Rivaroxaban versus aspirin for secondary prevention of ischaemic stroke in patients with cancer: a subgroup analysis of the NAVIGATE ESUS randomized trial.

BACKGROUND AND PURPOSE: Cancer is a frequent finding in ischaemic stroke patients. The frequency of cancer amongst participants in the NAVIGATE ESUS randomized trial and the distribution of outcome events during treatment with aspirin and rivaroxaban were investigated. METHODS: Trial participation required a recent embolic stroke of undetermined source. Patients' history of cancer was recorded at the time of study entry. During a mean follow-up of 11 months, the effects of aspirin and rivaroxaban treatment on recurrent ischaemic stroke, major bleeding and all-cause mortality were compared between patients with cancer and patients without cancer. RESULTS: Amongst 7213 randomized patients, 543 (7.5%) had cancer. Of all patients, 3609 were randomized to rivaroxaban [254 (7.0%) with cancer] and 3604 patients to aspirin [289 (8.0%) with cancer]. The annual rate of recurrent ischaemic stroke was 4.5% in non-cancer patients in the rivaroxaban arm and 4.6% in the aspirin arm [hazard ratio (HR) 0.98, 95% confidence interval (CI) 0.78-1.24]. In cancer patients, the rate of recurrent ischaemic stroke was 7.7% in the rivaroxaban arm and 5.4% in the aspirin arm (HR 1.43, 95% CI 0.71-2.87). Amongst cancer patients, the annual rate of major bleeds was non-significantly higher for rivaroxaban than aspirin (2.9% vs. 1.1%; HR 2.57, 95% CI 0.67-9.96; P for interaction 0.95). All-cause mortality was similar in both groups. CONCLUSIONS: Our exploratory analyses show that patients with embolic stroke of undetermined source and a history of cancer had similar rates of recurrent ischaemic strokes and all-cause mortality during aspirin and rivaroxaban treatments and that aspirin appeared safer than rivaroxaban in cancer patients regarding major bleeds. www.clinicaltrials.gov (NCT02313909).

Guidelines for the treatment of acute ischaemic stroke.

INTRODUCTION: Update of Acute Ischaemic Stroke Treatment Guidelines of the Spanish Neurological Society based on a critical review of the literature. Recommendations are made based on levels of evidence from published data and studies. DEVELOPMENT: Organized systems of care should be implemented to ensure access to the optimal management of all acute stroke patients in stroke units. Standard of care should include treatment of blood pressure (should only be treated if values are over 185/105 mmHg), treatment of hyperglycaemia over 155 mg/dl, and treatment of body temperature with antipyretic drugs if it rises above 37.5 °C. Neurological and systemic complications must be prevented and promptly treated. Decompressive hemicraniectomy should be considered in cases of malignant cerebral oedema. Intravenous thrombolysis with rtPA should be administered within 4.5 hours from symptom onset, except when there are contraindications. Intra-arterial pharmacological thrombolysis can be considered within 6 hours, and mechanical thrombectomy within 8 hours from onset, for anterior circulation strokes, while a wider window of opportunity up to 12-24 hours is feasible for posterior strokes. There is not enough evidence to recommend routine use of the so called neuroprotective drugs. Anticoagulation should be administered to patients with cerebral vein thrombosis. Rehabilitation should be started as early as possible. CONCLUSION: Treatment of acute ischaemic stroke includes management of patients in stroke units. Systemic thrombolysis should be considered within 4.5 hours from symptom onset. Intra-arterial approaches with a wider window of opportunity can be an option in certain cases. Protective and restorative therapies are being investigated.

Clinical management guidelines for subarachnoid haemorrhage. Diagnosis and treatment.

