Telephone audit for monitoring stroke unit facilities: a post hoc analysis from PROSIT study.

BACKGROUND: Although several valid approaches exist to measure the number and the quality of acute stroke units, only few studies tested their reliability. This study is aimed at establishing whether the telephone administration of the PROject of Stroke unIt ITaly (PROSIT) audit questionnaire is reliable compared with direct face-to-face interview. METHODS: Forty-three medical leaders in charge of in-hospital stroke services were interviewed twice using the same PROSIT questionnaire with 2 different modalities. First, the interviewers approached the medical leaders by telephone. Thereafter, they went to the hospital site and performed a direct face-to-face interview. Six independent couples of trained researchers conducted the audit interviews. The degree of intermodality agreement was measured with kappa statistic. RESULTS: We found a perfect agreement for stroke units identification between the 2 different audit modalities (K = 1.00; standard error [SE], 1.525). The agreement was also very good for stroke dedicated beds (K = 1.00; SE, 1.525) and dedicated personnel (K = 1.00; SE, 1.525), which are the 2 components of stroke unit definition. The agreement was lower for declared in use process of care and availability of diagnostic investigations. CONCLUSIONS: The telephone audit can be used for monitoring stroke unit structures. It is more rapid, less expensive, and can repeatedly be used at appropriate intervals. However, a reliable description of the process of care and diagnostic investigations indicators should be obtained by either local site audit visit or prospective stroke register based on individual patient data.

Considerations on a mutation in the NOTCH3 gene sparing a cysteine residue: a rare polymorphism rather than a CADASIL variant.

Some missense mutations and small deletions in the NOTCH3 gene, not involving cysteine residues, have been described in patients considered to be affected by paucisymptomatic CADASIL. However, the significance of such molecular variants is still unclear. We describe a 49-year-old woman with a CADASIL-like phenotype, carrying a novel cysteine-sparing mutation in exon 29 of the NOTCH3 gene, and discuss the possible pathogenetic role of this molecular variant. Even though atypical clinical and MRI findings make a diagnosis of CADASIL unlikely in this patient, our report nevertheless underlines the intriguing genotype-phenotype relationship in NOTCH3 mutations and the importance of functional investigation to ascertain the role of new NOTCH3 mutations in CADASIL pathogenesis.

Lombardia GENS: a collaborative registry for monogenic diseases associated with stroke.

The Italian region of Lombardy, with its existing stroke centers and high-technology laboratories, provides a favorable context for studying monogenic diseases associated with stroke. The Lombardia GENS project was set up to create a regional network for the diagnosis of six monogenic diseases associated with stroke: CADASIL, Fabry disease, MELAS, familial and sporadic hemiplegic migraine, hereditary cerebral amyloid angiopathy and Marfan syndrome. The network comprises 36 stroke centers and seven high-technology laboratories, performing molecular analysis. In this context, all stroke/TIA patients fulfilling clinical criteria for monogenic diseases are currently being included in an ongoing study. Demographic, clinical and family data and diagnostic criteria are collected using standardized forms. On the basis of stroke incidence in Lombardy and the reported prevalence of the diseases considered, we expect, during the course of the study, to collect datasets and DNA samples from more than 200 stroke patients suspected of having monogenic diseases. This will allow evaluation of the regional burden and better phenotype characterization of monogenic diseases associated with stroke.

Stem cell transplantation for ischemic stroke.

