The Causative Classification of Stroke system: an international reliability and optimization study.

BACKGROUND: Valid and reliable ischemic stroke subtype determination is crucial for well-powered multicenter studies. The Causative Classification of Stroke System (CCS, available at http://ccs.mgh.harvard.edu) is a computerized, evidence-based algorithm that provides both causative and phenotypic stroke subtypes in a rule-based manner. We determined whether CCS demonstrates high interrater reliability in order to be useful for international multicenter studies. METHODS: Twenty members of the International Stroke Genetics Consortium from 13 centers in 8 countries, who were not involved in the design and development of the CCS, independently assessed the same 50 consecutive patients with acute ischemic stroke through reviews of abstracted case summaries. Agreement among ratings was measured by kappa statistic. RESULTS: The κ value for causative classification was 0.80 (95% confidence interval [CI] 0.78-0.81) for the 5-subtype, 0.79 (95% CI 0.77-0.80) for the 8-subtype, and 0.70 (95% CI 0.69-0.71) for the 16-subtype CCS. Correction of a software-related factor that generated ambiguity improved agreement: κ = 0.81 (95% CI 0.79-0.82) for the 5-subtype, 0.79 (95% CI 0.77-0.80) for the 8-subtype, and 0.79 (95% CI 0.78-0.80) for the 16-subtype CCS. The κ value for phenotypic classification was 0.79 (95% CI 0.77-0.82) for supra-aortic large artery atherosclerosis, 0.95 (95% CI 0.93-0.98) for cardioembolism, 0.88 (95% CI 0.85-0.91) for small artery occlusion, and 0.79 (0.76-0.82) for other uncommon causes. CONCLUSIONS: CCS allows classification of stroke subtypes by multiple investigators with high reliability, supporting its potential for improving stroke classification in multicenter studies and ensuring accurate means of communication among different researchers, institutions, and eras.

Stenting for the treatment of high-grade intracranial stenoses.

To date, evidence to recommend endovascular treatment in patients with intracranial stenoses is lacking. Recently, the introduction of self-expanding stents (Wingspan Stent System) aroused considerable expectations in their employ for stroke prevention. We report a single-center experience of percutaneous transluminal angioplasty and stenting in a series of consecutive patients with intracranial stenoses and compare the safety and performance of balloon-mounted stents versus self-expanding stent systems (Wingspan). Thirty-four patients with 39 severe (>70%) intracranial stenoses were treated during a 6-year period. An independent stroke neurologist collected data about intra and periprocedural complications and short-term outcome. We considered as endpoint measures (1) any 30-day stroke or death (2) any major 30-day complication and (3) procedure technical success. Technical success was achieved in all patients. No vessel dissection or ruptures were observed. The 30-day stroke/death rate was 17.9%. Five ischemic strokes in the territory of treated vessels and two intracranial hemorrhages occurred respectively within 24 h and 5 days after endovascular treatment. Three (17.6%) patients of Wingspan treated group and four (18.2%) of the patients treated with different stent systems had unfavorable outcome. Our study confirms that endovascular treatment can be performed with a high technical success rate, even though the safety of these devices has still to be demonstrated.

Intra-arterial or intravenous thrombolysis for acute ischemic stroke? The SYNTHESIS pilot trial.

OBJECTIVE To assess the feasibility, safety and preliminary efficacy of intra-arterial thrombolysis (IAT) compared with standard intravenous thrombolysis (IVT) for acute ischemic stroke. METHODS Eligible patients with ischemic stroke, who were devoid of contraindications, started IVT within 3 h or IAT as soon as possible within 6 h. Patients were randomized within 3 h of onset to receive either intravenous alteplase, in accordance with the current European labeling, or up to 0.9 mg/kg intra-arterial alteplase (maximum 90 mg), over 60 min into the thrombus, if necessary with mechanical clot disruption and/or retrieval. The purpose of the study was to determine the proportion of favorable outcome at 90 days. Safety endpoints included symptomatic intracranial hemorrhage (SICH), death and other serious adverse events. RESULTS 54 patients (25 IAT) were enrolled. Median time from stroke onset to start to treatment was 3 h 15 min for IAT and 2 h 35 min for IVT (p<0.001). Almost twice as many patients on IAT as those on IVT survived without residual disability (12/25 vs 8/29; OR 3.2; 95% CI 0.9 to 11.4; p=0.067). SICH occurred in 2/25 patients on IAT and in 4/29 on IVT (OR 0.5; CI 0.1 to 3.3; p=0.675). Mortality at day 7 was 5/25 (IAT) compared with 4/29 (IVT) (OR 1.6; CI 0.4 to 6.7; p=0.718). There was no significant difference in the rate of other serious adverse events. CONCLUSIONS Rapid initiation of IAT is a safe and feasible alternative to IVT in acute ischemic stroke.

Transthyretin Asn90 variant: amyloidogenic or non-amyloidogenic role.

