Abstract: Cerebrovascular and cardiovascular diseases are the leading causes of death and disability worldwide. They are complex disorders resulting from the interplay of genetic and environmental factors, and may share several susceptibility genes. Several recent studies have implicated variants of the Kalirin (KALRN) gene with susceptibility to cardiovascular and metabolic phenotypes, but no studies have yet been performed in stroke patients. KALRN is involved, among others, in the inhibition of inducible nitric oxide synthase, in the regulation of ischemic signal transduction, and in neuronal morphogenesis, plasticity, and stability. The goal of the present study was to determine whether SNPs in the KALRN region on 3q13, which includes the Ropporin gene (ROPN1), predispose to ischemic stroke (IS) in a cohort of Portuguese patients and controls. We genotyped 34 tagging SNPs in the KALRN and ROPN1 chromosomal region on 565 IS patients and 517 unrelated controls, and performed genotype imputation for 405 markers on chromosome 3. We tested the single-marker association of these SNPs with IS. One SNP (rs4499545) in the ROPN1-KALRN intergenic region and two SNPs in KALRN (rs17286604 and rs11712619) showed significant (P < 0.05) allelic and genotypic (unadjusted and adjusted for hypertension, diabetes, and ever smoking) association with IS risk. Thirty-two imputed SNPs also showed an association at P < 0.05, and actual genotyping of three of these polymorphisms (rs7620580, rs6438833, and rs11712039) validated their association. Furthermore, rs11712039 was associated with IS (0.001 < P < 0.01) in a recent well-powered genomewide association study (Ikram et al. 2009). These studies suggest that variants in the KALRN gene region constitute risk factors for stroke and that KALRN may represent a common risk factor for vascular diseases.
Abstract: BACKGROUND AND PURPOSE: Fabry disease is an X-linked monogenic disorder caused by mutations in the GLA gene. Recent data suggest that stroke in young adults may be associated with Fabry disease. We aimed to ascertain the prevalence of this disorder among young adult patients with stroke in Portugal by GLA genotyping. METHODS: During 1 year, all patients aged 18 to 55 years with first-ever stroke, who were admitted into any of 12 neurology hospital departments in Portugal, were prospectively enrolled (n=625). Ischemic stroke was classified according to Trial of Org 10172 in Acute Stroke Treatment criteria. Alpha-galactosidase activity was further assayed in all patients with GLA mutations. RESULTS: Four hundred ninety-three patients (mean age, 45.4 years; 61% male) underwent genetic analyses: 364 with ischemic stroke, 89 with intracerebral hemorrhage, 26 with subarachnoid hemorrhage, and 14 with cerebral venous thrombosis. Twelve patients had missense GLA mutations: 9 with ischemic stroke (p.R118C: n=4; p.D313Y: n=5), including 5 patients with an identified cause of stroke (cardiac embolism: n=2; small vessel disease: n=2; other cause: n=1), 2 with intracerebral hemorrhage (p.R118C: n=1; p.D313Y: n=1), and one with cerebral venous thrombosis (p.R118C: n=1). Leukocyte alpha-galactosidase activity was subnormal in the hemizygous males and subnormal or low-normal in the heterozygous females. Estimated prevalence of missense GLA mutations was 2.4% (95% CI, 1.3% to 4.1%). CONCLUSIONS: Despite a low diagnostic yield, screening for GLA mutations should probably be considered in different types of stroke. Restricting investigation to patients with cryptogenic stroke may underestimate the true prevalence of Fabry disease in young patients with stroke.
Abstract: BACKGROUND AND AIMS: Diffusion weighted imaging (DWI) displays a high sensitivity to white matter changes, even in areas where no lesions are visible. Correlation with vascular risk factors and cognitive dysfunction seems to be feasible using this technique. We aimed to test relations between age, blood pressure and cognitive function,with lesion load and average Apparent Diffusion Coefficient (ADC) values in lesioned (LWM) and in normal appearing white matter (NAWM), in patients with age related white matter lesions (ARWML). METHODS: Subjects were 29 patients (mean age 72.6 +/- 5.2 years) with different severity of ARWML on MRI and no (or mild) disability assessed by the Instrumental Activities of Daily Living Scale. Imaging lesion load was quantified in bilateral frontal, temporal, parieto-occipital, basal ganglia and infratentorial regions, using a simple visual rating scale; ADC was measured bilaterally in Regions of Interest in parieto-occipital and frontal NAWM, and in frontal periventricular LWM. Neuropsychological examination consisted of Raven Colored Progressive Matrices, Rey's Complex Figure, Digit Canceling. Symbol digit Substitution, Inverse Digit Repetition and Verbal Fluency tests. RESULTS: Visual scales scores and ADC were significantly higher in frontal and parieto-occipital regions. Both were significantly correlated to age and blood pressure, in frontal (visual scale scores and ADC) and parieto-occipital regions (ADC). Attention skills were negatively correlated to ADC in LWM and NAWM in frontal regions and with frontal region visual scale scores. CONCLUSION: Our findings suggest that severity of white matter ischemic changes is correlated with worse cognitive function, as well as advanced age and higher blood pressure.A higher vulnerability of frontal white matter to vascular disease seems to play an important role in executive dysfunction, mainly determined by impairment of attentional skills.DWI results suggest this could be true even for NAWM.
