Growth factors in ischemic stroke.

Data from pre-clinical and clinical studies provide evidence that colony-stimulating factors (CSFs) and other growth factors (GFs) can improve stroke outcome by reducing stroke damage through their anti-apoptotic and anti-inflammatory effects, and by promoting angiogenesis and neurogenesis. This review provides a critical and up-to-date literature review on CSF use in stroke. We searched for experimental and clinical studies on haemopoietic GFs such as granulocyte CSF, erythropoietin, granulocyte-macrophage colony-stimulating factor, stem cell factor (SCF), vascular endothelial GF, stromal cell-derived factor-1α and SCF in ischemic stroke. We also considered studies on insulin-like growth factor-1 and neurotrophins. Despite promising results from animal models, the lack of data in human beings hampers efficacy assessments of GFs on stroke outcome. We provide a comprehensive and critical view of the present knowledge about GFs and stroke, and an overview of ongoing and future prospects.

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.

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.

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.

Antidepressant drugs for narcolepsy.

BACKGROUND: Narcolepsy is a disorder of the central nervous system, the main symptoms of which are excessive daytime sleepiness (EDS) and cataplexy (an abrupt and reversible decrease in or loss of muscle tone, affecting the limbs or trunk or both, elicited by emotional stimuli). Narcolepsy has an adverse impact on people's quality of life. Together with stimulant drugs (used to control EDS), antidepressants are usually recommended to counteract cataplexy. In addition, some antidepressants are also reported to improve EDS. OBJECTIVES: To evaluate the effects of antidepressant drugs on EDS, cataplexy, quality of life, and their side effects in people with narcolepsy. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 2, 2007), MEDLINE (1966 to 2007), EMBASE (1980 to 2007), PsycINFO (1872 to 2007), and CINAHL (1981 to 2007). Bibliographies of identified articles were reviewed to find additional references. Unpublished randomised trials were searched for by consulting governmental and non-governmental clinical trial registers, disease-specific websites, investigators and experts in the field, pharmaceutical companies/manufacturers. SELECTION CRITERIA: Parallel or cross-over randomised or quasi-randomised controlled trials testing the treatment of narcolepsy with any type of antidepressant drug versus no treatment, placebo, or another antidepressant drug. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. MAIN RESULTS: Three cross-over and two parallel trials were included with a total of 246 participants. The methodological quality of all studies was unclear. As the trials tested different comparisons, or had a different design or dealt with different outcome measures, meta-analysis was not performed. In one cross-over trial (10 participants) femoxetine had no significant effect in eliminating or reducing EDS but significantly reduced cataplexy. Mild and transient side effects were reported in the femoxetine treatment period by two participants. In a second cross-over trial (56 participants) viloxazine significantly reduced EDS and cataplexy. In a third cross-over trial the authors inappropriately treated the trial design as a parallel study and no conclusions can be reached in favour of either drug. Two more trials with parallel design tested ritanserin versus placebo without finding differences of effectiveness in reducing EDS or cataplexy. AUTHORS' CONCLUSIONS: There was no good quality evidence that antidepressants are effective for narcolepsy or improve quality of life. Despite the clinical consensus recommending antidepressants for cataplexy there is scarce evidence that antidepressants have a positive effect on this symptom. There is a clear need for well-designed randomised controlled trials to assess the effect of antidepressants on narcolepsy.

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.

Antidepressant drugs for narcolepsy.

BACKGROUND: Narcolepsy is a disorder of the central nervous system, the main symptoms of which are excessive daytime sleepiness (EDS) and cataplexy (an abrupt and reversible decrease in or loss of muscle tone, affecting the limbs and/or trunk, elicited by emotional stimuli). Narcolepsy has an adverse impact on people's quality of life. Together with stimulant drugs (used to control EDS), antidepressants are usually recommended to counteract cataplexy. In addition, some antidepressants are also reported to improve EDS. OBJECTIVES: To evaluate the effects of antidepressant drugs on EDS, cataplexy, quality of life, and their side effects in people with narcolepsy. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3, 2003), MEDLINE (1966 to 2003), EMBASE (1980 to 2003), PsycINFO (1872 to 2003), and CINAHL (1981 to 2003). Bibliographies of identified articles were reviewed to find additional references. Unpublished randomised trials were searched for by consulting governmental and non-governmental clinical trial registers, disease-specific websites, investigators and experts in the field, pharmaceutical companies/manufacturers. SELECTION CRITERIA: Parallel or cross-over randomised or quasi-randomised controlled trials testing the treatment of narcolepsy with any type of antidepressant drug versus no treatment, placebo, or another antidepressant drug. DATA COLLECTION AND ANALYSIS: Two reviewers independently selected trials for inclusion and extracted data. Outcomes were: (a) elimination of EDS; (b) mean reduction of EDS; (c) elimination of cataplexy; (d) 50% or greater reduction in cataplexy frequency; (e) mean reduction of cataplexy; (f) mean improvement in quality of life; (g) adverse events; (h) withdrawal from treatment. MAIN RESULTS: Two cross-over trials were included. The methodological quality of both studies was unclear and so the influence of common biases was impossible to define. As the trials tested two different comparisons (one femoxetine versus placebo, the other fluvoxamine versus clomipramine) meta-analysis was not performed. In the first trial (10 participants) femoxetine had no significant effect in eliminating or reducing EDS; a significant reduction of cataplexy was in favour of femoxetine. Mild and transient side effects were reported in the femoxetine treatment period by two participants. In the second trial the authors inappropriately treated the trial design as a parallel study and no conclusions can be reached in favour of either drug. AUTHORS' CONCLUSIONS: There was no good quality evidence that antidepressants are effective for narcolepsy or improve quality of life. Despite the clinical consensus recommending antidepressants for cataplexy there is scarce evidence that antidepressants have a positive effect on this symptom. There is a clear need for well-designed randomised controlled trials to assess the effect of antidepressants on narcolepsy.