A number of mutations were described in the TTR gene. They were generally related to a variety of inherited syndromes named 'familial TTR-related amyloidoses'. Although TTR mutations were mostly associated with familial amyloid polyneuropathy (FAP), these molecular variants were also found in patients with recurrent stroke, subarachnoidal bleeding and radiological findings of cerebral, cerebellar, cortical-subcortical infarctions and hemosiderosis. We describe a 46 y.o. man with recurrent cerebral haemorrhages carrying Asn90His variant of TTR gene. This mutation has been reported both in FAP and asymptomatic subjects raising the doubt on the possible amyloidogenetic role of this variant. The absence of mutation in the patient's father, who had a history of unexplained cerebral haemorrhage and the lack of symptoms and sign of cerebral bleeding in the two patient's sisters, carrying the same mutation, seem to support the hypothesis that His90Asn TTR mutation do not have an impact in amyloid formation. It has still to be established whether other gene variants in our patient could act synergistically with His90Asn TTR mutation in increasing the risk of CNS haemorrhages.

Safety of carotid stenting for stroke prevention: need of an independent outcome assessor.

Safety and efficacy of carotid artery stenting have still to be fully established. We propose a standardized registry of carotid artery stenting in use at our hospital to evaluate whether the presence of an independent neurologist performing basal, procedural and post-procedural observation increases the accuracy of outcome assessment. We collected a cohort of patients receiving carotid stenting. An external neurologist supervised the endovascular intervention and monitored the patient's clinical conditions during procedure and follow-up time (12 months). The procedure was carried out successfully in all cases. We registered two intra-procedural strokes and two strokes within 24 h. The risk of major complications in our study was 9.1% at 30 days. Our complication rate is higher than in previous studies. These findings could be partly explained by the unemployment of distal protection devices, but also by the presence of an independent observer that might have increased the accuracy of neurological evaluation.

Stem cell therapy in stroke.

Recent work has focused on cell transplantation as a therapeutic option following ischemic stroke, based on animal studies showing that cells transplanted to the brain not only survive, but also lead to functional improvement. Neural degeneration after ischemia is not selective but involves different neuronal populations, as well as glial and endothelial cell types. In models of stroke, the principal mechanism by which any improvement has been observed, has been attributed to the release of trophic factors, possibly promoting endogenous repair mechanisms, reducing cell death and stimulating neurogenesis and angiogenesis. Initial human studies indicate that stem cell therapy may be technically feasible in stroke patients, however, issues still need to be addressed for use in human subjects.

Statins and stroke.

Pharmacological studies highlighted pleiotropic effects of statins, that seem to influence atherogenesis not only by increasing atherosclerotic plaque stability but also by modulating endothelial function and inflammation and acting on platelet aggregation and thrombosis. Despite a strong association between increased levels of low-density lipoprotein cholesterol (LDL-C) and the incidence of coronary heart disease (CHD) has been well proven, it not yet established whether serum LDL-C levels are related to stroke incidence. The major aim of this paper is to perform a comprehensive up-to-date review of research papers, meta-analyses and randomized controlled clinical trials reporting the effects of statins in primary and secondary stroke prevention strategies. In addition, our work provides an overview on statin chemical structure, mechanism of action and pharmacological properties, investigating also most common adverse effects and relationship between statin therapy and haemorrhagic stroke risk, in order to assess drugs safety. Although studies are heterogeneous, our analysis shows that statins reduce the risk of stroke occurrence in high risk patients and seem also to reduce stroke recurrence. Moreover, the low incidence and reversibility of adverse effects, and the unclear association with hemorrhagic events, support the safe use of these drugs.

Recovery after L-DOPA treatment in peginterferon and ribavirin induced parkinsonism.

BACKGROUND: Hepatitis C virus (HCV) chronically infects approximately 2% of the European population. Antiviral therapy with pegInterferon-alpha (PegIFN) and ribavirin (Rbv) is the standard of care, leading to HCV eradication in roughly 50% of patients. IFN-based therapy has been associated with high rates (20%) of central nervous system side effects, but only a few case reports exist on extrapyramidal side effects. RESULTS: We report a 64-year-old man developing parkinsonism during PegIFN alfa-2a and ribavirin therapy for chronic hepatitis C. No improvement was observed after treatment discontinuation. Therefore, on the basis of previous clinical and experimental reports, levodopa-benserazide treatment was started. After substantial improvement, symptoms relapsed following drug tapering. CONCLUSIONS: This is the first case of parkinsonism in a Caucasian patient receiving PegIFN/Rbv therapy. The rapid and significant improvement of symptoms obtained in our patient with levodopa-benserazide, suggests that this therapy could be considered as first line symptomatic treatment.

Genetic polymorphisms for the study of multifactorial stroke.