OBJECTIVE: To update the Spanish Society of Neurology's guidelines for subarachnoid haemorrhage diagnosis and treatment. MATERIAL AND METHODS: A review and analysis of the existing literature. Recommendations are given based on the level of evidence for each study reviewed. RESULTS: The most common cause of spontaneous subarachnoid haemorrhage (SAH) is cerebral aneurysm rupture. Its estimated incidence in Spain is 9/100 000 inhabitants/year with a relative frequency of approximately 5% of all strokes. Hypertension and smoking are the main risk factors. Stroke patients require treatment in a specialised centre. Admission to a stroke unit should be considered for SAH patients whose initial clinical condition is good (Grades I or II on the Hunt and Hess scale). We recommend early exclusion of aneurysms from the circulation. The diagnostic study of choice for SAH is brain CT (computed tomography) without contrast. If the test is negative and SAH is still suspected, a lumbar puncture should then be performed. The diagnostic tests recommended in order to determine the source of the haemorrhage are MRI (magnetic resonance imaging) and angiography. Doppler ultrasonography studies are very useful for diagnosing and monitoring vasospasm. Nimodipine is recommended for preventing delayed cerebral ischaemia. Blood pressure treatment and neurovascular intervention may be considered in treating refractory vasospasm. CONCLUSIONS: SAH is a severe and complex disease which must be managed in specialised centres by professionals with ample experience in relevant diagnostic and therapeutic processes.

Guidelines for the preventive treatment of ischaemic stroke and TIA (I). Update on risk factors and life style.

OBJECTIVE: To update the ad hoc Committee of the Cerebrovascular Diseases Study Group of The Spanish Neurological Society guidelines on prevention of ischaemic stroke (IS) and transient ischaemic attack (TIA). METHODS: We reviewed available evidence on risk factors and means of modifying them to prevent ischaemic stroke and TIA. Levels of evidence and recommendation grades are based on the classification of the Centre for Evidence-Based Medicine. RESULTS: This first section summarises the recommendations for action on the following factors: blood pressure, diabetes, lipids, tobacco and alcohol consumption, diet and physical activity, cardio-embolic diseases, asymptomatic carotid stenosis, hormone replacement therapy and contraceptives, hyperhomocysteinemia, prothrombotic states and sleep apnea syndrome. CONCLUSIONS: Changes in lifestyle and pharmacological treatment for hypertension, diabetes mellitus and dyslipidemia, according to criteria of primary and secondary prevention, are recommended for preventing ischemic stroke.

Diagnosis of CADASIL disease in normotensive and non-diabetics with lacunar infarct.

BACKGROUND: CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is characterized by recurrent cerebral ischemic episodes of the lacunar subtype usually without traditional vascular risk factors. We investigated the frequency of CADASIL among selected patients with cerebral ischemia of the lacunar subtype. METHODS: we studied patients under 65 years old who presented cerebral ischemia of the lacunar subtype without hypertension, diabetes mellitus or other causes that explained the cerebral ischemia. On the skin biopsies, we performed immunostaining analysis on 5µm frozen sections with monoclonal antibody anti-Notch 3 (1E4). We also performed a genetic analysis of the Notch 3 gene (exons 3,4,5,6,11 and 19). RESULTS: of 1.519 patients analyzed, only 57 (3.7%) fulfilled the selection criteria, and 30 of them accepted to participated in the study. We studied 30 patients, mean age was 53 years (range 34 to 65), 50% were men and all patients suffered a lacunar stroke. Immunostaining analysis was positive in two patients (6.6%) and the genetic analysis confirmed a mutation characteristic of CADASIL in exon 4 nt 622C/T (Arg 182 Cys) and 694 T/C (Cys206Arg) respectively. CONCLUSIONS: CADASIL disease was present in 6.6% of patients younger than 65 years with a lacunar stroke and without hypertension or diabetes mellitus. Screening for CADASIL should be considered in these patients.

In-hospital stroke: a multi-centre prospective registry.

