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.

Declining incidence of intracerebral hemorrhage over two decades in a population-based study.

BACKGROUND AND PURPOSE: The incidence and case-fatality rate (CFR) of primary intracerebral hemorrhage (PICH) over two decades were assessed in a prospective population-based study. METHODS: Cases of incident first-ever PICH were recorded over a 2-year period (2011-2012) from multiple sources in the district of L'Aquila, central Italy. Included patients were followed up to 1 year after the event to ascertain CFRs. Current data were compared with those previously collected from 1994 through 1998. RESULTS: In all, 115 patients (52 men; 45.2%) with a first-ever PICH were included. Mean age ± SD was 77.4 ± 11.8 years. The hemorrhage was lobar in 43 (37.4%) patients, deep in 56 (48.7%), in the posterior fossa in 11 (9.6%) and intraventricular or multiple localized in five (4.3%). Crude annual incidence rate was 19.3 per 100 000 and 14.8 per 100 000 when standardized to the 2011 European population, indicating a 48% reduction comparing data of 2011-2012 to those of 1994-1998 (incidence rate ratio 0.52; 95% confidence interval 0.43-0.64; P < 0.001). In 2011-2012, the 7-day CFR was 27.8%, the 30-day CFR was 42.6% and the 1-year CFR was 52.2%; the 1-year standardized mortality ratio was 0.81 (95% confidence interval 0.63-1.04) compared with 1994-1998. CONCLUSIONS: The annual incidence rate of PICH was lower than that found two decades before and close to the rates recently found in other western countries. Data also indicated a non-significant trend towards a decrease in mortality, which nonetheless remained high, pointing to the need for more appropriate treatments in order to reduce PICH severity and mortality.

Occurrence and long-term outcome of tumefactive demyelinating lesions in multiple sclerosis.

Although tumefactive multiple sclerosis is a well recognized variant of multiple sclerosis, prognostic uncertainty still exists about long term prognosis. The aim of this study was to estimate the occurrence and long term outcome of tumefactive demyelinating lesions (TDLs) in a cohort of multiple sclerosis patients. We reviewed brain MRI of 443 patients referred to our MS clinic. All patients meeting the McDonald criteria for multiple sclerosis and showing at least one TDL were included. Kaplan-Meier estimates of disease-free survival in patient cohort were compared with control group without TDLs using a log-rank test. Seven cases with TDLs were identified (occurrence 1.58 %). Tumefactive demyelinating lesion recurrence was 16.6 %. Cumulative proportion of patients free from clinical relapse and from new T2 lesions was lower in the control group although not reaching statistical significance (30 vs 50 %; P = 0.666 and 21.7 vs 33.3 %; P = 0.761, respectively). Disability progression analysis showed a not significant trend towards lower probability of remaining progression free for TDL patients (50 vs 61 %; P = 0.295). Occurrence of tumefactive demyelinating lesions in our cohort was higher than those reported in other studies. Overall, TDLs were not predictive of poor outcome in terms of disability progression.

Migraine and risk of ischaemic heart disease: a systematic review and meta-analysis of observational studies.

BACKGROUND AND PURPOSE: Several studies have assessed the risk of ischaemic heart diseases in migraineurs, drawing different conclusions. To define and update the issue, a systematic review and meta-analysis of the available observational studies was performed. METHODS: PubMed and EMBASE were systematically searched up to April 2014 for observational studies dealing with the risk of any form of ischaemic heart disease in migraineurs. Studies assessing migraine as exposure and several types of ischaemic heart disease as outcomes were included in the analysis. A random effects model was used to pool the effect sizes. RESULTS: Out of 3348 records, 15 studies (one case-control, one cross-sectional and 13 cohort studies) were identified and were included in the meta-analysis. The pooled analysis indicated an increased risk of myocardial infarction (pooled adjusted effect estimate 1.33, 95% confidence interval 1.08-1.64; P = 0.007) and of angina (pooled adjusted effect estimate 1.29, 95% confidence interval 1.17-1.43; P < 0.0001) in migraineurs compared to non-migraineurs. CONCLUSIONS: Based on our data indicating an association of migraine with myocardial infarction and angina and on previous data showing an association of migraine, and particularly migraine with aura, with an increased risk for stroke, migraine can be appropriately considered an overall risk factor for cardiovascular diseases.

Insulin resistance in migraineurs: results from a case-control study.