Abstract: BACKGROUND: The genetic contribution to stroke is well established but it has proven difficult to identify the genes and the disease-associated alleles mediating this effect, possibly because only nuclear genes have been intensely investigated so far. Mitochondrial DNA (mtDNA) has been implicated in several disorders having stroke as one of its clinical manifestations. The aim of this case-control study was to assess the contribution of mtDNA polymorphisms and haplogroups to ischemic stroke risk. METHODS: We genotyped 19 mtDNA single nucleotide polymorphisms (SNPs) defining the major European haplogroups in 534 ischemic stroke patients and 499 controls collected in Portugal, and tested their allelic and haplogroup association with ischemic stroke risk. RESULTS: Haplogroup H1 was found to be significantly less frequent in stroke patients than in controls (OR = 0.61, 95% CI = 0.45-0.83, p = 0.001), when comparing each clade against all other haplogroups pooled together. Conversely, the pre-HV/HV and U mtDNA lineages emerge as potential genetic factors conferring risk for stroke (OR = 3.14, 95% CI = 1.41-7.01, p = 0.003, and OR = 2.87, 95% CI = 1.13-7.28, p = 0.021, respectively). SNPs m.3010G>A, m.7028C>T and m.11719G>A strongly influence ischemic stroke risk, their allelic state in haplogroup H1 corroborating its protective effect. CONCLUSION: Our data suggests that mitochondrial haplogroup H1 has an impact on ischemic stroke risk in a Portuguese sample.
Abstract: BACKGROUND: Oral anticoagulants are better than aspirin for secondary prevention after myocardial infarction and after cerebral ischaemia in combination with non-rheumatic atrial fibrillation. The European/Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT) aimed to determine whether oral anticoagulation with medium intensity is more effective than aspirin in preventing future vascular events in patients with transient ischaemic attack or minor stroke of presumed arterial origin. METHODS: In this international, multicentre trial, patients were randomly assigned within 6 months after a transient ischaemic attack or minor stroke of presumed arterial origin either anticoagulants (target INR range 2.0-3.0; n=536) or aspirin (30-325 mg daily; n=532). The primary outcome was the composite of death from all vascular causes, non-fatal stroke, non-fatal myocardial infarction, or major bleeding complication, whichever occurred first. In a post hoc analysis anticoagulants were compared with the combination of aspirin and dipyridamole (200 mg twice daily). Treatment was open, but auditing of outcome events was blinded. Primary analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial (number ISRCTN73824458) and with ClinicalTrials.gov (NCT00161070). FINDINGS: The anticoagulants versus aspirin comparison of ESPRIT was prematurely ended because ESPRIT reported previously that the combination of aspirin and dipyridamole was more effective than aspirin alone. Mean follow-up was 4.6 years (SD 2.2). The mean achieved INR was 2.57 (SD 0.86). A primary outcome event occurred in 99 (19%) patients on anticoagulants and in 98 (18%) patients on aspirin (hazard ratio [HR] 1.02, 95% CI 0.77-1.35). The HR for ischaemic events was 0.73 (0.52-1.01) and for major bleeding complications 2.56 (1.48-4.43). The HR for the primary outcome event comparing anticoagulants with the combination treatment of aspirin and dipyridamole was 1.31 (0.98-1.75). INTERPRETATION: Oral anticoagulants (target INR range 2.0-3.0) are not more effective than aspirin for secondary prevention after transient ischaemic attack or minor stroke of arterial origin. A possible protective effect against ischaemic events is offset by increased bleeding complications.