BACKGROUND: in-hospital strokes (IHS) are relatively frequent. Avoidable delays in neurological assessment have been demonstrated. We study the clinical characteristics, neurological care and mortality of IHS. METHODS: multi-centre 1-year prospective study of IHS in 13 hospitals. Demographic and clinical characteristics, admission diagnosis, quality of care, thrombolytic therapy and mortality were recorded. RESULTS: we included 273 IHS patients [156 men; 210 ischaemic strokes (IS), 37 transient ischaemic attacks (TIA) and 26 cerebral haemorrhages]. Mean age was 72 ± 12 years. Cardiac sources of embolism were present in 138 (50.5%), withdrawal of antithrombotic drugs in 77 (28%) and active cancers in 35 (12.8%). Cardioembolic stroke was the most common subtype of IS (50%). Reasons for admission were programmed or urgent surgery in 70 (25%), cardiac diseases in 50 (18%), TIA or stroke in 30 (11%) and other medical illnesses in 71 (26%). Fifty-two per cent of patients were evaluated by a neurologist within 3 h of stroke onset. Thirty-three patients received treatment with tPA (15.7%). Thirty-one patients (14.7%) could not be treated because of a delay in contacting the neurologist. During hospitalization, 50 patients (18.4%) died, 41 of them because of the stroke or its complications. CONCLUSIONS: cardioembolic IS was the most frequent subtype of stroke. Cardiac sources of embolism, active cancers and withdrawal of antithrombotic drugs constituted special risk factors for IHS. A significant proportion of patients were treated with thrombolysis. However, delays in contacting the neurologist excluded a similar proportion of patients from treatment. IHS mortality was high, mostly because of stroke.

Proliferation in the human ipsilateral subventricular zone after ischemic stroke.

BACKGROUND: It is uncertain whether neurogenesis occurs in humans after stroke. We studied the morphologic changes that occurred in the subventricular zone (SVZ) in patients who died following an acute ischemic stroke. METHODS: We examined coronal brain slices from patients who died after a first-ever cerebral nonlacunar infarction in the middle cerebral artery territory. We evaluated the morphologic changes in the ipsilateral and contralateral SVZ by light and electron microscopy. Using immunochemistry with Ki-67 and PCNA, we detected cell proliferation. We used Tuj-1 for immature neurons and PSA-NCAM for migrating cells. RESULTS: The study included 7 patients with a mean age of 82 +/- 5 (mean +/- SD) years; 4 were men. They died a mean of 10 +/- 5 days after the ischemic stroke. Brain samples were obtained a mean of 4 +/- 2 hours after death. In comparison with the contralateral SVZ, the following changes were observed in the ipsilateral SVZ: an increase in the width of the gap and ribbon layers, as well as in the cell density of the ribbon layer, an enlargement of the cytoplasmic volume of astrocytes, and an increase of Ki-67-positive cells. In the ipsilateral SVZ, mitoses and cells that stained for either Tuj-1 or PSA-NCAM markers were observed more frequently than in the contralateral SVZ. CONCLUSION: We found unequivocal evidence of active cell proliferation in the ipsilateral subventricular zone following an acute ischemic stroke in our patients.

B-cell translocation gene 2 is over-expressed in peri-infarct neurons after ischaemic stroke.

OBJECTIVES: Recovery from stroke is dependent on the survival of neurons in the dynamic peri-infarcted region. Although several markers of neuronal injury and apoptotic cell death have been described, administration of neuroprotective drugs directed at specific molecules has had limited success. A complete understanding of deregulated genes associated with neuronal death would be beneficial. Our previous microarray studies identified increased expression of a novel protein, the B-cell translocation gene 2 (BTG2), in infarcted regions. METHODS: We have used immunohistochemistry and Western blotting to examine the expression and localization of BTG2 in stroked brain tissue and immunofluorescent staining of human fetal brain neurons to determine if oxygen-glucose deprivation affected its expression. RESULTS: We show that BTG2 is strongly expressed in peri-infarcted and infarcted regions of brain tissue, localizing in neuronal nuclei and cytoplasm, whilst being absent or very weakly expressed in normal looking contralateral tissue. Exposure of human fetal brain neurons to oxygen-glucose deprivation also induced BTG2 expression in the cytoplasm and perinuclear regions of cells staining positive for propidium iodide (a marker of nuclear damage). CONCLUSIONS: BTG2 may be a modulator of cell survival and differentiation and could help to protect against cell death by inhibition of necrosis and/or apoptotic signalling pathways.

[Carotid thrombus and cerebral infarction as the initial clinical manifestation of polycythemia vera]. / Trombo carotídeo e infarto cerebral como manifestación clínical inicial de policitemia vera.

