Immunological profile of silent brain infarction and lacunar stroke.

Neuroinflammation is believed to be involved in the pathophysiological mechanisms of silent brain infarcts (SBI). However, the immunological profile of SBI has been scarcely investigated. In the context of a national research project named SILENCE, aimed at investigating clinical, biochemical and pathogenic features of SBI, we have measured the plasma profile of some inflammatory-related molecules in SBI patients (n = 21), patients with recent lacunar infarcts (LI, n = 28) and healthy controls (n = 31), consecutively enrolled in four Italian centres. A panel of chemokines (MIG, CTACK, IL16, SDF1a, MCP1), growth factors (SCF, SCGFb, HGF, IL3), immunoglobulin-type adhesion molecules (ICAM1, VCAM1), proinflammatory cytokines (IL18, INFa2, MIF, IL12p40), cell surface receptors on T-cells (IL2Ra), and inductors of apoptosis (TRAIL) was assessed in plasma samples by Luminex xMAP™ technology. Immunological parameters were compared using non-parametric statistics and performance to distinguish SBI and LI was evaluated by receiver operating characteristic (ROC) analysis. Plasma levels of ICAM1 were significantly higher in both SBI and LI patients as compared to controls (SBI≥LI>Ctrl). A different trend was observed for IL16 (SBI

Lipid profiles and outcome in patients treated by intravenous thrombolysis for cerebral ischemia.

OBJECTIVE: To determine whether low low-density lipoprotein cholesterol (LDL-C) but not high-density lipoprotein cholesterol (HDL-C) and triglyceride concentrations are associated with worse outcome in a large cohort of ischemic stroke patients treated with IV thrombolysis. METHODS: Observational multicenter post hoc analysis of prospectively collected data in stroke thrombolysis registries. Because of collinearity between total cholesterol (TC) and LDL-C, we used 2 different models with TC (model 1) and with LDL-C (model 2). RESULTS: Of the 2,485 consecutive patients, 1,847 (74%) had detailed lipid profiles available. Independent predictors of 3-month mortality were lower serum HDL-C (adjusted odds ratio [(adj)OR] 0.531, 95% confidence interval [CI] 0.321-0.877 in model 1; (adj)OR 0.570, 95% CI 0.348-0.933 in model 2), lower serum triglyceride levels ((adj)OR 0.549, 95% CI 0.341-0.883 in model 1; (adj)OR 0.560, 95% CI 0.353-0.888 in model 2), symptomatic ICH, and increasing NIH Stroke Scale score, age, C-reactive protein, and serum creatinine. TC, LDL-C, HDL-C, and triglycerides were not independently associated with symptomatic ICH. Increased HDL-C was associated with an excellent outcome (modified Rankin Scale score 0-1) in model 1 ((adj)OR 1.390, 95% CI 1.040-1.860). CONCLUSION: Lower HDL-C and triglycerides were independently associated with mortality. These findings were not due to an association of lipid concentrations with symptomatic ICH and may reflect differences in baseline comorbidities, nutritional state, or a protective effect of triglycerides and HDL-C on mortality following acute ischemic stroke.

Demographic and geographic vascular risk factor differences in European young adults with ischemic stroke: the 15 cities young stroke study.

BACKGROUND AND PURPOSE: We compared among young patients with ischemic stroke the distribution of vascular risk factors among sex, age groups, and 3 distinct geographic regions in Europe. METHODS: We included patients with first-ever ischemic stroke aged 15 to 49 years from existing hospital- or population-based prospective or consecutive young stroke registries involving 15 cities in 12 countries. Geographic regions were defined as northern (Finland, Norway), central (Austria, Belgium, France, Germany, Hungary, The Netherlands, Switzerland), and southern (Greece, Italy, Turkey) Europe. Hierarchical regression models were used for comparisons. RESULTS: In the study cohort (n=3944), the 3 most frequent risk factors were current smoking (48.7%), dyslipidemia (45.8%), and hypertension (35.9%). Compared with central (n=1868; median age, 43 years) and northern (n=1330; median age, 44 years) European patients, southern Europeans (n=746; median age, 41 years) were younger. No sex difference emerged between the regions, male:female ratio being 0.7 in those aged <34 years and reaching 1.7 in those aged 45 to 49 years. After accounting for confounders, no risk-factor differences emerged at the region level. Compared with females, males were older and they more frequently had dyslipidemia or coronary heart disease, or were smokers, irrespective of region. In both sexes, prevalence of family history of stroke, dyslipidemia, smoking, hypertension, diabetes mellitus, coronary heart disease, peripheral arterial disease, and atrial fibrillation positively correlated with age across all regions. CONCLUSIONS: Primary preventive strategies for ischemic stroke in young adults-having high rate of modifiable risk factors-should be targeted according to sex and age at continental level.

