifest Huntington's disease (preHD) may depend on the availability of biomarkers. It was previously shown in symptomatic HD that, the grip force variability coefficient-of-variation (GFV-C) in a grasping paradigm was correlated to the Unified-Huntington's-Disease-Rating-Scale-Total-Motor-Score (UHDRS-TMS) and increased in a 3 year follow-up study. To further elucidate its potential as a biomarker, we investigated whether GFV-C is able to detect a motor phenotype in preHD and is correlated to the genotype assessed by a disease-burden-score. The ability of preHD (n = 15) and symptomatic HD subjects (n = 20) to maintain stable grip forces, while holding an object (250 g and 500 g), was measured and compared with the controls (n = 19). GFV-C was increased in preHD at 500 g, in symptomatic subjects at both weights and was correlated to the disease-burden-score and UHDRS-TMS. GFV-C may be a useful objective and quantitative marker of motor dysfunction across genetically diagnosed premanifest and symptomatic HD subjects.

Severe leukoencephalopathy with fulminant cerebral edema reflecting immune reconstitution inflammatory syndrome during HIV infection: a case report.

INTRODUCTION: Immune reconstitution inflammatory syndrome is a well-known complication in HIV-infected patients after initiation of highly active antiretroviral therapy resulting in rapid CD4+ cell count recovery and suppression of viral load. Generally, immune reconstitution inflammatory syndrome is based on opportunistic infections, but rare cases of immune reconstitution inflammatory syndrome inducing demyelinization of the nervous system have also been observed. CASE PRESENTATION: A 37-year-old African woman with HIV infection diagnosed at 13 years of age was admitted to the emergency department after experiencing backache, severe headache, acute aphasia and psychomotor slowing for one week. Nine weeks earlier, highly active antiretroviral therapy in this patient had been changed because of loss of efficacy, and a rapid increase in CD4+ cell count and decrease of HIV viral load were observed. Magnetic resonance imaging of the brain showed extensive white matter lesions, and analysis of cerebrospinal fluid revealed an immunoreactive syndrome. Intensive investigations detected no opportunistic infections. A salvage therapy, including osmotherapy, corticosteroids and treatment of epileptic seizures, was performed, but the patient died from brainstem herniation 48 hours after admission. Neuropathologic examination of the brain revealed diffuse swelling, leptomeningeal infiltration by CD8 cells and enhancement of perivascular spaces by CD8+ cells. CONCLUSION: Immune reconstitution inflammatory syndrome in this form seems to represent a severe autoimmunologic disease of the brain with specific histopathologic findings. This form of immune reconstitution inflammatory syndrome did not respond to therapy, and extremely rapid deterioration led to death within two days. Immune reconstitution inflammatory syndrome may also occur as severe leukoencephalopathy with fulminant cerebral edema during HIV infection with rapid immune reconstitution.

Tactile thermal oral stimulation increases the cortical representation of swallowing.

BACKGROUND: Dysphagia is a leading complication in stroke patients causing aspiration pneumonia, malnutrition and increased mortality. Current strategies of swallowing therapy involve on the one hand modification of eating behaviour or swallowing technique and on the other hand facilitation of swallowing with the use of pharyngeal sensory stimulation. Thermal tactile oral stimulation (TTOS) is an established method to treat patients with neurogenic dysphagia especially if caused by sensory deficits. Little is known about the possible mechanisms by which this interventional therapy may work. We employed whole-head MEG to study changes in cortical activation during self-paced volitional swallowing in fifteen healthy subjects with and without TTOS. Data were analyzed by means of synthetic aperture magnetometry (SAM) and the group analysis of individual SAM data was performed using a permutation test. RESULTS: Compared to the normal swallowing task a significantly increased bilateral cortical activation was seen after oropharyngeal stimulation. Analysis of the chronological changes during swallowing suggests facilitation of both the oral and the pharyngeal phase of deglutition. CONCLUSION: In the present study functional cortical changes elicited by oral sensory stimulation could be demonstrated. We suggest that these results reflect short-term cortical plasticity of sensory swallowing areas. These findings facilitate our understanding of the role of cortical reorganization in dysphagia treatment and recovery.

