Association between cholesterol levels and infections after ischemic stroke.

BACKGROUND AND PURPOSE: Multiple studies have suggested an immunomodulatory role of cholesterol. We investigated whether cholesterol levels are associated with the risk of infectious complications (ICs) in acute ischemic stroke patients. METHODS: A single-center prospective cohort was analyzed. Total (TOTc), low-density lipoprotein cholesterol and high-density lipoprotein cholesterol levels were measured within 24 h from admission. The outcome of interest was the occurrence of any IC (pneumonia, urinary tract infection, sepsis, other infection) during hospitalization. Predictors of ICs were investigated with multivariable logistic regression. RESULTS: A total of 603 patients were included (median age 78 years, 49.3% males), of whom 134 (22.2%) developed an IC. Subjects with ICs had lower TOTc compared with patients without ICs (median 157 vs. 173 mg/dL; P < 0.001). When TOTc was stratified in quartiles, we observed a linear decrease in the prevalence of ICs with higher TOTc levels (Q1, <144 mg/dL, 32.7%; Q2, 145-168 mg/dL, 24.7%; Q3, 169-197 mg/dL, 17.8%; Q4, >197 mg/dL, 13.3% P < 0.001). The inverse relationship between TOTc and ICs remained significant after adjustment for confounders in logistic regression [odds ratio (OR) for 10 mg/dL increase, 0.92; 95% confidence intervals (CI), 0.87-0.97; P = 0.001]. This association was also confirmed for low-density lipoprotein cholesterol (OR, 0.93; 95% CI, 0.88-0.99; P = 0.013) and high-density lipoprotein cholesterol (OR, 0.85; 95% CI, 0.73-0.98; P = 0.026) and was not mediated by statin treatment. CONCLUSION: Higher cholesterol levels are independently associated with lower risk of ICs in ischemic stroke patients. Further studies are needed to confirm our findings and characterize the biological mechanisms underlying this association.

The organisation of the acute ischemic stroke management: key notes of the Italian Neurological Society and of the Italian Stroke Organization.

The main aim of acute ischemic stroke treatment is the as much possible prompt, safe and effective arterial recanalisation, in order to restore reperfusion into the ischemic brain area. The procedures obtaining this result are rapidly evolving and in the last years, we observed new evidences that affirmed the therapeutical benefit of the concomitant treatment using endovenous thrombolysis and mechanical thrombectomy in selected patients with ischemic stroke. However, all treatments are time-sensitive and the main limitation for their application is represented by the time. For this reason, the optimisation of the acute stroke management that includes a pre-hospital and an in-hospital phase is essential to reduce the avoidable delay, increasing the number of patients potentially treatable. The purpose of this document is to define the main elements and to suggest the principal key points constituting the optimal pathway of stroke management in Italian care settings, in line with the recommendations coming from the current national and international guidelines.

Early ficolin-1 is a sensitive prognostic marker for functional outcome in ischemic stroke.

BACKGROUND: Several lines of evidence support the involvement of the lectin pathway of complement (LP) in the pathogenesis of acute ischemic stroke. The aim of this multicenter observational study was to assess the prognostic value of different circulating LP initiators in acute stroke. METHODS: Plasma levels of the LP initiators ficolin-1, -2, and -3 and mannose-binding lectin (MBL) were measured in 80 stroke patients at 6 h only and in 85 patients at 48 h and later. Sixty-one age- and sex-matched healthy individuals served as controls. Stroke severity was measured on admission using the National Institutes of Health Stroke Scale (NIHSS). The outcome was measured at 90 days by the modified Rankin Scale (mRS). RESULTS: Ficolin-1 was decreased in patients compared with controls measured at 6 h (median 0.13 vs 0.33 µg/ml, respectively, p < 0.0001). At 48 h, ficolin-1 was significantly higher (0.45 µg/ml, p < 0.0001) compared to the 6 h samples and to controls. Likewise, ficolin-2 was decreased at 6 h (2.70 vs 4.40 µg/ml, p < 0.0001) but not at 48 h. Ficolin-3 was decreased both at 6 and 48 h (17.3 and 18.23 vs 21.5 µg/ml, p < 0.001 and <0.05, respectively). For MBL no difference was detected between patients and controls or within patients at the different time points. In multivariate analysis, early ficolin-1 was independently associated with unfavorable mRS outcome (adjusted odds ratio (OR): 2.21, confidence interval (CI) 95 % 1.11-4.39, p = 0.023). Early ficolin-1 improved the discriminating ability of an outcome model including NIHSS and age (area under the curve (AUC) 0.95, CI 95 % 0.90-0.99, p = 0.0001). CONCLUSIONS: The ficolins are consumed within 6 h after stroke implicating activation of the LP. Early ficolin-1 is selectively related to 3-month unfavorable outcome.