BACKGROUND: Studies in animal models of ischemic stroke have shown that stem cells transplanted into the brain can lead to functional improvement. However, to date, evidence for the benefits of stem cell transplantation in ischemic stroke patients is lacking. OBJECTIVES: To assess the efficacy and safety of stem cell transplantation compared with conventional treatments in patients with ischemic stroke. SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (last searched February 2010), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2009, Issue 3), MEDLINE (1966 to August 2008), EMBASE (1980 to August 2008), Science Citation Index (1900 to August 2008), and BIOSIS (1926 to August 2008). We handsearched potentially relevant conference proceedings, screened reference lists, and searched ongoing trials and research registers (last searched November 2008). We also contacted individuals active in the field and stem cell manufacturers (last contacted December 2008). SELECTION CRITERIA: We included randomized controlled trials (RCTs) recruiting patients with ischemic stroke, in any phase of the disease, and an ischemic lesion confirmed by computerized tomography or magnetic resonance imaging scan. We included all types of stem cell transplantation regardless of cell source (autograft, allograft, or xenograft; embryonic, fetal, or adult; from brain or other tissues), route of cell administration (systemic or local), and dosage. The primary outcome was efficacy (assessed as combined functional outcome or disability and dependency) at longer follow-up (minimum six months). Secondary outcomes included post-procedure safety outcomes (death, worsening of neurological deficit, infections and neoplastic transformation). DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed trial quality. We contacted study authors for additional information. MAIN RESULTS: We identified three very small RCTs. Two are still awaiting classification because only subgroups of patients could be included in this meta-analysis and additional unpublished data are needed. The third trial randomized 30 patients to intravenous transplantation of autologous mesenchymal stem cell (10 participants) or reference group (20 participants) (five participants, initially randomized to the intervention group, refused the treatment and were allocated to the reference group) and found a statistically non-significant functional improvement in treated patients at longer follow-up. No adverse cell-related events were reported. AUTHORS' CONCLUSIONS: No large trials of stem cell transplantation have been performed in ischemic stroke patients and it is too early to know whether this intervention can improve functional outcome. Large, well-designed trials are needed.

Stroke-unit care for acute stroke patients: an observational follow-up study.

BACKGROUND: Large numbers of stroke patients arrive at hospital at a very early stage, and effective treatments for the acute phase of the disease are available. However, evidence that patients with acute stroke benefit from stroke-unit care is scarce. Our aim was to determine whether admission to a stroke unit, rather than a conventional ward, affected the outcome of patients with acute stroke. METHODS: We did an observational follow-up study of 11 572 acute stroke patients hospitalised within 48 h of the onset of symptoms either in a stroke unit (n=4936) or in a conventional ward (6636). Patients were identified retrospectively from discharge records from 260 Italian hospitals. The primary outcome was mortality or disability (Rankin score greater than two), assessed prospectively by independent, masked assessors 2 years after admission. Analyses were adjusted for patient characteristics and clustered at the hospital level. FINDINGS: Overall, 1576 patients died in hospital; 2169 died during the follow-up period. 347 patients were lost to follow-up. Compared with conventional-ward care, stroke-unit care was associated with a reduced probability of death or being disabled at the end of follow-up (odds ratio 0.81, 95% CI 0.72-0.91; p=0.0001). The potential benefit was significant across all age ranges and clinical characteristics, except for unconsciousness. No specific elements of setting, organisation, or process of care were associated with outcome. INTERPRETATION: Admission to a stroke-unit ward with dedicated beds and staff within 48 h of onset should be recommended for all patients with acute stroke.

The role of clinical and neuroimaging features in the diagnosis of CADASIL.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common familial cerebral small vessel disease, caused by NOTCH3 gene mutations. The aim of our study was to identify clinical and neuroradiological features which would be useful in identifying which patients presenting with lacunar stroke and TIA are likely to have CADASIL. METHODS: Patients with lacunar stroke or TIA were included in the present study. For each patient, demographic and clinical data were collected. MRI images were centrally analysed for the presence of lacunar infarcts, microbleeds, temporal lobe involvement, global atrophy and white matter hyperintensities. RESULTS: 128 patients (mean age 56.3 ± 12.4 years) were included. A NOTCH3 mutation was found in 12.5% of them. A family history of stroke, the presence of dementia and external capsule lesions on MRI were the only features significantly associated with the diagnosis of CADASIL. Although thalamic, temporal pole gliosis and severe white matter hyperintensities were less specific for CADASIL diagnosis, the combination of a number of these factors together with familial history for stroke result in a higher positive predictive value and specificity. CONCLUSIONS: A careful familial history collection and neuroradiological assessment can identify patients in whom NOTCH3 genetic testing has a higher yield.