OBJECTIVES: Several studies have suggested an association between migraine and insulin resistance (IR) without adequately addressing the issue according to migraine type. We assessed IR in subjects with migraine with aura (MwA) and migraine without aura (MwoA) to estimate the consistency of the possible association. METHODS: In a case-control study we included case subjects with MwA and MwoA, who were consecutively selected from those referred to our Regional Headache Center from September 2011 to February 2013, and age-matched control subjects selected using general practitioners' databases. IR was calculated by means of the homeostatic model assessment of IR (HOMA-IR), ß-cell function (HOMA-B), and the quantitative insulin sensitivity check index (QUICKI) measuring glucose and insulin values in a blood sample collected in the morning after overnight fasting. Data regarding anthropometric measures, comorbidity risk factors, and migraine characteristics were also recorded. RESULTS: We recruited 50 case subjects with MwA (38 women) and 50 with MwoA (40 women) and 50 control subjects (40 women). Proportions of arterial hypertension, cigarette smoking, hypercholesterolemia, use of oral contraceptives, and mean values of the body mass index (BMI) were similar in the three groups. We found significantly different glucose values among and within groups considering case subjects with MwA and MwoA and control subjects (4.9 ± 0.6 vs 4.7 ± 0.5 vs 4.6 ± 0.5 mmol/l; P = 0.018) in the absence of any difference in insulin (53.1 ± 24.0 vs 56.7 ± 34.4 vs 53.8 ± 24.4 pmol/l; P = 0.811), HOMA-IR (1.6 ± 0.8 vs 1.7 ± 1.0 vs 1.6 ± 0.7; P = 0.765), HOMA-B (121.4 ± 71.1 vs 149.2 ± 93.8 vs 162.8 ± 109.7; P = 0.107), and QUICKI (0.36 ± 0.03 vs 0.37 ± 0.03 vs 0.37 ± 0.03; P = 0.877) values. The logistic regression model showed increased odds of MwA in subjects exposed to the highest tertile of glucose values. This association was confirmed in the adjusted model, in which case subjects with MwA were compared with those with MwoA but not with control subjects. CONCLUSIONS: In contrast to what has been shown by the majority of the available studies, the results of our study do not support the association of migraine with IR. As our study was not population-based and several patients had low disease activity, these findings need further confirmation.

Natalizumab treatment in multiple sclerosis patients: a multicenter experience in clinical practice in Italy.

We evaluated efficacy of natalizumab in relapsing-remitting multiple sclerosis patients in a clinical practice setting. We report data on the first consecutive 343 patients receiving natalizumab in 12 multiple sclerosis (MS) Italian centers enrolled between April 2007 and November 2010. The main efficacy endpoints were the proportion of patients free from relapses, disease progression, combined clinical activity, defined as presence of relapse or disease progression, from MRI activity, and from any disease activity defined as the absence of any single or combined activity. At the end of follow-up, the cumulative proportion of patients free from relapses was 68%; the proportion of patients free from Expanded Disability Status Scale (EDSS) progression was 93%; the proportion of patients free from combined clinical activity was 65%; the proportion of patients free from MRI activity was 77%; and the proportion of patients free from any disease activity was 53%. Natalizumab was effective in reducing clinical and neuroradiological disease activity. Its effectiveness in clinical practice is higher than that reported in pivotal trials and was maintained over time.

Ascertainment bias in dementias: a secondary to tertiary centre analysis in Central Italy and conceptual review.

BACKGROUND AND AIMS: Ascertainment bias (AB) indicates a bias of an evaluation centre in estimating the prevalence/incidence of a disease due to the specific expertise of the centre. The aim of our study was to evaluate classification of different types of dementia in new cases appearing in secondary and tertiary centres, in order to evidence possible occurrence of AB in the various (secondary to tertiary) dementia centres. METHODS: To assess the mechanism of AB, the rates of new cases of the different forms of dementia reported by different centres were compared. The centres involved in the study were 11 hospital-based centres including a tertiary centre, located in the University Department of Clinical Neurology. The tertiary centre is endowed with state-of-the-art diagnostic facilities and its scientific production is prominently focused on dementia with Lewy bodies (DLB) thus suggesting the possible occurrence of a bias. Four main categories of dementia were identified: Alzheimer's disease (AD), DLB, fronto-temporal dementia (FTD), vascular dementia (VaD), with other forms in a category apart. The classification rate of new cases of dementia in the tertiary centre was compared with rates reported by secondary centres and rates of recoding were calculated during a follow-up of 2 years. RESULTS: The study classified 2,042 newly diagnosed cases of dementia in a population of 1,370,000 inhabitants of which 315,000 were older than 65. AD was categorized in 48-52 % of cases, DLB in 25-28 %, FTD in 2-4 % and VaD in 17-28 %. During the 2-year follow-up the diagnosis was re-classified in 40 patients (3 %). The rate of recoding was 5 % in the tertiary centre, 2-8 % in referrals from secondary to tertiary centre, 2-10 % in recodings performed in secondary centres and addressed to tertiary centre. Recoding or percentages of new cases of AD or DLB were not different in the comparison between secondary or between secondary and tertiary centres. FTD and VaD were instead significantly recoded. CONCLUSION: The results of the study suggest that in a homogeneous area, AB is not interfering with diagnosis of AD or DLB.