Previous infection and the risk of ischaemic stroke in Italy: the IN2 study.

BACKGROUND AND PURPOSE: There is an increasing interest in new risk factors for ischaemic stroke. Acute and chronic infections could contribute to different aetiological mechanisms of atherosclerosis that lead to cerebrovascular disease. The aim of this study was to investigate the hypothesis that previous infections and Chlamydia pneumoniae in particular increase the risk of ischaemic stroke in the population. METHODS: This was a prospective case-control study involving 11 Italian stroke units. Controls were age- and sex-matched with cases, represented by patients admitted to hospital for acute ischaemic stroke. For each participant classical vascular risk factors and previous inflammatory and infectious events up to 1 month before were registered. Blood samples were collected to analyse inflammatory markers and titres of antibodies against C. pneumoniae. RESULTS: A total of 1002 participants were included (mean age 69 years) with 749 ischaemic stroke patients. Infections occurred within 1 month previously in 12% of the entire sample with a higher prevalence in the case group (14.4% vs. 3.9%). At multivariate analysis of the seropositivity of IgA antibodies against C. pneumoniae increased the risk of stroke significantly (relative risk 2.121; 95% confidence interval 1.255-3.584) and an early previous infection (up to 7 days before the event) contributed to a rise in probability of acute cerebral ischaemia (relative risk 3.692; 95% confidence interval 1.134-6.875). CONCLUSIONS: Early previous infections and persistent chronic infection of C. pneumoniae could contribute to increase the risk of ischaemic stroke significantly, in the elderly especially.

Understanding the multifaceted role of inflammatory mediators in ischemic stroke.

The evolution of ischemic brain damage is strongly affected by an inflammatory reaction that involves soluble mediators, such as cytokines and chemokines, and specialized cells activated locally or recruited from the periphery. The immune system affects all phases of the ischemic cascade, from the acute intravascular reaction due to blood flow disruption, to the development of brain tissue damage, repair and regeneration. Increased endothelial expression of adhesion molecules and blood-brain barrier breakdown promotes extravasation and brain recruitment of blood-borne cells, including macrophages, neutrophils, dendritic cells and T lymphocytes, as demonstrated both in animal models and in human stroke. Nevertheless, most anti-inflammatory approaches showing promising results in experimental stroke models failed in the clinical setting. The lack of translation may reside in the redundancy of most inflammatory mediators, exerting both detrimental and beneficial functions. Thus, this review is aimed at providing a better understanding of the dualistic role played by each component of the inflammatory/immune response in relation to the spatio-temporal evolution of ischemic stroke injury.

A rare association of early-onset inclusion body myositis, rheumatoid arthritis and autoimmune thyroiditis: a case report and literature review.

Sporadic inclusion body myositis (sIBM) is a slowly progressive, red-rimmed vacuolar myopathy leading to muscular atrophy and progressive weakness; it predominantly affects males older than fifty years, and is resistant to immunotherapy. It has been described in association with immuno-mediated thrombocytopenic purpura, multiple sclerosis, connective tissue disorders and, occasionally, rheumatoid arthritis. A 37-year-old man with longstanding rheumatoid arthritis and autoimmune thyroiditis with hypothyroidism was referred to us with slowly progressive, diffuse muscle weakness and wasting, which had initially involved the volar finger flexors, and subsequently also the ankle dorsiflexors and knee extensors. Needle electromyography showed typical myopathic motor unit potentials, fibrillation and positive sharp waves with normal nerve conduction studies. Quadriceps muscle biopsy was suggestive of sIBM. Considering data published in the literature, this case may be classified as an early-onset form. The patient was treated with long-term intravenous immunoglobulin and obtained a substantial stabilization of his muscle strength.