Single-gene disorders explain only a minority of stroke cases. Stroke represents a complex trait, which is usually assumed to be polygenic. On this topic, the role of a wide number of candidate genes has been investigated in stroke through association studies, with controversial results. Therefore, it is difficult for the clinician to establish the validity and the level of clinical applicability of the previously reported associations between genetic factors and stroke. This review is an update and an extensive analysis of the more recent association studies conducted in stroke. We evaluated a number of studies on several candidate genes (including F5, F2, FGA/FGB/FGG, F7, F13A1, vWF, F12, SERPINE1, ITGB3/PLA1/PLA2/ITGA2B, ITGA2, GP1BA, ACE, AGT, NOS3, APOE, LPL, PON1, PDE4D, ALOX5AP, MTHFR, MTR, and CBS), providing a final panel of genes and molecular variants. We categorized this panel in relation to the degree of association with stroke, supported by the results of meta-analyses and case-control studies. Our findings could represent a useful tool to address further molecular investigations and to realize more detailed meta-analyses.

Amino acid changes in the amino terminus of the Na,K-adenosine triphosphatase alpha-2 subunit associated to familial and sporadic hemiplegic migraine.

Familial hemiplegic migraine (FHM) is a rare subtype of migraine with aura inherited with an autosomal dominant pattern. Here, we report the genetic analysis of four families and one sporadic case with hemiplegic migraine (HM) in whom we searched for mutations in the three genes associated with the disease CACNA1A, ATP1A2 and SCN1A. Two novel amino acid changes p.Arg65Trp and p.Tyr9Asn, in the Na,K-adenosine triphosphatase (ATPase) alpha-2 subunit encoded by the ATP1A2 gene, were found in one FHM family and in the sporadic case, respectively. These mutations are peculiar for their location in the extreme N-terminus, an uncommon mutation target in this protein. Low frequency of migraine attacks in all our mutant patients with low complexity of the associated aura symptoms in the sporadic case is also observed. Besides the two novel mutations, the data here reported confirm the involvement of ATP1A2 gene in the sporadic form of HM, while the negative results on the other families tested for all genes known in HM strengthen the hypothesis of the existence of at least another locus involved in FHM.

Monogenic vessel diseases related to ischemic stroke: a clinical approach.

The identification of stroke cases caused by monogenic disorders is important both for therapeutic decisions and genetic counselling, although they represent less than 1% of all stroke patients. The purpose of this review is to summarize genetic, pathological, and clinical features of single-gene disorders related to ischemic stroke. The following monogenic disorders are considered: cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy, cerebral autosomal-recessive arteriosclerosis with subcortical infarcts and leukoencephalopathy, hereditary endotheliopathy with retinopathy, nephropathy, and stroke, Fabry disease, pseudoxanthoma elasticum, Neurofibromatosis type 1, familial MoyaMoya disease, Ehlers-Danlos syndrome type IV, Marfan syndrome. For each monogenic disorder, mode of inheritance, pathophysiological aspects, clinical phenotype, and diagnostic tools are carefully described. Furthermore, the classification of monogenetic disorders is presented according to stroke mechanisms, which include small vessel diseases, large artery diseases, and arterial dissections. This review could be useful to identify specific diagnostic pathways for patients with a suspicion of monogenic disease.

The dual role of endothelial differentiation-related factor-1 in the cytosol and nucleus: modulation by protein kinase A.

Endothelial differentiation-related factor (EDF)-1 is involved in the repression of endothelial cell differentiation and is the first studied calmodulin (CaM)-binding protein in endothelial cells. Here we report that (i) EDF-1 is in vitro and in vivo phosphorylated by protein kinase A (PKA); (ii) EDF-1/CaM interaction is modulated by the phosphorylation of EDF-1 by PKA; (iii) forskolin stimulates nuclear accumulation of EDF-1, and (iv) PKA phosphorylation enhances EDF-1 interaction with the TATA-binding protein. CaM modulates the activity of several enzymes, among which is nitric oxide synthase (NOS). EDF-1, but not phosphorylated EDF-1, inhibits the activity of NOS. Accordingly, we detected an increase in NOS activity in cells that express low amounts of EDF-1. Our results indicate that EDF-1 serves two main functions in endothelial cells: (i) it regulates CaM availability in the cytosol, and (ii) it acts in the nucleus as a transcriptional coactivator.

Promoter analysis of TFPT (FB1), a molecular partner of TCF3 (E2A) in childhood acute lymphoblastic leukemia.

We previously identified the TFPT (FB1) gene as a molecular partner of TCF3 (E2A) in childhood pre-B cell acute lymphoblastic leukemia (ALL). TFPT (FB1) alignment in man, mouse and rat displays a very high degree of identity, indicating that it may play a basic role in mammalian cells. To get insights into this role, we have identified and studied the TFPT (FB1) promoter and its responsiveness to hematopoietic transcriptional factors. We found that the TFPT (FB1) 5' flanking sequence displays the features of a TATA-less promoter with weak homology to Inr (Initiator) elements. Starvation experiments suggested that TFPT (FB1) expression might be constitutive. Nevertheless, the TFPT (FB1) promoter, tested by transactivation assays, was found to be responsive to Ikaros 2 and, mainly, to PU.1, a transcription factor belonging to the Ets family. Thus, these hematopoietic factors, known to play critical roles during the early stages of B cell differentiation and to be involved in leukemia, might modulate TFPT (FB1) expression during hematopoiesis and/or leukemia development.