Soluble CD30: a biomarker for evaluating the clinical risk versus benefit of IFNbeta1A treatment in multiple sclerosis patients.

Aberrant redox regulation occurs in immune and neurological pathologies, hence targeting the pathways involved in the regulation of the redox system could provide further insights into these diseases and open up new avenues for therapy. Soluble (s) CD30 is of key clinical importance in this respect, as its levels reflect the functionality of the CD30 receptor (CD30R), the specific lymphocyte receptor for thiol disulfide/oxidoreductase thioredoxin 1 (Trx1) which is known to regulate important immune and neurological processes. Increased levels of sCD30 appear to be a common element of oxidative stress, immunological alterations and neurological deficit, therefore these increases could be used as a clinical biomarker and target for therapy. We targeted sCD30 in our study of dendritic cell (DC) regulation of the T helper (Th) cell network in multiple sclerosis (MS) patients, as abnormalities in T regulatory (Treg)/Th1/Th17 pathways contribute to the pathogenesis of this immunological/neurological disease. DC profiles in Treg/Th1/Th2/Th17-types of cytokine production in culture supernatants were used as they determine the type of Th differentiation. Our results show that sCD30 levels increase significantly in MS patients, reflecting the disruption in the regulation of the Treg/Th1/Th17 cell network. A fall in the level of soluble CD30, induced by IFNbeta1a therapy, opposed the increase of neurological deficit through increasing IL10 and TGFbeta levels, thus re-establishing network homeostasis but only when this was accompanied by an increase in IL12p70 levels. Since IL12p70 cytokine production is regulated by Trx1, our results indicate that redox system alterations may be the cause of IFNbeta1a therapeutic inefficacy. We conclude that an increase in the level of IL10, TGFbeta and IL12p70 and a fall in the level of sCD30 represent a means of evaluating the clinical risk/benefit of IFNbeta1a treatment.

Gender and stroke: acute phase treatment and prevention.

Stroke is the third most common cause of death in women and a major cause of disability. Many aspects of stroke are similar in men and women, including clinical presentation, main risk factors, and distribution of the main subtypes. There are, however, some gender differences and specificities in stroke including some aspects related to treatment. Women are less likely to receive thrombolysis than men; however, in treated cases, the efficacy of intravenous thrombolysis is higher in women than in men. Hormone replacement therapy has been suggested as a possible strategy to reduce the occurrence of stroke in postmenopausal women but several clinical trials failed to show any benefit in stroke and cardiovascular disease prevention. Also in stroke prevention with antiplatelets there emerge some important gender differences: in primary prevention of stroke, aspirin was effective in women but not in men while in secondary prevention no gender differences were found with any of the available antiplatelet agents.

Effects of interferon beta, cyclophosphamide and azathioprine on cytokine profile in patients with multiple sclerosis.

We assessed the in vitro effects of interferon beta-1b (IFNbeta-1b), cyclophosphamide (CY), and azathioprine (AZA) alone and of the combination of IFNbeta-1b with CY or AZA on the production of Th1 and Th2 cytokines in 10 patients with multiple sclerosis. Cytokine levels were determined at baseline and after stimulation with IFNbeta-1b, CY, and AZA alone or with the combination of IFNbeta-1b with CY or AZA. The combination of IFNbeta-1b with CY resulted in a statistically significant decrease in the production of interleukin-2 (IL-2) (P=0.003) and tumor necrosis factor alpha (TNF-alpha) (P=0.03). An additive effect on the production of interferon gamma (IFN-gamma) (P=0.2) and interleukin-10 (IL-10) (P=0.6), and a positive interaction on the production of interleukin-4 (IL-4) (P=0.08) were observed although the findings were not statistically significant. The combination of IFNbeta-1b with AZA resulted in a significant negative effect on the production of IL-2 (P=0.006), whereas TNF-alpha (P=0.02), IFN-gamma (P=0.03), IL-4 (P=0.2), and IL-10 (P=0.3) were not statistically impacted. Our data show that CY was able to improve the effects of IFNbeta-1b on the ratio of Th1/Th2 cytokines.