The role of diet and lifestyle in adolescents with headache: a review.

Several dietary habits and lifestyles can be associated with different headache types or with their progression to chronic forms. Different population-based studies have tried to investigate this relationship with poor or contradictory results. We shortly reported the current knowledges available in literature in this regard, paying particular attention to the role that certain factors play in modifying frequency and intensity of headache in adults and in adolescents. Future studies are necessary to clarify the real weight which the different factors have in natural history and in clinic evolution of headache, especially in adolescence, but the already known data suggest an important modulating action. If they will be confirmed, these results will be likely to influence clinical practice as well to address educational programs in preadolescents and adolescents.

Genetics of cerebral hemorrhage and microbleeds.

Intracerebral haemorrhage (ICH) is the least treatable and often fatal form of stroke. Literature data suggest a strong familial contribution to ICH. The identification of genetic factors with a role in ICH could enhance the understanding of the pathogenesis of hemorrhagic brain injury leading to new treatment and prevention approaches with the final goal of identifying high risk individuals in which genetic pattern may influence clinical and therapeutical decisions. Herein, we provide an updated review on genetic factors associated with occurrence and outcome of ICH. Except for monogenic disease which account for a minor proportion of hemorrhages, most of hemorrhagic stroke heritability is believed to be polygenic. However, the results of candidate gene studies did not show significant results except for the association between apoE genotype and ICH, which has been replicated in large population studies. These data may support the hypothesis that the risk that can be attributed to each of these polymorphisms taken individually is still moderate and some relatively common variants could contribute in determining the disease acting in synergy with other genetic factors.

Improving thrombolysis for acute ischemic stroke in Lombardia stroke centers.

The purpose of this study is to identify which factors are able to limit or hamper the access to systemic thrombolysis (evTPA) in Lombardia to define corrective interventions. We analyzed 1,015 patients with ischemic stroke admitted to emergency departments (ED) participating to the Lombardia Stroke Unit Registry and eligible for evTPA; 303 (29.9%) patients were treated with evTPA (evTPA+ group) and 712 (70.1%) were not (evTPA- group). We collected case-mix and stroke care process variables.The evTPA+ group was characterized by a shorter ED arrival time, a greater neurological impairment, a more chance to be admitted to ED linked to comprehensive stroke center (CSC) and a shorter waiting time to access to diagnostic procedures. The chance to be treated with evTPA was greater if neurological evaluation anticipated neuroimaging (p = 0.0003). The multivariate analysis confirmed that the admission to ED linked to CSC (OR: 2.50, 95% CI: 1.39-4.48, p < 0.0001) and neurological evaluation performed before neuroimaging (OR: 2.34, 95% CI: 1.35-4.04, p = 0.002) increased the probability to receive rtPA. The evTPA treatment is strictly dependent on pre-hospital and ED care process phases and strongly influenced by the degree of stroke severity. Door-to-needle time is shorter in patients with a greater stroke severity and a shorter ED arrival time. A 24-h/week availability of the neurologist in ED can increase the percentage of thrombolysis optimizing the selection of patients and the timing of the diagnostic procedures.

The genetics of small-vessel disease.

