Patrizia Nencini

Effect of a Novel Free Radical Scavenger, Edaravone (MCI-186), on Acute Brain Infarction

Edaravone, a novel free radical scavenger, demonstrates neuroprotective effects by inhibiting vascular endothelial cell injury and ameliorating neuronal damage in ischemic brain models. The present study was undertaken to verify its therapeutic efficacy following acute ischemic stroke. We performed a multicenter, randomized, placebo-controlled, double-blind study on acute ischemic stroke patients commencing within 72 h of onset. Edaravone was infused at a dose of 30 mg, twice a day, for 14 days. At discharge within 3 months or at 3 months after onset, the functional outcome was evaluated using the modified Rankin Scale. Two hundred and fifty-two patients were initially enrolled. Of these, 125 were allocated to the edaravone group and 125 to the placebo group for analysis. Two patients were excluded because of subarachnoid hemorrhage and disseminated intravascular coagulation. A significant improvement in functional outcome was observed in the edaravone group as evaluated by the modified Rankin Scale (p = 0.0382). Edaravone represents a neuroprotective agent which is potentially useful for treating acute ischemic stroke, since it can exert significant effects on functional outcome as compared with placebo.

Lupus anticoagulant and anticardiolipin antibodies in young adults with cerebral ischemia.

Our study evaluates in an unselected young population with cerebral ischemia the frequency of antiphospholipid antibodies; the relationship of antiphospholipid antibodies to conventional risk factors for and pathological mechanisms of cerebral ischemia; and the risk of recurrence of cerebral ischemia or systemic thrombotic events in patients with antiphospholipid antibodies compared with those without. Methods We prospectively tested for antiphospholipid antibodies in 55 of 59 young (aged 15-44 years) adults consecutively examined for ischemic stroke (n=44) or transient ischemic attack (n=11). These patients underwent a complete clinical and laboratory assessment for cerebral ischemia and had a 3-year mean follow-up. Results Ten patients (18%), all with stroke, had antiphospholipid antibodies. Antiphospholipid antibodies were significantly more frequent in women than in men (Fishers test, p=0.014). Two patients with antiphospholipid antibodies had a new diagnosis of systemic lupus erythematosus. On angiography, none of the patients with antiphospholipid antibodies had extracranial lesions. Patients with antiphospholipid antibodies had significantly more prior cerebral events (Fishers test, p=0.014), and, by survival analysis, higher probability of cerebral ischemic or systemic thrombotic events during follow-up than patients without (log rank test, p<0.005). Conclusions We conclude that the prevalence of antiphospholipid antibodies is rather high in young adults with cerebral ischemia; that patients with cerebral ischemia and antiphospholipid antibodies may have unrecognized systemic lupus erythematosus; and that, among young patients with cerebral ischemia, patients with antiphospholipid antibodies constitute a subgroup at high risk of cerebral ischemic or systemic thrombotic recurrence. Prevention in this latter group may require close follow-up and treatment.

Incidence of stroke in young adults in Florence, Italy.

A population-based study specifically addressing stroke in young adults (aged 15-44 years) was conducted in Florence, Italy, from 1983 to 1985. We identified 47 cases of first stroke by means of a daily check of the medical facilities of the city and nearby towns and a review of death certificates. Patients were assessed by a neurologist shortly after the onset of the stroke, and computed tomography or autopsy was performed in 96%. The average annual incidence rate for all stroke (cases per 100,000 population per year) was 9.0 (95% confidence interval 5.8-13.4) for males and 8.7 (95% confidence interval 5.5-13.0) for females. The average annual incidence rates for the pathologic types of stroke were 3.4 for cerebral infarction, 3.2 for subarachnoid hemorrhage, and 1.9 for intracerebral hemorrhage. The case-fatality ratio was 23.4% at 1 month. Among patients with ischemic strokes, atherosclerosis and cardiac disease accounted for 50% of the cases. Based on angiography or autopsy findings, aneurysm or arteriovenous malformation were demonstrated in 88% of the patients with subarachnoid hemorrhage. In 50% of the patients with intracerebral hemorrhage, no cause of bleeding was detected. Our study may supply information about stroke pathologic types in an unselected series of young adults.