Neurosonographical follow-up in patients with spontaneous cervical artery dissection.

OBJECTIVE: Neurovascular ultrasound (nUS) is widely used as a screening and monitoring tool in patients with spontaneous cervical artery dissection (sCAD). The aim of the study was to describe the sonographical course of the affected arteries in patients with a MRI-proven sCAD by repetitive nUS. METHODS: Thirty-seven consecutive patients aged<60 years with 1.5 T MRI-proven sCAD were prospectively investigated by nUS, and within 48 hours after admission before MRI. The patients were re-investigated after 6 months and again after a period>12 months. RESULTS: Forty-nine sCAD were detected in 37 patients; 24 lesions (49%) were located in the internal carotid arteries (ICA), and 25 (51%) in the vertebral arteries (VA). An arterial occlusion was found in 13 arteries (27%). The recanalization rate of occluded arteries was 62%. Regression of stenosis/occlusion within the first 6 months was found in 34 (69%) of the affected arteries, while between 6 and >12 months, the improvement rate was lower (19%). A complete recanalization without residual stenosis after 6 months was found in 39%. In only one artery, initial high grade ICA stenosis progressed to complete persistent occlusion (2%). DISCUSSION: The course of arterial stenosis or occlusion caused by sCAD is highly dynamic during the first 6 month after the event. The vast majority of arteries show regression of stenosis or recanalization of initial occlusion. Only a minority of patients experience a persistent deterioration of the vessel status.

Do nasogastric tubes worsen dysphagia in patients with acute stroke?

BACKGROUND: Early feeding via a nasogastric tube (NGT) is recommended as safe way of supplying nutrition in patients with acute dysphagic stroke. However, preliminary evidence suggests that NGTs themselves may interfere with swallowing physiology. In the present study we therefore investigated the impact of NGTs on swallowing function in acute stroke patients. METHODS: In the first part of the study the incidence and consequences of pharyngeal misplacement of NGTs were examined in 100 stroke patients by fiberoptic endoscopic evaluation of swallowing (FEES). In the second part, the effect of correctly placed NGTs on swallowing function was evaluated by serially examining 25 individual patients with and without a NGT in place. RESULTS: A correctly placed NGT did not cause a worsening of stroke-related dysphagia. Except for two cases, in which swallowing material got stuck to the NGT and penetrated into the laryngeal vestibule after the swallow, no changes of the amount of penetration and aspiration were noted with the NGT in place as compared to the no-tube condition. Pharyngeal misplacement of the NGT was identified in 5 of 100 patients. All these patients showed worsening of dysphagia caused by the malpositioned NGT with an increase of pre-, intra-, and postdeglutitive penetration. CONCLUSION: Based on these findings, there are no principle obstacles to start limited and supervised oral feeding in stroke patients with a NGT in place.

Cortical recovery of swallowing function in wound botulism.

BACKGROUND: Botulism is a rare disease caused by intoxication leading to muscle weakness and rapidly progressive dysphagia. With adequate therapy signs of recovery can be observed within several days. In the last few years, brain imaging studies carried out in healthy subjects showed activation of the sensorimotor cortex and the insula during volitional swallowing. However, little is known about cortical changes and compensation mechanisms accompanying swallowing pathology. METHODS: In this study, we applied whole-head magnetoencephalography (MEG) in order to study changes in cortical activation in a 27-year-old patient suffering from wound botulism during recovery from dysphagia. An age-matched group of healthy subjects served as control group. A self-paced swallowing paradigm was performed and data were analyzed using synthetic aperture magnetometry (SAM). RESULTS: The first MEG measurement, carried out when the patient still demonstrated severe dysphagia, revealed strongly decreased activation of the somatosensory cortex but a strong activation of the right insula and marked recruitment of the left posterior parietal cortex (PPC). In the second measurement performed five days later after clinical recovery from dysphagia we found a decreased activation in these two areas and a bilateral cortical activation of the primary and secondary sensorimotor cortex comparable to the results seen in a healthy control group. CONCLUSION: These findings indicate parallel development to normalization of swallowing related cortical activation and clinical recovery from dysphagia and highlight the importance of the insula and the PPC for the central coordination of swallowing. The results suggest that MEG examination of swallowing can reflect short-term changes in patients suffering from neurogenic dysphagia.