Cerebral small-vessel disease (SVD) is a well-known cause of stroke, dementia and death, but its pathogenesis is not yet completely understood. The spectrum of neuroradiological manifestations associated with SVD is wide and may result from chronic and diffuse or acute and focal ischemia (leukoaraiosis and lacunar infarction) as well as from small-vessel rupture (cerebral microbleeds and intracerebral hemorrhage). Several lines of evidence from family and twin studies support the hypothesis that genetic factors may contribute to SVD pathogenesis. Identification of genetic susceptibility factors for SVD may improve our knowledge of SVD pathogenesis and help to identify new therapeutic targets to reduce the burden of SVD-related cognitive decline and stroke disability. A number of monogenic conditions presenting with clinical features of SVD have been described. Although monogenic disorders account for only a small proportion of SVD, study of these diseases may provide further insight into the pathogenesis of SVD. In most cases, however, SVD is thought to be a multifactorial disorder. Several genetic association studies, conducted using the candidate gene and, more recently, the genome-wide approach, have so far failed to demonstrate a convincing association between SVD and genetic variants. Methodological issues, particularly related to inaccurate or heterogeneous phenotyping and insufficient sample sizes, have been invoked as possible reasons for this. Large collaborative efforts and robust replication, as well as implementation of new genetic approaches, are necessary to identify genetic susceptibility factors for complex SVD.

Neurological features of Fabry disease: clinical, pathophysiological aspects and therapy.

Fabry disease is a multisystem, X-linked, lysosomal storage disorder caused by a mutation in the GLA gene on chromosome Xq22 resulting in alpha-galactosidase A enzyme (α-Gal A) deficiency. Neurological manifestations other than cerebrovascular accidents include small fibre neuropathy and dysautonomic disorders, which may be the presenting clinical features in a proportion of patients. An atypical disease onset may be misdiagnosed until the emergence of a more typical clinical picture, characterized by chronic renal and cardiac failure. Thus, neurologists should consider Fabry disease in differential diagnosis and provide an appropriate diagnostic work up. This review focuses on central and peripheral nervous system involving available diagnostic tools and diagnostic work up in Fabry disease. It also covers the most recent evidence regarding enzyme replacement therapy.

Migraine and depression: common pathogenetic and therapeutic ground?

Migraine and depression are recognized as comorbid disorders on the basis of several epidemiological data and on the possibility of shared mechanisms. On the other hand, there is a lack of studies concerning therapeutic strategies in patients with this comorbidity. The aim of this paper is to briefly review the literature about the migraine and depression comorbidity and on the putative common neurobiological mechanisms, as well to discuss the possible therapeutic options in treating patients with both disorders.

Inconsistent detection of changes in cerebral blood volume by near infrared spectroscopy in standard clinical tests.

The attractive possibility of near infrared spectroscopy (NIRS) to noninvasively assess cerebral blood volume and oxygenation is challenged by the possible interference from extracranial tissues. However, to what extent this may affect cerebral NIRS monitoring during standard clinical tests is ignored. To address this issue, 29 healthy subjects underwent a randomized sequence of three maneuvers that differently affect intra- and extracranial circulation: Valsalva maneuver (VM), hyperventilation (HV), and head-up tilt (HUT). Putative intracranial ("i") and extracranial ("e") NIRS signals were collected from the forehead and from the cheek, respectively, and acquired together with cutaneous plethysmography at the forehead (PPG), cerebral blood velocity from the middle cerebral artery, and arterial blood pressure. Extracranial contribution to cerebral NIRS monitoring was investigated by comparing Beer-Lambert (BL) and spatially resolved spectroscopy (SRS) blood volume indicators [the total hemoglobin concentration (tHb) and the total hemoglobin index, (THI)] and by correlating their changes with changes in extracranial circulation. While THIe and tHbe generally provided concordant indications, tHbi and THIi exhibited opposite-sign changes in a high percentage of cases (VM: 46%; HV: 31%; HUT: 40%). Moreover, tHbi was correlated with THIi only during HV (P < 0.05), not during VM and HUT, while it correlated with PPG in all three maneuvers (P < 0.01). These results evidence that extracranial circulation may markedly affect BL parameters in a high percentage of cases, even during standard clinical tests. Surface plethysmography at the forehead is suggested as complementary monitoring helpful in the interpretation of cerebral NIRS parameters.

Stroke Unit care in Italy. Results from PROSIT (Project on Stroke Services in Italy). A nationwide study.