Cross-national interrater agreement on the clinical diagnostic criteria for dementia.

We assessed the interobserver agreement on the clinical diagnosis of dementia syndrome and dementia subtypes as part of a cross-national project on the prevalence of dementia. Fourteen clinicians from the participating countries (Canada, Chile, Malta, Nigeria, Spain, and the United States) independently assessed the diagnosis of 51 patients whose clinical information was in standard records written in English. We used the DSM-III-R and ICD-10 criteria for dementia syndrome, the NINCDS-ADRDA criteria for Alzheimers disease (AD), and the ICD-10 criteria for other dementing diseases, and measured interobserver agreement. We found comparable levels of agreement on the diagnosis of dementia using the DSM-III-R (K = 0.67) as well as the ICD-10 criteria (K = 0.69). Cognitive impairment without dementia was a major source of disagreement (K = 0.10). The kappa values were 0.58 for probable AD, 0.12 for possible AD, and rose to 0.72 when the two categories were merged. The interrater reproducibility of the diagnosis of vascular dementia was 0.66 in terms of kappa index; the diagnoses of other dementing disorders as a whole reached a kappa value of 0.40. This study suggests that clinicians from different cultures and medical traditions can use the DSM-III-R and the ICD-10 criteria for dementia effectively and thus reliably identify dementia cases in cross-national research. The interrater agreement on the diagnosis of dementia might be improved if clear-cut guidelines in the definition of cognitive impairment are provided. To improve the reliability of AD diagnosis in epidemiologic studies, we suggest that the NINCDS-ADRDA “probable” and “possible” categories be merged.

Systemic thrombolysis in patients with acute ischemic stroke and Internal Carotid ARtery Occlusion: the ICARO study

Background and Purpose— The beneficial effect of intravenous thrombolytic therapy in patients with acute ischemic stroke attributable to internal carotid artery (ICA) occlusion remains unclear. The aim of this study was to evaluate the efficacy and safety of intravenous recombinant tissue-type plasminogen activator in these patients. Methods— ICARO was a case-control multicenter study on prospectively collected data. Patients with acute ischemic stroke and ICA occlusion treated with intravenous recombinant tissue-type plasminogen activator within 4.5 hours from symptom onset (cases) were compared to matched patients with acute stroke and ICA occlusion not treated with recombinant tissue-type plasminogen activator (controls). Cases and controls were matched for age, gender, and stroke severity. The efficacy outcome was disability at 90 days assessed by the modified Rankin Scale, dichotomized as favorable (score of 0–2) or unfavorable (score of 3–6). Safety outcomes were death and any intracranial bleeding. Results— Included in the analysis were 253 cases and 253 controls. Seventy-three cases (28.9%) had a favorable outcome as compared with 52 controls (20.6%; adjusted odds ratio (OR), 1.80; 95% confidence interval [CI], 1.03–3.15; P=0.037). A total of 104 patients died, 65 cases (25.7%) and 39 controls (15.4%; adjusted OR, 2.28; 95% CI, 1.36–3.22; P=0.001). There were more fatal bleedings (2.8% versus 0.4%; OR, 7.17; 95% CI, 0.87–58.71; P=0.068) in the cases than in the controls. Conclusions— In patients with stroke attributable to ICA occlusion, thrombolytic therapy results in a significant reduction in the proportion of patients dependent in activities of daily living. Increases in death and any intracranial bleeding were the trade-offs for this clinical benefit.