Contribution of resident endoneurial macrophages to the local cellular response in experimental autoimmune neuritis.

Macrophages are intimately involved in the pathogenesis of inflammatory neuropathies. The contribution of resident endoneurial macrophages is unknown since their differentiation from infiltrating macrophages is difficult due to missing cellular markers. Previous studies demonstrated the participation of resident macrophages in Wallerian degeneration and the pathogenesis of hereditary neuropathies. The question arises whether resident macrophages are involved in experimental autoimmune neuritis (EAN) where they could contribute to immunosurveillance and antigen presentation. To address this question we used bone marrow chimeric rats, allowing the differentiation between resident and hematogenous cells. Immunohistochemistry and in situ hybridization were applied on to identify and characterize resident macrophages in terms of morphological features, expression of activation markers, proliferation, phagocytosis, and MHC-II expression. Endoneurial macrophages of resident origin were detectable at all stages of disease with a contribution of at least 27% of the total macrophages. They appeared activated by morphological and immunohistochemical criteria and proliferated early. MHC-II-positive resident macrophages were observed that had phagocytosed myelin. These results demonstrate that the macrophage response in EAN is partly of intrinsic origin. The rapid activation and proliferation of resident endoneurial macrophages points toward an active role of these cells in inflammatory peripheral nerve disease, especially early in disease.

Idiopathic spinal cord herniation causing progressive Brown-Séquard syndrome.

We report a 59-year-old woman with a 2.5 year history of progressive loss of temperature sensation and dysesthesia in the right and weakness in the contralateral lower limb. Magnetic resonance imaging (MRI) and computed tomography myelography of the spinal cord demonstrated transdural herniation and deformation of the spinal cord in the upper thoracic spine. The herniated part of the spinal cord was untethered and replaced, and the anterior dural defect was closed. At a clinical follow-up 3 months later, the motor and sensory functions were almost restored. MRI at this time showed disentanglement of spinal cord adherence.

Prophylaxis of thrombotic and embolic events in acute ischemic stroke with the low-molecular-weight heparin certoparin: results of the PROTECT Trial.

BACKGROUND AND PURPOSE: Patients with stroke are at substantial risk of thromboembolic complications and therefore require antithrombotic prophylaxis. To show the noninferiority of the low-molecular-weight heparin certoparin to unfractionated heparin (UFH) for the prevention of thromboembolic complications, we performed a randomized, double-blind, active-controlled multicenter trial in patients with acute ischemic stroke. METHODS: Overall, 545 patients were randomized within 24 hours of stroke onset to treatment with certoparin (3000 U anti-Xa OD; n=272) or UFH (5000 U TID; n=273) for 12 to 16 days. Patients with paresis of a leg and an National Institutes of Health Stroke Scale score of 4 to 30 points were included. The primary end point was a composite outcome of proximal deep vein thrombosis, pulmonary embolism, or death related to venous thromboembolism during treatment. Computed tomography was performed at trial entry, after 7 days, and when clinical deterioration occurred. RESULTS: The per-protocol analysis revealed 17 (7.0%) primary events in the certoparin group compared with 24 (9.7%) in the UFH group, thereby demonstrating noninferiority (P=0.0011), confirmed by intention-to-treat analysis (6.6% versus 8.8%; P=0.008). Major bleeding occurred during treatment in 3 patients allocated to certoparin (1.1%) and 5 patients allocated to UFH (1.8%). CONCLUSIONS: Certoparin (3000 U anti-Xa OD) is at least as effective and safe as UFH (TID) for the prevention of thromboembolic complications in patients with acute ischemic stroke.

Abnormal brain activation during movement observation in patients with conversion paralysis.

Dissociative paralysis in conversion disorders has variably been attributed to a lack of movement initiation or an inhibition of movement. While psychodynamic theory suggests altered movement conceptualization, brain activation associated with observation and replication of movements has so far not been assessed neurobiologically. Here, we measured brain activation by functional magnetic resonance imaging during observation and subsequent imitative execution of movements in four patients with dissociative hand paralysis. Compared to healthy controls conversion disorder patients showed decreased activation of cortical hand areas during movement observation. This effect was specific to the side of their dissociative paralysis. No brain activation compatible with movement inhibition was observed. These findings indicate that in dissociative paralysis, there is not only derangement of movement initiation but already of movement conceptualization. This raises the possibility that strategies targeted at reestablishing appropriate movement conceptualization may contribute to the therapy of dissociative paralysis.