Predictive value of admission blood glucose level on short-term mortality in acute cerebral ischemia.

BACKGROUND: Admission hyperglycemia increases the risk of death in patients with acute stroke. However, the most appropriate cut-off of glucose level indicating an increased risk of short-term mortality remains unknown. PURPOSE AND METHODS: We aimed at establishing the optimum cut-offs of several variables (including admission blood glucose levels) predicting case-fatality (72hours, 7days) and unfavorable outcome [modified Rankin Scale (mRS) score 5-6 at 7 days] in consecutive first-ever acute ischemic stroke. Receiver operating characteristic (ROC) curves were constructed. RESULTS: Eight hundred eleven consecutive patients were included [median age of 77 (69-83) years; 418 (52%) male; 239 (30%) diabetics; median admission National Institutes of Health Stroke Scale (NIHSS) 7 (4-12), 32 (4%) dead within 72hours; 64 (8%) dead within day 7; 155 (19%) with unfavorable outcome]. Median admission glucose levels were 113 (97-155)mg/dL. Diabetics had significantly higher median glucose levels than non-diabetics [163 (133-214) vs. 107 (92-123) mg/dL, p<0.001]. According to ROC analysis, the only significant predictive value of glycemia was ≥143mg/dL for 72-hour fatality (sensitivity 88% and specificity 70%) especially in non-diabetics (sensitivity 88% and sensitivity 62%). This cut-off point was an independent predictor for 72-hour fatality (overall: OR=4.0, CI=1.6-9.9, p=0.003; non-diabetics: OR=4.9, CI=1.7-14.5, p=0.004). The cut-offs of fasting total cholesterol levels and admission leukocytes had poor predictive values for each outcome, while those of admission NIHSS had good discrimination in predicting short-term outcome measures. CONCLUSIONS: Admission hyperglycemia (≥143mg/dL) is a strong and an independent predictor for 72-hour fatality, especially in patients with no prior history of diabetes mellitus.

Admission leukocytosis in acute cerebral ischemia: influence on early outcome.

BACKGROUND: Leukocytes are the first cells that arrive in the stroke region(s), and they increase in peripheral blood. The contribution or leukocytes in the early acute phase of cerebral ischemia has not yet been investigated. METHODS: In consecutive first-ever acute ischemic stroke patients whose symptoms had started <12 hours earlier, we aimed to establish whether admission leukocyte count affects the short-term neurologic outcome, and whether there are differences between the various clinical syndromes of stroke. The National Institutes of Health Stroke Scale (NIHSS) was assessed at admission (NIHSS(0)) and after 72 hours (NIHSS(72)). Modified Rankin scale (mRS) scores were evaluated at discharge. The Spearman rank correlation was used for the correlation between leukocytes and outcome measures. RESULTS: Eight hundred and eleven patients were included (median age 77 years [range 68-82]; 418 [53%] were male; the median NIHSS(0) score was 7 [range 4-12], the median NIHSS(72) score was 6 [range 3-12], and the median mRS score was 2 [range 2-4]). The median leukocyte count at admission was 8100/mm(3) (range 6500-10300). Higher leukocyte levels predicted a worst clinical presentation and a poor functional outcome (NIHSS(0)P < .001; NIHSS(72)P < .001; mRS P < .001). The correlation between leukocyte count and outcome measures remained significant after multivariate analysis (NIHSS(0)P < .001; NIHSS(72)P < .001; mRS P < .008). Focusing on clinical syndromes, a higher leukocyte count predicted severe NIHSS(0) and NIHSS(72) scores in patients with total anterior cerebral stroke (P = .001), partial anterior cerebral stroke (P = .004), or posterior cerebral stroke (P = .026). CONCLUSIONS: An elevated leukocyte count in the acute phase of cerebral ischemia is a significant independent predictor of poor initial stroke severity, poor clinical outcome after 72 hours, and discharge disability. The involved underlying mechanism is still to determined.

Ischaemic stroke following tranexamic acid in young patients carrying heterozygosity of MTHFR C677T.