Prognostic significance of hyperglycemia in acute stroke.

Prognostic significance of hyperglycemia on short-term survival was evaluated in 72 patients with acute hemispheric stroke. All patients were admitted within 48 hours of onset, and the neurologic deficit was assessed by means of a standardized score. A computed tomogram was taken in all cases on admission. Mortality was higher in hyperglycemic patients with no history of diabetes mellitus (78%) than in diabetic (45%) and in normoglycemic nondiabetic (29%) patients. In nondiabetic patients, the glucose level correlated with the neurologic score and with lesion size on computed tomogram. Reactive hyperglycemia due to a major stress response accounts for the worse prognosis of these patients. This correlation was not found in diabetic patients. Preexisting hyperglycemia, as well as systemic complications, could explain the higher mortality in these patients compared with normoglycemic nondiabetic patients.

Cortical pathophysiology and clinical neurologic abnormalities in acute cerebral ischemia. A serial study with single photon emission computed tomography.

We studied brain cortical radioactive tracer activity in a consecutive series of nine patients with acute hemispheric ischemic stroke at their first cerebral ischemic stroke at their first cerebral ischemic episode. Results from N,N,N'-trimethyl-N'- (2-hydroxy-3-methyl-5-[123-I]-iodobenzyl)-1,3 propanediamine-2HCl (four patients) and technetium Tc 99m hexamethylpropyleneamine oxime (five patients) single photon emission computed tomographic studies were compared with x-ray computed tomography (CT) and clinical findings within the first 48 hours, on day 10, and on day 30 after the clinical ictus. Cortical hypoactivity agreeing with the clinical findings was found on all initial scans but not in the follow-up studies. Cortical activity on the affected side in patients with stroke was significantly lower when compared with cortical activity in sex- and age-matched controls (n = 21). Computed tomography (with contrast) was less sensitive in detecting the ischemic lesions. These studies demonstrate that in the acute phase of stroke there is a single photon emission computed tomographic cortical disturbance that agrees with clinical findings, even when computed tomography scan infarction is limited to subcortical structures.

Venous thromboembolism in acute stroke. Prognostic importance of hypercoagulability.

To assess the incidence, risk factors, and clinical importance of deep vein thrombosis in acute stroke, we studied 70 consecutive patients who underwent hemostasis screening at the time of entry into the study and followed up these patients with serial venous Doppler examinations and the iodine 125-labeled fibrinogen uptake test. Mortality was significantly higher among the 20 patients who developed a deep vein thrombosis, and eight of them had necropsy evidence of pulmonary embolism. Severity of leg paresis and a shortened activated partial thromboplastin time were significantly associated with subsequent deep vein thrombosis with multivariate analysis. Significantly higher levels of fibrinopeptide A were found in patients with postmortem evidence of pulmonary embolism. Deep vein thrombosis is a frequent complication of acute stroke and may influence the prognosis by inducing pulmonary embolism. Our findings allow rapid identification of high-risk patients who may benefit maximally from prophylactic treatment of venous thromboembolism.

Hypercoagulability in acute stroke: prognostic significance.

To evaluate the clinical significance of hemostatic abnormalities in acute stroke, we studied coagulation and platelet function in 70 patients with recent cerebral infarction or hemorrhage and in 45 age-matched controls. Higher levels of one-stage factor VIII coagulant activity, fibrinopeptide A (FPA), and beta-thromboglobulin were associated with the occurrence of stroke. All hemostatic test results were remarkably similar in patients with ischemic and hemorrhagic stroke. FPA levels and size of the lesion on CT were the only variables independently predicting mortality in a multivariate regression analysis. Our findings demonstrate that hypercoagulability is an important prognostic factor in stroke and lend support to clinical trials of drugs interfering with the coagulation system in the early phase of cerebral ischemia.