The future challenge for improving stroke patients' outcome will be to implement new Stroke Units (SUs) worldwide. However the best SU model remains uncertain. The aim of this study was to evaluate the number of SUs and the quality characteristics of acute stroke care in Italy. We conducted a SU survey in Italy, interviewing the directors of the hospital wards that discharged at least 50 acute stroke patients a year. A SU was defined as an acute ward area with stroke-dedicated beds and staff. To compare the quality of care provided in SUs with that in general wards (GWs) we investigated the characteristics of five domains: hospital setting, unit setting, staffing, process of care and diagnostic investigations. We identified 68 SUs and 677 GWs. Multivariate logistic regression analyses demonstrated that SUs compared to GWs had higher quality scores in unit setting (ROC area=0.9721), staffing (ROC area=0.8760) and care organisation (ROC area=0.7984). The hospital setting (ROC area=0.7033) and the availability of rapid diagnostic investigations (ROC area=0.7164) had lower power in discriminating SU from GW. In Italy in 2003/04 only 9% of the hospital services had organised SU care. The study demonstrated that SUs admitted more than 100 patients per year, had more monitoring equipment and staffing time, and practised multidisciplinary meetings and early mobilisation. The utility of these structural and performance characteristics needs validation from outcome studies.

The Stroke in Italy and Related Impact on Outcome (SIRIO) study: design and baseline data.

The SIRIO study collected detailed information on the stroke care of patients treated in neurological departments in Italy. This report refers to the baseline profile of patients. Each centre recorded the incident cases of ischaemic and haemorrhagic stroke, excluding SAH, for 1-4 months. Baseline data include demographics, risk factors, comorbidities, pre-event medications, social conditions, NIHSS and Rankin scale on entry, Barthel Index pre-event, diagnostic tests and treatments applied on entry. Overall, 3018 patients (56.7% men; mean age 72.1+/-12.2 years) with ischaemic (85.3%) or haemorrhagic stroke were hospitalised in 103 centres; 51% arrived by ambulance. Median time to hospital was 140 min (RIQ: 60-615). TOAST classification of the 2573 ischaemic strokes was: 29.4% large-artery atherosclerosis, 24.6% cardioembolic, 26.2% small vessels occlusion, 6.5% other determined causes and 13.3% undetermined. CT and/or MR were performed in all patients. Total Greenfield's comorbidity score was 5.4+/-3.5. Mean Barthel Index pre-event was 93+/-17; Rankin score on entry was 4-5 in 48% of the patients and 0-1 in 25%. Mean NIHSS on entry was 7.1+/-5.4; 52% of the patients had a NHISS <6 and 1% >22. SIRIO began giving the expected insights on the in-hospital management of stroke in Italy. Further information will be provided by the longitudinal phase of the study, which is in progress. Pre-event patient management and mode of reporting call for additional educational actions.

Lombardia Stroke Unit Network Project.

Stroke unit care represents the major advancement in stroke management and it is applicable to all stroke patients. The Lombardia Health-Care Program for the period 2000-2004 planned to implement new semi-intensive stroke units in order to guarantee access to such units to all stroke patients. As has happened in other countries, there is a need to coordinate and streamline the process of care in order to optimise resources and outcome. The aim of the Stroke Unit Network (SUN) project is the improvement of the quality of stroke care in the acute and post-acute phase, developing an efficient network between hospitals involved in stroke care in order to quickly identify patients' needs and to improve cultural exchange on clinical and therapeutic information between people involved in the process of care. A web-based network has been created connecting the Lombardia Stroke Units and the departments in which stroke units will be implemented; a website to facilitate the exchange of scientific data, the discussion of clinical problems, the sharing of research projects and results, and a web-based quality register in order to verify quality, efficacy and efficiency of stroke units participating in the project providing important, consistently available data to monitor progress in reducing the incidence of stroke and associated disability and mortality. The Lombardia Stroke Unit Network Project, promoting and facilitating the exchange of know-how and collecting data on the quality of the processes of care provided, can significantly improve stroke care in Lombardia.

Stroke Active Guideline Evaluation (STAGE) project.