Abstract: Cerebellar apparent diffusion coefficient (ADC) was found to be increased after acute cerebral hemispheric stroke. There are no data on cerebellar ADC changes in patients with chronic, age-related white matter lesions (ARWML). We aimed to determine longitudinal ADC variations on cerebral hemispheric and cerebellar white matter regions of patients with ARWML in order to study relations between ADC changes in both regions. ADC was measured serially (1-year interval) on lesioned periventricular frontal white matter, frontal and parietoccipital normal appearing white matter and middle cerebellar peduncles, on 19 aged patients with ARWML, which also underwent gait assessment. We compared regional ADC at 0 and 1 year and calculated variation percentages for each region. Correlation analysis was made between ADC variation in cerebellar regions and in contralateral hemispheric regions and between cerebellar ADC at 1 year and walking speed. After 1 year, ADC was higher on lesioned periventricular frontal white matter and lower on cerebellar regions. ADC variations on these regions were negatively correlated. Cerebellar ADC measured after 1 year was positively correlated with walking speed. This suggests a link between vascular disease progression inside frontal lesions and ADC reduction in contralateral cerebellar peduncles. Chronic ischemia in frontal white matter could have interrupted frontal-cerebellar circuits, producing hypometabolism in cerebellar regions (and worse performance on motor tasks), decreased perfusion and hence ADC reduction.
Abstract: Although classically considered to be involved only in motor coordination, the cerebellum has more recently been implicated also in cognitive control. Anatomical studies have shown the cerebellum to be linked to pre-frontal, occipito-parietal and temporal cortical associative areas, as well as to the limbic system, in a closed loop circuit. Functional studies revealed activation of the cerebellum during performance on cognitive tasks not related to movement. Pathological, morphological and functional imaging studies have shown the cerebellum to be one of the cerebral structures affected in some of the cognitive and behavioural developmental disorders, like Attention Deficit with Hyperactivity Disorder, Autism and Schizophrenia. Neuropsychological studies in patients with degenerative cerebellar ataxia also showed cognitive dysfunction, mainly of the executive type. Investigation performed with child and adult patients with focal lesions of the cerebellum has helped to better discriminate the cognitive role of specific areas on the cerebellum, revealing a characteristic constellation of cognitive deficits, affecting executive, visual-spatial, linguistic and behavioural functions. However, much remains to be explained on the precise nature of cerebellar contributions to cognition, in part because of the difficulty in finding adequate investigation models. Studies performed on primates have contributed to better delineate the connections between the cerebellum and cortical cognitive domains, but is always uncertain to transfer this kind of data to the human brain. Functional imaging studies although useful to investigate directly in the human model and in real time, are not yet able to completely isolate cerebellar cognitive and behavioural functions. Degenerative and developmental disorders are not the most adequate model for studying cerebellar influence on higher mental functions, as they affect other regions besides the cerebellum. Young patients with isolated cerebellar stroke provide a useful clinical model for investigating cerebellar cognitive functions, because they permit to isolate in space and time the specific contribution of the cerebellum to the cognitive deficits.
Abstract: Benign cerebral angiopathy and postpartum cerebral angiopathy are reversible cerebral arterial vasoconstriction syndromes. Presentation includes recurrent severe headaches, altered consciousness, and focal neurologic deficits; ischemic and/or hemorrhagic strokes can occur. No standard management has been established, but most authors agree that 1) acute-phase treatment includes cessation of vasoconstrictors, treatment of associated conditions, vasospasm treatment (calcium channel antagonists), and corticosteroids; 2) other measures include headache relief, blood pressure control, and stroke, cerebral edema, and seizure treatment; 3) definitive diagnosis requires conventional angiography and exclusion of alternative diagnosis; 4) a second arterial examination after 4 to 6 weeks is mandatory to confirm reversibility of vasoconstriction; 5) brain biopsy is indicated to rule out cerebral vasculitis in severe cases with clinical deterioration under steroid treatment or atypical findings; 6) immunosuppression should be reserved for patients with brain-leptomeningeal biopsy-proven vasculitis or used while waiting for a brain biopsy result; and 7) long-term measures include secondary stroke prevention and treatment of complications.
Abstract: There is insufficient information on the prognosis and safety of anticoagulation in acute cerebral vein and dural sinus thrombosis (CVDST). To describe the clinical aspects and medical management of CVDST in Portuguese hospitals, to evaluate the safety of anticoagulation in this setting, and to identify subgroups of CVDST patients with different prognoses, we registered symptomatic CVDST patients admitted to Portuguese hospitals since 1980. Cases were collected from file review up to 6/95 and from consecutively admitted patients from 6/95 to 6/98. One hundred and forty-two patients were included from 20 centers (51 retrospectively and 91 prospectively). One hundred and twelve patients (79%) were anticoagulated. There were only 6 new intracranial hemorrhages (4 in anticoagulated patients) and 2 systemic hemorrhages. Nine (6%) patients died. At discharge, 96 (68%), had recovered completely and only 6 (4%) were dependent (Rankin > or = 3). Significant multivariate predictors of death/dependency were central nervous system infection as a predisposing cause (odds ratio, OR = 15.4; 95% confidence interval CI = 111-1.1), encephalopathy on admission (OR = 5.2; 95% CI = 18.7-1.5) and hemorrhage on admission CT/MR (OR = 3.6; 95% CI = 12.9-1). Significant predictors of complete recovery were no encephalopathy on admission (OR = 5; 95% CI = 12.5-2.1), age < 45 years (OR = 3.8; 95% CI = 9.2-1.6) and anticoagulation (OR = 3.8; 95% CI = 9.6-1.5). It is possible to identify CVDST patients with potential bad or good prognosis in the acute phase. Anticoagulation was safe and a predictor of complete recovery in acute CVDST.