Steroids for multiple sclerosis and optic neuritis: a meta-analysis of randomized controlled clinical trials.

We conducted a meta-analysis of randomized controlled clinical trials on steroid treatment for multiple sclerosis and optic neuritis. Of the 25 trials comparing steroids and controls without steroid treatment that we identified 12 were selected for this review. A meta-analysis was conducted to calculate the overall odds ratio across the studies for the numbers of patients without functional improvement and with new relapses. The trials included a total of 1714 patients: 998 with multiple sclerosis and 716 with optic neuritis. Any type of corticosteroids or adrenocorticotropic hormone (ACTH) treatment was considered, as was any dosage, route of administration, and length of treatment. Main outcome measures were: (a) number of multiple sclerosis patients who did not improve by at least one point on the EDSS or equivalent scale, or number of optic neuritis patients without complete recovery of visual acuity at 8 or 30 days and at longer follow-up; (b) number of multiple sclerosis patients with at least one new relapse, or number of optic neuritis patients in whom definite multiple sclerosis was diagnosed at longer follow-up. We found that corticosteroids or ACTH produced a significant improvement in disability or visual acuity at 30 days (odds ratio 0.49; 95% CI 0.37-0.64). The improvement was not statistically significant at longer follow-up (0.85; 95% CI 0.67-1.09). The treatment did not significantly reduce the number of patients with relapses (0.74; 95% CI 0.54-1.01). Both low and high doses were effective for 30-day improvement, but only high-dose and short-term therapy were factors that identified subgroups with some reduction in the risk of new relapse. However, the power of the statistical analysis to detect a reliable difference in the subgroups was low. Steroid treatment is therefore effective in accelerating short-term recovery in patients with multiple sclerosis or optic neuritis. Whether steroids are also effective in reducing the risk of relapse, and the optimal dose and length of treatment must still be determined.

The influence of baseline prognostic variables on outcome after thrombolysis. MAST-Italy Collaborative Group.

Thrombolysis increases case fatality but reduces the proportion of disabled survivors in recent trials in acute ischaemic stroke, although some trials show much higher mortality rates than others. One possible explanation for the different outcomes between trials is that the treatment effect with thrombolysis varies with baseline prognostic factors such as stroke severity. We examined the interaction between baseline risk and thrombolysis on outcome using individual patient data from the Multicentre Acute Stroke Trial-Italy (MAST-I). A multiple logistic regression of the MAST-I data was performed to identify which factors, identifiable at randomisation, most strongly predict a poor functional outcome. We then stratified the patients into those with severe strokes and those with mild strokes and examined the effect of thrombolysis on (a) case fatality and (b) dependency at 6 months after the stroke in the 157 patients who received streptokinase alone and the 156 controls. Streptokinase was found to cause an absolute increase of about 3% in case fatality in both "severe" and "mild" strokes; however, there was a 12% reduction in the number of dead or dependent "mild" strokes but a 6% increase in "severe" strokes. The number of patients was small, and therefore neither finding was statistically significant. In this exploratory analysis, the hazard with streptokinase appears similar in "severe" and "mild" strokes, but the benefit may be greater in "mild" strokes. Thrombolysis may be more effective in patients with "mild" strokes, but more information is required to confirm this hypothesis.

Gangliosides for acute ischaemic stroke.

BACKGROUND: Gangliosides may have a protective effect on the central and peripheral nervous systems. OBJECTIVES: The objective of this review was to assess the effect of exogenous gangliosides in acute ischaemic stroke. SEARCH STRATEGY: We searched the Cochrane Stroke Group trials register (last searched: May 2001) and contacted drug companies and main investigators of included trials. SELECTION CRITERIA: Randomised trials of gangliosides compared with placebo or standard treatment in people with definite or presumed ischaemic stroke. Trials were included if people were randomised within 15 days of symptom onset and if mortality data were available. DATA COLLECTION AND ANALYSIS: One reviewer applied the inclusion criteria. Two reviewers independently extracted the data. Trial quality was assessed. MAIN RESULTS: Twelve trials involving 2265 people were included. All the trials tested purified monosialoganglioside GM1. Only three trials described the randomisation procedure. Follow-up was between 15 to 180 days. Death at the end of follow-up showed no significant difference (odds ratio 0.91, 95% confidence interval 0.73 to 1.13). There was no difference shown between early (within 48 hours) and delayed treatment. For disability, three trials did not show any improvement in Barthel index score with gangliosides (weighted mean difference 2.1; 95% confidence interval -4.8 to 8.9). In two trials, eight patients experienced adverse effects that led to discontinuation of ganglioside treatment, seven had skin reactions and one developed Guillain-Barré syndrome. REVIEWER'S CONCLUSIONS: There is not enough evidence to conclude that gangliosides are beneficial in acute stroke. Caution is warranted because of reports of sporadic cases of Guillain-Barré syndrome after ganglioside therapy.