The objective of this study is to report a new manifestation of acute stroke following antifibrinolytic agent administration in young women carrying heterozygosity for methylene-tetrahydrofolate reductase (MTHFR) C677T. The study included two young women who developed an acute ischaemic stroke following three days of tranexamic acid administration for bleeding gynaecological disorders. Case 1, a 44-year-old woman, presented left hemiplegia, mild dysarthria and anosognosia. Brain magnetic resonance imaging showed right ischaemic fronto-temporal lesion due to subocclusion of the right middle cerebral artery. Case 2, a 49-year-old woman, developed aphasia and right hemiplegia. Neuroimaging showed left capsular and periventricular infarcts due to near occlusion of the left internal carotid artery. Thrombophilia screening, coagulation parameters, homocysteine testing, 12-lead electrocardiography, and transthoracic and transoesophageal echocardiography were unremarkable. Genetic assay showed that both patients carried heterozygosity for MTHFR C677T, in which cytosine (C) is replaced by thymidine (T) at base position 677. To our knowledge, this is the first report describing the association between genetic factors and the onset of stroke following antifibrinolytic drugs intake. These data suggest a synergic effect of plasminogen activator inhibitor and heterozygosity for MTHFR C677T on the pathogenetic mechanisms leading to ischaemic stroke in young people.

Influence of lipid profiles on the risk of hemorrhagic transformation after ischemic stroke: systematic review.

BACKGROUND: It has been suggested that low cholesterol levels might be associated with an increased risk of hemorrhagic transformation (HT) in patients with acute cerebral ischemia. We systematically reviewed the literature to determine the influence of lipid profiles on the HT risk. METHODS: We searched PubMed from 1966 and EMBASE from 1980 for studies that investigated the association between lipid profiles and HT. We performed a meta-analysis (weighted mean difference method) for the comparison between presence and absence of HT (all or symptomatic) for total, low-density-lipoprotein (LDL) and high-density-lipoprotein (HDL) cholesterol, and triglycerides. RESULTS: Eight studies investigating 1,763 patients were eligible, but none was designed specifically to address this question. All studies recruited acute stroke patients selected on the presumed cause of cerebral ischemia or treatment received. The meta-analysis showed that: (i) patients with all HT had lower LDL cholesterol levels (p = 0.008) but no difference in HDL cholesterol levels (p = 0.066), total cholesterol (p = 0.129) and triglycerides (p = 0.900); (ii) patients with symptomatic HT had lower total cholesterol levels (p = 0.035) but did not differ in LDL (p = 0.056) and HDL cholesterol (p = 0.138) and triglyceride (p = 0.851) levels. CONCLUSION: HT is associated with baseline total and LDL cholesterol levels, but the mechanism of this association needs to be explored to identify preventive strategies.

Ifosfamide encephalopathy and use of methylene blue. A case report of different sequential neurotoxicity.

Neurotoxicity is a clinically relevant adverse event observed with the use of ifosfamide. It is usually mild, occasionally severe and seldom fatal. Ifosfamide-induced encephalopathy requires interruption of chemotherapy, intravenous hydration and administration of methylene blue. Less is known about the efficacy of methylene blue in avoiding a second episode of ifosfamide-induced encephalopathy while maintaining chemotherapy with ifosfamide. We report a case of a different clinical manifestation of ifosfamide-induced encephalopathy after continued ifosfamide use and despite methylene blue in a patient with retroperitoneal sarcoma.

Association between migraine and headache attributed to stroke: a case-control study.

BACKGROUND: Several studies were carried out to investigate the occurrence of headache attributed to acute stroke in patients with a lifetime history of migraine. METHODS: In a case-control series of 96 acute stroke patients with a lifetime history of migraine (M+) and 96 stroke patients without (M-), ischemic stroke patients only, without secondary infarction, were selected. The headache attributed to acute ischemic stroke was then analyzed. RESULTS: (M+) patients complained of headache more often than (M-) patients (P < .0001), mainly in the 24 hours before stroke onset (P < .0001). Migraine-like features of headache were recognized in a greater proportion of cases in the (M+) patient group with ischemic stroke (P < .018). A preferential brainstem location of ischemic stroke in (M+) patients emerged compared with (M-) patients (P = .014). DISCUSSION: The high prevalence of headache attributed to stroke in (M+) patients, in a relevant proportion of cases presenting as a sentinel headache, suggests that cerebral ischemia lowers the threshold for head pain more easily in these "susceptible" patients. The most frequent involvement of the brainstem in (M+) patients with ischemic infarction concurs with recent reports that emphasized a greater headache frequency when cerebral infarctions are localized in this structure or deep brain gray matter.

Language disturbances as a side effect of prophylactic treatment of migraine.