An evaluation of a colour food photography atlas as a tool for quantifying food portion size in epidemiological dietary surveys.

OBJECTIVE: To test the validity of a colour food photography atlas for quantifying portion size eaten compared with weighed foods. DESIGN: The colour food photography atlas was prepared by cooking, weighing and taking digital photographs of three portion sizes of 434 foods and beverages typical of the Italian diet. SUBJECTS AND INTERVENTIONS: In all, 448 male and female volunteers aged 6-60 y from a wide variety of social backgrounds completed 9075 assessments of food portions eaten at lunch and dinner in relation to a set of colour food photographs during 8 weeks of investigation. The amounts of foods eaten by individuals in five different cafeterias in Pavia, Northern Italy, were weighed by trained investigators at the time of serving and, within 5-10 min of the end of the meal, each subject was asked to quantify all foods consumed with reference to one of the three food photographs or in terms of virtual portions among those shown in the photographs. RESULTS: Multiple regression analysis shows that weights of portion sizes chosen from the set of photographs are significantly associated (P<0.05) to weights of eaten portions (beta=0.81; R(2)=0.70) and are independent of age, gender and BMI. The differences between mean weights of the portions chosen by individuals from photographs and mean weights of eaten foods are significant for all food categories (P<0.05), except for bread. However, because of the very large number of observations, the mean differences are very small (range: from +23.2 g (+11.2%) for first courses to -1.3 g (-2.7%) for bread). Bland-Altman plots show that first courses limits of agreement are wide because the dispersion is increasing while weights are rising. CONCLUSIONS: The use of a series of three photographs and virtual portion sizes being associated with relatively small errors, our findings support the validity of using this colour food photography atlas as a tool for quantifying food portion size in epidemiological dietary surveys on different age groups of Italian subjects.

Stroke in young adults in the community-based L'Aquila registry: incidence and prognosis.

BACKGROUND AND PURPOSE: Stroke type in the young may influence the outcome and may have a dramatic impact on the quality of life in survivors. This study aimed to evaluate the incidence and prognosis of first-ever stroke in the young and to make comparisons with older patients within a well-defined population. METHODS: All first-ever strokes occurring in the L'Aquila district, central Italy, were traced by active monitoring of inpatient and outpatient health services. Incidence rates were standardized to the 1996 European population according to the direct method. Long-term survival was estimated by the Kaplan-Meier method; outcome in survivors was evaluated by the modified Rankin scale. RESULTS: Of 4353 patients who had a first-ever stroke, 89 patients <45 years of age (55 men and 34 women) (2%) were identified in a 5-year period. Mean age+/-SD was 36.1+/-8.1 years. Twenty patients (22.5%) had a subarachnoid hemorrhage, 18 (20.2%) an intracerebral hemorrhage, and 51 (57.3%) a cerebral infarction. The corresponding proportions in patients >45 years of age were 2.4%, 13.3%, and 83.1%. Neuroimaging studies of the brain detected 14 intracranial aneurysms and 6 arteriovenous malformations in 20 of 38 patients (52.6%) with either subarachnoid (n=17) or intracerebral (n=3) hemorrhage. The crude annual incidence rate was 10.18/100,000 (95% CI, 8.14 to 12.57) and 10.23/100,000 when standardized to the 1996 European population. The 30-day case-fatality rate was 11.2% (95% CI, 6.2 to 19.4). Patients with subarachnoid hemorrhage had the highest proportion of good recovery (60%), patients with intracerebral hemorrhage had the highest mortality (44%), and patients with cerebral infarction had the highest proportion of severe disability (47%). CONCLUSIONS: Stroke patients <45 years of age showed a disproportionate cumulative high prevalence (42.7%) of subarachnoid and intracerebral hemorrhage with respect to older patients (15.7%), mainly (52.6%) due to aneurysms and arteriovenous malformations. Therefore, screening procedures and preventive strategies in the young should also be addressed to subjects at risk of subarachnoid and intracerebral hemorrhage.

Transcranial Doppler in acute hemispheric brain infarction.