Gangliosides for acute ischaemic stroke.

BACKGROUND: Gangliosides may have a protective effect on the central and peripheral nervous systems. OBJECTIVES: The objective of this review was to assess the effect of exogenous gangliosides in acute ischaemic stroke. SEARCH STRATEGY: We searched the Cochrane Stroke Group trials register (last searched: March 1999) and contacted drug companies. SELECTION CRITERIA: Randomised trials of gangliosides compared with placebo or standard treatment in people with definite or presumed ischaemic stroke. Trials were included if people were randomised within 15 days of symptom onset and if mortality data were available. DATA COLLECTION AND ANALYSIS: One reviewer applied the inclusion criteria. Two reviewers independently extracted the data. Trial quality was assessed. MAIN RESULTS: Eleven trials involving 2257 people were included. All the trials tested purified monosialoganglioside GM1. Only three trials described the randomisation procedure. Follow-up was between 15 to 180 days. Death at the end of follow-up showed no significant difference (odds ratio 0.91, 95% confidence interval 0.73 to 1.14). There was no difference shown between early (within 48 hours) and delayed treatment. For disability, two trials showed an improved Barthel index score with gangliosides (weighted mean difference 8.6, 95% confidence interval 1.2 to 16.0). In two trials, eight patients experienced adverse effects that led to discontinuation of ganglioside treatment, seven had skin reactions and one developed Guillain-Barré syndrome. REVIEWER'S CONCLUSIONS: There is not enough evidence to conclude that gangliosides are beneficial in acute stroke. Caution is warranted because of reports of sporadic cases of Guillain-Barré syndrome after ganglioside therapy.

Corticosteroids or ACTH for acute exacerbations in multiple sclerosis.

BACKGROUND: Corticosteroids are often used to improve the rate of recovery from acute exacerbation in multiple sclerosis (MS) patients. However, it is still unclear just how relatively effective these agents are and the type of drug, optimal dose, frequency, duration of treatment and route of administration are unknown. OBJECTIVES: The object of this review was to determine the efficacy and safety of corticosteroids or ACTH in reducing the short and long term morbidity from MS. Moreover, we wished to examine from indirect comparisons if the effect of corticosteroids is different according to different doses and drugs, routes of administration, length of treatment. SEARCH STRATEGY: A search strategy developed for the Cochrane MS Group (last searched: June 1999) completed with handsearching and personal contacts with trialists and pharmaceutical companies was used. SELECTION CRITERIA: All randomised, double-blind, unconfounded trials comparing corticosteroids or ACTH to placebo in patients with MS, treated for acute exacerbations, without any age or severity restrictions, were evaluated. DATA COLLECTION AND ANALYSIS: Two reviewers independently selected articles for inclusion, assessed trials' quality and extracted the data. A third reviewer cross-checked them and disagreements were resolved by a joint discussion. MAIN RESULTS: Six trials contributed to this review; a total of 377 participants (199 treatment, 178 placebo) were randomised. The drugs analysed were methylprednisolone (MP) (four trials, 140 patients) and ACTH (two trials, 237 patients). Overall, MP or ACTH showed a protective effect against the disease getting worse or stable within the first five weeks of treatment (odds ratio[OR]=0.37, 95% confidence interval [CI] 0.24-0.57) with some but non significant greater effect for MP and intravenous administration. Short (five days) or long (15 days) duration of treatment with MP did not show any significant difference. Only one study (with 51 patients) reported data after one year of follow-up: no difference between oral MP and placebo in the prevention of new exacerbations or improvement in long term disability was detected. No data are available beyond one year of follow-up to indicate whether steroids or ACTH have any effect on long-term progression. One study reported that a short term treatment with high dose intravenous MP was not attended by adverse events. On the contrary, gastrointestinal symptoms and psychic disorders were significantly more common in the oral, high-dose MP than in the placebo group. Weight gain and edema were significantly more frequent in the ACTH group than in controls. REVIEWER'S CONCLUSIONS: We found evidence favouring the corticosteroid MP for acute exacerbation in MS patients. Data are insufficient to reliably estimate effect of corticosteroids on prevention of new exacerbations and reduction of long-term disability. Studies assessing long term risk/benefit and adverse effects of corticosteroids in MS patients are urgently needed.

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.