Abstract: We aimed to study in-hospital mortality after a first-ever stroke (brain infarction or parenchymatous hemorrhage) and to determine its predictors using easily obtainable variables. The main outcome measure was vital status at hospital discharge. Clinical features and type of stroke, with a particular emphasis on age, stroke topography and presumed causes of stroke, were studied in 3362 consecutive patients from the Lausanne Stroke Registry. Overall mortality was 4.8%. Brain hemorrhage mortality was 14.4% (48/333) and brain infarction mortality was 3.70% (112/3029). Localizations with high mortality included infratentorial (17.5%) and deep hemispheric (15.9%) territories for brain hemorrhage and, for brain infarction, multiple localizations in the posterior circulation (18.4%) and large middle cerebral artery territory (15.5%). Presumed causes of stroke associated with high mortality included saccular aneurysm (58.3%) and hypertensive arteriopathy (13.0%) for brain hemorrhage and, for brain infarction, dissection (10.4%), arteritis (8.3%), hematologic conditions (6.7%) and coexisting arterial and cardiac sources of embolism (5.2%). Multivariate logistic analysis showed that impaired consciousness on admission and limb weakness were good predictors of mortality for brain hemorrhage, while impaired consciousness and the cumulative effect of progressive worsening, limb weakness, left ventricular hypertrophy, past history of cardiac arrhythmia and previous transient ischemic attack were predictors of mortality for brain infarction. Age was not an independent predictor of stroke mortality, but for brain infarction the number of cumulative factors considered in the model increased with age. Our study shows that several factors associated with death risk are available during the first few hours after onset of stroke. Age alone is not critical, although its interaction with other factors should be considered.
Abstract: Death from acute hemispheric infarction is commonly associated with stroke size, but the potential role of the internal carotid artery (ICA) in this phenomenon is poorly understood. The aim of the present study was to analyse the relation between the degree of ipsilateral and contralateral ICA stenosis, infarct type and death. We studied 2,148 first-ever stroke patients with anterior circulation infarction from the Lausanne Stroke Registry. Doppler ultrasonography with frequency spectral analysis and Duplex-scanning were performed systematically during the acute phase of stroke. The patients were divided into groups according to the degree of ipsilateral and contralateral ICA stenosis. The case fatality ratios (CFR) at hospital discharge were obtained for each group. Several clinical features including age, stroke topography, level of consciousness, limb weakness on admission, type of onset, hyperglycemia, previous transient ischemic attack, cardiac ischemia, cardiac arrhythmia and left ventricular hypertrophy were also studied. Mortality increased significantly with ipsilateral ICA stenosis: </=50% stenosis, 2.8%, (44/1,549); >50% and </=90% stenosis, 3.5%, (6/170); >90% stenosis, 5.6%, (24/429); p = 0.026, but not significantly with contralateral ICA stenosis. However, patients without ipsilateral ICA stenosis had significantly higher mortality when contralateral stenosis was present: 16.7% (3/18) versus 2.7% (41/1,531), p = 0.013. This corresponded to an increased frequency of strokes involving the whole middle cerebral artery territory, with impaired consciousness at onset of stroke. Patients with ipsilateral stenosis had similar CFR independently of the presence or absence of contralateral stenosis. In conclusion, patency of the contralateral ICA may be an important contributory factor of larger infarction and indirectly of stroke mortality in patients with no ipsilateral stenosis.
Abstract: Striato-pallido-dentate calcifications (SPDC) is a well defined entity, characterized by calcium deposits in the basal ganglia, dentate nuclei and the centrum semiovale. Several metabolic derangements have been associated with this entity, particularly parathyroid disorders. The traditional designation of Fahr's syndrome should be restricted to the idiopathic cases. The authors report a study of seven patients with SPDC. Hypocalcemia was found in three cases, two with pseudohypoparathyroidism and one with hypoparathyroidism. Fahr's syndrome was diagnosed in four patients. Clinical and laboratory features are presented. Neurological manifestations included epilepsy, dementia and parkinsonism. Discussion focuses on the distinction of this entity from the small pallidal calcifications and on the pathophysiology of basal ganglia mineralisation, in view of recent reports.