We studied cerebrovascular anatomy using intra-arterial digital angiography, and blood flow velocity in the middle cerebral artery (MCA) using transcranial Doppler (TCD) ultrasonography in 42 patients with acute hemispheric ischemic brain infarction. We compared angiography with TCD and the clinical findings within 6 hours of the onset of symptoms. The location and extent of the chronic ischemic brain damage was assessed by CT performed 1 to 3 months after the ictus. Abnormal TCD, as manifested by either an unobtainable MCA flow signal or a significantly depressed MCA flow velocity, was highly associated with proximal MCA occlusions demonstrated by angiography. Abnormal TCD predicted both larger chronic CT lesions and more extensive ischemic change within the MCA territory. These data demonstrate that early TCD conveys useful information concerning cerebral tissue prognosis following hemispheric ischemia.

Systemic hypertension as a treatable risk factor for cerebrovascular disease.

It has long been established that hypertension is the major risk factor for stroke. Three Italian studies have been reviewed in order to examine different aspects of the problem. In the first study, the role played by the systolic, diastolic and systodiastolic components of hypertension in causing atherosclerotic damage of extracerebral and intracerebral arteries was examined. At the extracranial level, a significant correlation between systolic hypertension and atherosclerotic lesions was evident. The second study evaluated the risk of major stroke, myocardial infarction and death in patients with transient ischemic attacks and reversible ischemic neurologic deficits. Possible prognostic predictors of these events were thoroughly considered: Cumulative survival with the multivariate Kaplan-Meier analysis was significantly lower in hypertensive than in normotensive subjects, particularly for cerebral deaths and for all deaths. The third study was aimed at assessing the risk factors for transient ischemic attacks and stroke in young adults. Again, hypertension emerged as a fundamental risk factor, significantly more frequent in the subgroup of older patients than in the younger subgroup.

[Controlled double-blind study (SAMe-imipramine) in depressive syndromes]. / Studio controllato in doppio cieco (SAMe-Imipramina) nelle sindromi depressive

Thirty one patients were treated with either S-Adenosylmethionine or Imipramine in a double-blind clinical trial comparing S-Adenosylmethionine (25 mg i.m. three times daily) with Imipramine (25 mg i.m. three times daily) administered for a period of three weeks. Hamilton Rating scores showed no significant differences between treatments, but such slight differences as were observed favoured S-Adenosylmethionine.

[Effect of S-adenosyl-methionine (SAMe) on some endocrine parameters in normal adult subjects]. / Effetto della S-adenosil-metionina (SAMe) su alcuni parametri endocrini, in soggetti adulti normali

No changes in serum prolactin, TSH and LH were noted when the antidepressant s-adenosylmethionine was given i.v. to 7 normal adults of both sexes. It would thus appear that the drug's antidepressant effect is not mediated by TSH. The results obtained are not comparable with those observed by other workers in the rat.

[Neuroendocrine aspects of Parkinson's disease. Therapeutic/effect of a prolactin inhibitor]. / Aspetti neuroendocrinologici del morbo di Parkinson. Interesse all'effetto terapeutico di un inibitore della prolattina

On the basis of a reassessment of the aetiopathogenetic problem and the neuroendocrine implications, the therapeutic effectiveness of a prolactin inhibitor, 2-alpha-Br-ergocryptine (CB 154), in Parkinson's disease is assessed. Five patients were treated for a total of two weeks using doses between 10 and 15 mg/die. CB 154 was found to act as a dopaminergic receptor agonist at nigro-striatal level, considerably improving tremor and rigidity and to a lesser extent bradykinesia and total disability.

Contrast-enhanced transcranial Doppler sonography in patients with acute cerebrovascular diseases.

The aim of the study was to evaluate the diagnostic potential of galactose-based microbubble suspension (Levovist) in patients with acute cerebrovascular disease and inadequate transtemporal acoustic window, when examined by transcranial Doppler (TCD). We studied 10 patients with either transient ischemic attack (no. = 3) or stroke (no. = 7). Inadequate transtemporal acoustic window was unilateral in 3 patients and bilateral in the remaining 7 patients. Signals from middle, anterior, and posterior cerebral arteries (MCA, ACA, PCA) were recorded after injecting Levovist 300 mg/ml. Six patients needed 3 injections of Levovist, 1 patient two, and 3 patients one. Mean +/- SD duration of optimal signal enhancement was 175.2 +/- 53.2 s, range 70-290 s. Doppler waveform analysis was possible in 14 (82.3%) MCA, 11 (65%) ACA, and 9 (53%) PCA. Levovist improved the reliability of TCD in patients with acute cerebrovascular disease and insufficient transtemporal insonation.