Targeting aspirin in acute disabling ischemic stroke: an individual patient data meta-analysis of three large randomized trials.

BACKGROUND: Aspirin is of moderate overall benefit for patients with acute disabling ischemic stroke. It is unclear whether functional outcome could be improved after stroke by targeting aspirin to patients with a high risk of recurrent thrombosis or a low risk of haemorrhage. AIMS: We aimed to determine whether patients at higher risk of thrombotic events or poor functional outcome, or lower risk of major haemorrhage had a greater absolute risk reduction of poor functional outcome with aspirin than the average patient. METHODS: We used data on individual ischemic stroke patients from three large trials of aspirin vs. placebo in acute ischemic stroke: the first International Stroke Trial (n = 18,372), the Chinese Acute Stroke Trial (n = 20,172) and the Multicentre Acute Stroke Trial (n = 622). We developed and evaluated clinical prediction models for the following: early thrombotic events (myocardial infarction, ischemic stroke, deep vein thrombosis and pulmonary embolism); early haemorrhagic events (significant intracranial haemorrhage, major extracranial haemorrhage, or haemorrhagic transformation of an infarct); and late poor functional outcome. We calculated the absolute risk reduction of poor functional outcome (death or dependence) at final follow-up in: quartiles of early thrombotic risk; quartiles of early haemorrhagic risk; and deciles of poor functional outcome risk. RESULTS: Ischemic stroke patients who were older, had lower blood pressure, computerized tomography evidence of infarct or more severe deficits due to stroke had increased risk of thrombotic and haemorrhagic events and poor functional outcome. Prediction models built with all baseline variables (including onset to treatment time) discriminated weakly between patients with and without recurrent thrombotic events (area under the receiver operating characteristic curve 0·56, 95% CI:0·53-0·59) and haemorrhagic events (0·57, 0·52-0·64), though well between patients with and without poor functional outcome (0·77, 0·76-0·78) in the International Stroke Trial. We found no evidence that the net benefit of aspirin increased with increasing risk of thrombosis, haemorrhage or poor functional outcome in all three trials. CONCLUSIONS: Using simple clinical variables to target aspirin to patients after acute disabling stroke by risk of thrombosis, haemorrhage or poor functional outcome does not lead to greater net clinical benefit. We suggest future risk stratification schemes include new risk factors for thrombosis and intracranial haemorrhage.

Molecular basis of young ischemic stroke.

Epidemiological and family studies have provided evidence on the role of genetic factors in stroke, particularly in stroke occurring at young age. However, despite its impact, young stroke continues to be understudied. This article reviews the existing literature on the most investigated monogenic disorders (CADASIL, Fabry disease, MELAS, RVCL, COL4A1, Marfan and Ehlers-Danlos syndromes) causing stroke in young and a number of candidate genes associated with stroke occurring in patients younger than 50 years. Although our study failed in identifying strong and reliable associations between specific genes and young stroke, our detailed literature revision on the field allowed us to compile a panel of genes possibly generating a susceptibility to stroke, which could be a starting point for future research. Since stroke is a potentially preventable disease, the identification of genes associated with young stroke may promote novel prevention strategies and allow the identification of therapeutic disease targets.

Clinical studies in stem cells transplantation for stroke: a review.

Stroke is a significant cause of long-term disability. Currently, once damage from a stroke is established little can be done to recover lost function. Cell transplantation emerged as possible alternative therapy, on the basis of animal studies showing that cells transplanted into the brain not only survive, but also lead to functional improvement in different neurodegenerative diseases. Stem cells have been tested in stroke patients as a possible treatment option. While initially stem cells seemed to work by a 'cell replacement' mechanism, it is emerging that cell therapy works mostly by providing trophic support to the injured tissue and brain, fostering both neurogenesis and angiogenesis. This review summarizes clinical studies on stem cell transplantation in stroke patients to evaluate the safety, feasibility of administration and tolerability of this experimental treatment. At present there is little evidence to assess the applicability of this treatment in stroke patients and well designed clinical trials are necessary to evaluate safety and toxicity as well as optimal cell type, route and time of delivery.