Polycythemia vera (PV) can produce cerebral infarction. The mechanisms proposed by most authors are hyperviscosity-related diminished cerebral blood flow and platelet function abnormalities. We present a 36-year-old woman whose initial clinical manifestation of PV consisted of cerebral ischemia due to a carotid thrombus, as well as occlusion of the middle cerebral artery and cortical branches of the anterior cerebral artery demonstrated by angiography. To our knowledge, this is the first published case of cerebral infarction in PV caused by a thrombus of an extracranial artery. Therefore, PV can produce ischemic stroke due to thrombosis not only in small distal arteries or arterioles but also in the carotid artery or main branches. Treatment of intraluminal thrombus in non-arteriosclerotic carotid artery is discussed. Myeloproliferative disorders, including PV, must be suspected in all stroke patients with an elevated platelet count, even in those who have potential causes of reactive thrombocytosis.

Blood pressure variability in Binswanger's disease and isolated lacunar infarction.

UNLABELLED: To determine whether blood pressure (BP) variability is increased in hypertensive patients with Binswanger's disease (BD), we studied two samples of consecutive treated hypertensive patients: (1) 11 with BD (mean age 71.3 +/- 5.2 years); (2) 16 with lacunar infarction (mean age 65.2 +/- 8.3 years) without cognitive impairment. An averaged baseline office BP was obtained for 3 consecutive weeks. Ambulatory BP monitoring was then carried out to obtain the averaged mean systolic (SBP) and diastolic BP, and BP variability was defined as the standard deviation of consecutive BP values. RESULTS: Diurnal SBP variability was significantly increased in the BD group (p = 0.04). However, with the analysis of covariance for age and baseline office BP, the difference was no longer significant (p = 0.17 and p = 0.09, respectively). We conclude that increased BP variability in BD patients is probably due to older age and increased baseline office BP. Increased BP variability may be a risk factor for small-vessel disease, but not for cognitive impairment.

[Cerebral venous thrombosis. Study of 17 cases]. / Trombosis venosa cerebral. Estudio de 17 casos.

BACKGROUND: We undertook this study to determine the clinical, neuroimaging findings, etiologies and final outcome of 17 patients with cerebral venous thrombosis diagnosed in a single center. PATIENTS AND METHODS: In this retrospective study we analyzed the clinical and neuroimaging findings of patients with cerebral venous thrombosis collected at our hospital from 1980 to 1997. The diagnosis of cerebral venous thrombosis was made by angiography and/or magnetic resonance imaging. Final outcome was assessed with the modified Rankin scale and patients were included in two groups. Differences between groups were tested using uni and multivariate analysis. RESULTS: Seventeen patients (10 women) with a mean age of 41.9 years were analyzed. The most frequent clinical pattern was focal cerebral signs (70.5%) followed by symptoms/signs of increased intracranial pressure (12%) and diffuse encephalopathy (12%). The diagnosis of cerebral venous thrombosis was made by conventional angiography in 12 cases (70.5%) and by magnetic resonance imaging in 5 (29.5%). The most frequent site of venous occlusion was superior sagittal sinus (47%) followed by lateral sinus (35%). Etiologies were hematologic disease (29%), neoplasms (23.5%), oral contraceptives (12%), infection (12%) and unknown in 18%. The majority of the patients (59%) had minor neurological sequelae during follow-up. A decreased level of consciousness and neoplasm were associated with a worse functional outcome. CONCLUSIONS: In our series the most frequent clinical pattern was focal cerebral signs and the main etiology was hematologic disease. A relatively good prognosis was observed in those patients. A decreased level of consciousness and presence of neoplasm were the factors associated with a bad prognosis in these cases.

Absence of thallium-201 brain uptake in progressive multifocal leukoencephalopathy in AIDS patients.