In 2005 the American Stroke Association's task force on the development of stroke systems established that providers and policymakers at the local, state and national levels can make significant contributions to reducing the devastating effects of stroke by working to promote coordinated systems that improve patient care. In the last few years in North America and Canada several quality stroke registers have been implemented with the aim of improving the processes of care by the diffusion and implementation of national guidelines and by the identification and correction of critical points of stroke care provided in the hospitals participating in the register. The Italian guidelines for stroke, SPREAD, have been developed with the aim of generating a tool applicable to the Italian clinical setting, able to promote the planning and linking of the assistant interventions between the different phases of the stroke care process, from the hyper-acute to the rehabilitation phase, and from primary to secondary prevention in order to harmonise and streamline the actions of the various health-care providers involved in the different phases of the diagnostic and therapeutic path of patients with stroke. The primary end-point of the Stroke Active Guideline Evaluation (STAGE) project, founded by the Italian Ministry of Health in 2003, is the diffusion, implementation and validation of the Italian Guideline for Stroke, SPREAD, in 15 acute care and 3 rehabilitative institutions across Italy. Secondary end-points are the evaluation of impact of the implementation of a workflow management in the processes of care and the identification of a national, streamlined diagnostic and therapeutic path for ischaemic stroke patients. An existing electronic patient record (EPR) has been shared with the referents of the Centres participating in the study and adapted to SPREAD's indicators. This EPR has been augmented with the decision support system. The STAGE project represents the first Italian effort in this direction. A lot of work has to be done before this goal will be achieved, but as Albert Einstein said "Imagination is more important than intelligence".

The objectives of the Banca Dati Italiana Ictus Acuto (BADIA) Project.

The rationale for the realisation of a stroke databank (BADIA: Banca Dati Italiana Ictus Acuto) is discussed on the basis of the recent development in Italy of interesting models (mostly web-based) for the validation of SPREAD guidelines, the definition of outcome indicators, the identification of therapeutic response to rt-PA and the evaluation of the real approach to acute stroke care in Italy in large groups of Italian hospitals distributed in almost all the national regions. The BADIA Project is considered on the basis of possible advantages and objectives but also difficulties in the realisation of the informatics platform adequate to a harmonic and homogeneous approach to stroke care in the different settings presented by Italian hospitals.

Vascular dementia.

Epidemiological, clinical, neuropsychological and neuroimaging features characterise vascular dementia (VaD) from other dementias of non-Alzheimer type. VaD does not represent a single entity, but quite a large group of conditions characterised by different pathophysiological correlates and various clinical findings. Subcortical VaD, in particular, is considered as a model of VaD because its well-defined diagnostic criteria allow identification of a homogeneous category for a better approach to investigation in diagnosis and treatment of vascular dementia.

Stroke units and general wards in seven Italian regions: the PROSIT study.

PROSIT (research PROject on Stroke services in ITaly) is a study performed to evaluate number and work organisation of acute in-hospital services (stroke units, SU) and general wards (GW), in seven Italian regions (Liguria, Lombardia, Lazio, Veneto, Friuli-Venezia-Giulia, Emilia Romagna, Toscana), which have a population of 29,169,811 inhabitants and a relative ratio of 225/100,000 hospitalisations for acute stroke. The registers of hospital discharges from January to December 1999 were looked at identify to services recording at least 50 acute stroke discharges (DRG14) per year. A structured questionnaire investigating stroke service characteristics was submitted to the doctors in charge of the identified units and completed in the presence of an external observer between October 2000 and February 2001. SUs were identified as units with dedicated beds (at least 80%) and team (at least 1 physician and 1 nurse) for acute stroke patients. SUs are still uncommon in many Italian regions because only, as 7% of the wards evaluated were found to be a SU and less than 10% of acute stroke patients resulted to be admitted to a SU. Great heterogeneity was found between the different regions surveyed. The most striking differences between SUs and GW were related to the staffing and care organisation, with higher number/patients ratio in SUs as far as physicians and nurses, speech therapists and social workers were concerned.