Plasma homocysteine, MTHFR C677T, CBS 844ins68bp, and MTHFD1 G1958A polymorphisms in spontaneous cervical artery dissections.

Mild hyperhomocysteinemia is a probable risk factor for atherosclerotic diseases and stroke. Recently, associations of elevated plasma homocysteine concentrations in the acute phase and of MTHFR 677 TT genotype with spontaneous cervical artery dissections (sCAD) have been reported. The purpose of this study was to test this hypothesis in the currently largest sample of patients with sCAD, taking into account known factors influencing plasma homocysteine levels. Ninety-five patients with past sCAD were compared with 95 age- and sex-matched healthy individuals. Homocysteine, vitamin B6, B12, folate, and polymorphisms of methylenetetrahydrofolate reductase (MTHFR C677T), cystathionine beta-synthase (CBS 844ins68bp) and methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthetase (MTHFD1 G1958A) were assessed and any associations were analysed using multivariate statistics. The occurrence of sCAD was associated with elevated homocysteine levels with an odds ratio of 1.327 per 20 % percentile. Homocysteine levels were influenced by gender, smoking status, occurrence of hypertension, vitamin B12 and folate levels, and by the MTHFR TT genotype. MTHFR, CBS 844ins68bp, and MTHFD1 G1958A genotype were not independently associated with the occurrence of sCAD. These data suggest that elevated homocysteine is associated with the occurrence of sCAD. The MTHFR C677T polymorphism is associated with the homocysteine level.

Solid or gaseous circulating brain emboli: are they separable by transcranial ultrasound?

High-intensity transient signals (HITS) detected by transcranial Doppler (TCD) ultrasound may correspond to artifacts or to microembolic signals, the latter being either solid or gaseous emboli. The goal of this study was to assess what can be achieved with an automatic signal processing system for artifact/microembolic signals and solid/gas differentiation in different clinical situations. The authors studied 3,428 HITS in vivo in a multicenter study, i.e., 1,608 artifacts in healthy subjects, 649 solid emboli in stroke patients with a carotid stenosis, and 1,171 gaseous emboli in stroke patients with patent foramen ovale. They worked with the dual-gate TCD combined to three types of statistical classifiers: binary decision trees (BDT), artificial neural networks (ANN), and support vector machines (SVM). The sensitivity and specificity to separate artifacts from microembolic signals by BDT reached was 94% and 97%, respectively. For the discrimination between solid and gaseous emboli, the classifier achieved a sensitivity and specificity of 81% and 81% for BDT, 84% and 84% for ANN, and 86% and 86% for SVM, respectively. The current results for artifact elimination and solid/gas differentiation are already useful to extract data for future prospective clinical studies.

The cerebral hemodynamics of headache associated with sexual activity.

Headache associated with sexual activity is an idiopathic headache disorder and regarded to be a vascular headache but no pathophysiological studies have been performed to date to elucidate the underlying mechanisms. We investigated 12 patients with the explosive type of sexual headache according to the criteria of the International Headache Society during a headache-free state by means of acetazolamide test and of stress Doppler sonography. Twelve age-matched migraine patients and 14 healthy subjects served as control groups. Changes of blood pressure, cerebral blood flow velocity (CBFV), and pulsatility index (PI) were evaluated. Patients with sexual headache showed a significantly higher increase of blood pressure during standardized physical exercise as compared to healthy subjects and migraine patients. Changes of CBFV by physical exercise were not different between the three examination groups. After 1g acetazolamide, CBFV showed a significantly higher increase in patients with sexual headache (plus 66%+/-16%) than in healthy subjects (plus 46%+/-18%), and PI showed a significantly lower decrease as compared to healthy subjects and migraine patients. These data suggest that in patients with sexual headache the metabolic rather than the myogenic component of the cerebral vasoneuronal coupling is impaired.