BACKGROUND: Language disturbances have been previously described as word-finding difficulties in epileptic patients. These disturbances have been recently reported in migraineurs in treatment with topiramate but they have never been defined and assessed in these patients with the aid of neuropsychological testing. OBJECTIVE: To verify the occurrence of language disturbances as a side effect of topiramate treatment in episodic and chronic migraine patients. METHODS: Language disturbances were recorded on the basis of spontaneous reports of 30 migraine patients treated with topiramate and 2 control groups (20 patients treated with other prophylactic drugs and 20 patients without prophylactic treatment) and were explored with neuropsychological tests. Psychiatric comorbidity was assessed using Zung Anxiety and Depression Scales. RESULTS: Language disturbances were referred by 26.7% (n=8) of patients during topiramate treatment but by none of the patients in the 2 control groups. All patients in the topiramate group had a worse performance on all tests compared to patients of the 2 control groups. Moreover, in the topiramate group, patients with referred language disturbances had higher scores for all neuropsychological test variables, indicative of a worse performance. Some language functions (Trail Making Tests A and B) seemed to be influenced by the concomitant presence of psychiatric comorbidities, particularly anxiety and depression. CONCLUSION: It can be hypothesized that a disorder such as migraine, which involves numerous cortical and subcortical circuits implicated in the transmission and behavioral and emotional processing of pain, represents a facilitated substrate for the occurrence of language disturbances due to topiramate. This could be the expression of a more generalized impairment of cognitive processing. These aspects should be investigated in prospective studies involving larger migraine patient samples.

Sensitization, glutamate, and the link between migraine and fibromyalgia.

Recent advances have shed insight on the pathophysiologic mechanisms of fibromyalgia and migraine, especially in the chronic form. A growing body of evidence supports the involvement of peripheral and central sensitization disturbances of pain-related processes underlying both disorders. They involve increased glutamate transmission through interaction with its ionotropic and metabotropic receptors. Few studies supporting the implication of this excitatory amino acid in chronic migraine and primary fibromyalgia demonstrated increased levels of glutamate in the cerebrospinal fluid of affected patients. These findings have implications for future therapies directed against glutamate receptors (in particular, N-methyl-D-aspartate receptors). Limited clinical experience in this regard, although promising, does not exclude additional mechanisms contributing to the maintenance of pain, which can be the target of therapeutic approaches in both disorders.

Increased levels of neurotrophins are not specific for chronic migraine: evidence from primary fibromyalgia syndrome.

UNLABELLED: All data obtained in experimental animal pain models support the role of nerve growth factor (NGF) as a putative candidate intervening in the pathogenesis of chronic pain, including chronic daily headache (CDH). Few studies have been carried out to establish its role in maintaining pain states in humans. The present study was aimed at investigating cerebrospinal fluid (CSF) levels of NGF and brain-derived neurotrophic factor (BDNF), both measured by sensitive immunoassay, in 20 chronic migraine (CM) patients and 20 patients affected by primary fibromyalgia syndrome (PFMS), compared with those of 20 age-matched control subjects. Significantly higher levels of both neurotrophins and glutamate were found. A significantly positive correlation emerged between CSF values of BDNF and those of NGF (r = .61, P < .001; r = .53, P < .01) and glutamate (r = .44, P < .02; r = .51, P < .01) in CM and PFMS patients, respectively. These findings suggest the possibility of a NGF-mediated up-regulation of BDNF involved in the pathophysiological events underlying long-term neuroplastic changes in persistent chronic painful conditions, such as CM and fibromyalgia. NGF might indirectly exert its effect through enhancing glutamatergic transmission via BDNF. The above mechanisms could account for sustained central sensitization in both chronic pain states. PERSPECTIVE: This article presents findings of higher NGF and BDNF levels correlated to increased glutamate levels in the CSF of both chronic migraine and fibromyalgia patients. This opens new insights into the pathogenic mechanisms of chronic pain and offers clinicians new therapeutic perspectives targeting the above mechanisms in both painful disorders.

First-ever stroke and outcome in patients admitted to Perugia Stroke Unit: predictors for death, dependency, and recurrence of stroke within the first three months.

Predictors of poor outcome after first-ever stroke within 3 months in consecutive patients admitted to our Stroke Unit were defined. Factors included age, sex, risk factors, occurrence of transient ischemic attacks, extension of cerebral infarction, presumed cause of stroke, clinical findings, and demographic characteristics. Multiple regression models were used to analyze predictors of mortality, dependency and stroke recurrence. A total of 435 patients with first-ever stroke were included. Of these, 358 patients had ischemic stroke and 77 hemorrhagic stroke. Three-month mortality rate was 20.5%. After the same period, 24.6% of survivors were dependent (mRS > or = 3) and 5.0% of patients had recurrent stroke. Age, the presence of atrial fibrillation, impaired consciousness on admission, and stroke severity were related to mortality. The presence of stroke due to an undetermined cause or small vessel disease was associated with lower mortality. Partial anterior circulation syndrome or lacunar syndrome were both related to better outcome. The best predictors for dependency after 3 months were age and stroke severity. The only variable identified as the best predictor for recurrence was the presence of diabetes mellitus.