Inclusion body myopathy and frontotemporal dementia caused by a novel VCP mutation.

Hereditary inclusion body myopathy (IBM) with Paget's disease of the bone (PDB) and frontotemporal dementia (FTD) is a rare autosomal dominant disease caused by mutations in the valosin-containing protein (VCP) gene. We report a novel heterozygous VCP gene mutation (R159C) in a 69-year-old Italian patient presenting with slowly progressive muscle weakness of the distal upper and proximal lower limbs since the age of 50 years, 18 years later FTD supervened. No dementia or myopathies were revealed in the family history covering two generations. Degenerative changes and rimmed vacuoles together with VCP- and ubiquitin-positive cytoplasmic and nuclear aggregates were observed at the muscle biopsy. Several elements support the pathogenic role of the R159C VCP gene mutation: the occurrence at the same codon of a different, previously identified pathogenic mutation within a VCP gene mutational hot-spot, the histopathological and biochemical evidence of muscle VCP accumulation and the combined clinical presentation of IBM and FTD. These findings suggest VCP gene investigation even in apparently sporadic cases.

Assessment of regional acute stroke unit care in Italy: the PROSIT study.

BACKGROUND/OBJECTIVES: The aim of this study was to survey acute in-hospital stroke services in seven Italian regions. METHODS: Regional hospital discharge registers were searched to identify hospital services that record at least 50 acute stroke discharges per year and the doctors in charge of these services were interviewed. RESULTS: Only 31 (7%) out of 447 services could be classified as stroke units (SUs). Of these, only 9 (29%) were found to have vital function monitoring systems available for all patients. The most striking differences between SUs and mixed stroke services emerged when comparing staff/patient ratios in the two types of unit. CONCLUSIONS: There are still not enough SUs in Italy, and fewer than 10% of stroke patients can be admitted to such units.

Stroke in an elderly population: incidence and impact on survival and daily function. The Italian Longitudinal Study on Aging.

BACKGROUND: Epidemiological data are essential to estimate the burden of stroke. We evaluated stroke incidence in older Italians and the effect of first-ever stroke on survival and activities of daily living (ADL). METHODS: The analysis was performed in the Italian Longitudinal Study on Aging (ILSA) sample, consisting of 5,632 individuals aged 65-84. The ILSA aims at major cardiovascular and neurological age-associated diseases. The baseline survey was performed in 1992 to detect prevalent diseases. The longitudinal examination started on September 1995 aiming at incidence, function and survival. RESULTS: Complete follow-up data were achieved for 77% of the baseline stroke-free cohort (4,164 persons; 50.9% males; mean age 74.5 +/- 5.7 years). Incidence for first-ever stroke was 9.51 (95% CI: 7.75-11.27) per 1,000 person years and 12.99 (95% CI: 10.99-14.98) including recurrent stroke (total incidence). Crude mortality was 49.2% among first stroke patients and 15% among persons without stroke. The first-ever stroke mortality risk ratio, adjusted for demographics and comorbidity, was 2.40 (95% CI: 1.62-3.54). In survivors, impairment of at least one ADL was present in 67.6% of first-ever stroke patients vs. 31.6% of individuals without stroke. The comorbidity-adjusted OR was 2.63 (95% CI: 1.20-5.78) in the total cohort, and 4.00 (95% CI: 1.39-11.46) in individuals without disability at baseline. CONCLUSIONS: The ILSA provides the first data on stroke incidence in Italy on a national basis. Overall, 153,000 new cases can be expected annually in the Italian elderly population. First-ever stroke still has a strong effect on survival and function of older persons.