OBJECTIVE: To evaluate the presence of thallium-201 brain uptake determined by thallium-201 brain SPECT (Tl-201 SPECT) in patients with progressive multifocal leukoencephalopathy (PML) and AIDS. MATERIAL AND METHODS: Six AIDS patients with stereotactic biopsy diagnosis of PML were prospectively evaluated with Tl-201 SPECT, Magnetic Resonance Imaging (MRI), and proton magnetic resonance spectroscopy (1H-MRS). Tl-201 SPECT results were compared with 2 patients with AIDS and biopsy proven primary CNS lymphoma. RESULTS: In all patients with PML, Tl-201 SPECT studies showed lack of uptake while MRI demonstrated subcortical white matter focal brain lesions and 1H-MRS disclosed metabolic abnormalities. Intense thallium uptake (uptake ratios of 3.2 and 5.6) was demonstrated in the 2 patients with primary CNS lymphoma. CONCLUSIONS: The present study shows that PML lesions are not detectable on Tl-201 SPECT while MRI and 1H-MRS demonstrate abnormalities, and intense thallium-201 uptake may be detected in primary CNS lymphoma. These results suggest that Tl-201 SPECT is a method which, combined with other non-invasive techniques such as MRI and 1H-MRS, may help in the diagnostic approach of PML and to differentiate PML from other high proliferative brain lesions characterized by positive thallium uptake.

Spontaneous primary intraventricular hemorrhage: clinical data, etiology and outcome.

The clinical features, etiology, and neurological outcome in patients with primary intraventricular hemorrhage (PIVH) have rarely been reported. We retrospectively reviewed the clinical data, complementary examinations, outcome, computed tomography (CT) blood amount, and ventricle size of 13 patients (mean age 60 years, five men). We defined PIVH as hemorrhage detected by CT in the ventricular system only. The major symptoms included headache (n = 13), decreased level of consciousness (n = 9), and nausea/vomiting (n = 7). The cause was unknown in five patients; and was associated with arterial hypertension in five, vascular malformations in two, and tumor in one, although arteriography was performed in only five patients. Outcomes were death in three, asymptomatic in six, mild disability in three, and moderate disability in one. Prognosis was not related to clinical or CT data. Clinical features can suggest the diagnosis of PIVH, but cerebral CT is required for confirmation.

Proton magnetic resonance spectroscopy pattern of progressive multifocal leukoencephalopathy in AIDS.

The objective was to determine whether the use of intermediate echo times (135 ms) in proton magnetic resonance spectroscopy (1H-MRS) detects a homogenous pattern in progressive multifocal leukoencephalopathy (PML) in HIV-1 infected people, and to confirm the results of previous studies. Six patients infected with HIV-1, with PML established by biopsy, and six healthy age and sex matched volunteers were evaluated to define their spectroscopic pattern. 1H-MRS spectra performed at 1.5 T were obtained with the STEAM sequence: TE/TM/TR, 20 ms/13.7 ms/2000 ms; 2500 Hz, size 2048 points, 256 acquisitions (STEAM-20) and with the PRESS sequence; TE/TR, 135 ms/2000 ms; 2500 Hz, size 2048 points, 256 acquisitions (PRESS-135). A single voxel was placed on the lesions and on the parieto-occipital white matter of controls. The peaks of N-acetylaspartate (NAA), choline (Cho), myoinositol (mI), lactate, and lipids were considered, and the results were expressed using creatine as reference. Spectra of PML lesions were characterised by significantly reduced NAA, lactate presence, and by significantly increased Cho and lipids compared with control group values. These results indicate that 1H-MRS detects a homogenous pattern in PML lesions. Recent studies, together with this, suggest that 1H-MRS may help in the diagnostic approach to patients with suspected PML lesions associated with AIDS.

[Post-radiotherapy brachial plexopathy and cervical myelopathy]. / Plexopatía braquial y mielopatía cervical posradioterapia.

The case of a 58-year-old male who, after 47 months of treatment with cervical radiotherapy for labial carcinoma, developed brachial plexopathy and six months later cervical myelopathy is herewith presented. Involvement of both the brachial plexus and the spinal cord in the same patient secondary to radiotherapy is exceptional.

Post-irradiation neuromyotonia in bilateral facial and trigeminal nerve distribution.

We describe a patient with episodic involuntary contraction in the lower facial and masseter muscles, in whom we recorded neuromyotonic discharges. The neuromyotonia was a delayed effect of radiation therapy and responded to carbamazepine therapy.