MMP9 Variation After Thrombolysis Is Associated With Hemorrhagic Transformation of Lesion and Death

Background and Purpose— Experimentally, matrix metalloproteinases (MMPs) play a detrimental role related to hemorrhagic transformation and severity of an ischemic brain lesion. Tissue-type plasminogen activator (tPA) enhances such effects. This study aimed to expand clinical evidence in this connection. Methods— We measured MMPs 1, 2, 3, 7, 8, 9, and tissue inhibitors of metalloproteinases 1, 2, 4 circulating level in blood taken before and 24 hours after tPA from 327 patients (mean age, 68.9±12.1 years; median National Institutes of Health Stroke Scale, 11) with acute ischemic stroke. Delta median values ([24 hours post tPA–pre tPA]/pre tPA) of each MMP or tissue inhibitors of metalloproteinase were analyzed across subgroups of patients undergoing symptomatic intracerebral hemorrhage, 3-month death, or 3-month modified Rankin Scale score 3 to 6. Results— Adjusting for major clinical determinants, only matrix metalloproteinase-9 variation proved independently associated with death (odds ratio [95% confidence interval], 1.58 [1.11–2.26]; P=0.045) or symptomatic intracerebral hemorrhage (odds ratio [95% confidence interval], 1.40 [1.02–1.92]; P=0.049). Both matrix metalloproteinase-9 and tissue inhibitors of metalloproteinase-4 changes were correlated with baseline, 24 hours, and 7 days National Institutes of Health Stroke Scale (Spearman P from <0.001 to 0.040). Conclusions— Our clinical evidence corroborates the detrimental role of matrix metalloproteinase-9 during ischemic stroke treated with thrombolysis, and prompts clinical trials testing agents antagonizing its effects.

The THRombolysis and STatins (THRaST) study

Objective: To assess the impact on stroke outcome of statin use in the acute phase after IV thrombolysis. Methods: Multicenter study on prospectively collected data of 2,072 stroke patients treated with IV thrombolysis. Outcome measures of efficacy were neurologic improvement (NIH Stroke Scale [NIHSS] ≤ 4 points from baseline or NIHSS = 0) and major neurologic improvement (NIHSS ≤ 8 points from baseline or NIHSS = 0) at 7 days and favorable (modified Rankin Scale [mRS] ≤ 2) and excellent functional outcome (mRS ≤ 1) at 3 months. Outcome measures of safety were 7-day neurologic deterioration (NIHSS ≥ 4 points from baseline or death), symptomatic intracerebral hemorrhage type 2 with NIHSS ≥ 4 points from baseline or death within 36 hours, and 3-month death. Results: Adjusted multivariate analysis showed that statin use in the acute phase was associated with neurologic improvement (odds ratio [OR] 1.68, 95% confidence interval [CI] 1.26–2.25; p < 0.001), major neurologic improvement (OR 1.43, 95% CI 1.11–1.85; p = 0.006), favorable functional outcome (OR 1.63, 95% CI 1.18–2.26; p = 0.003), and a reduced risk of neurologic deterioration (OR: 0.31, 95% CI 0.19–0.53; p < 0.001) and death (OR 0.48, 95% CI 0.28–0.82; p = 0.007). Conclusion: Statin use in the acute phase of stroke after IV thrombolysis may positively influence short- and long-term outcome.

Acute Inflammatory Events and Ischemic Stroke Subtypes

Background: Recent studies have suggested that previous infection may be a risk factor for ischemic stroke mainly in young and middle-aged patients. The present study sought to further investigate the association between recent inflammatory events (IE) and ischemic stroke without age restriction and to determine the role of recent IE in different ischemic stroke subtypes. Methods: We performed a case-control study with 93 consecutive hospitalized stroke patients and 200 (107 hospital and 93 community) controls. Acute IE, both infective and non-infective, occurring in the previous 30 days were assessed using a standard questionnaire. The TOAST criteria were used for ischemic stroke subtypes classification. Results: Acute IE in the previous 30 and 7 days were significantly and independently associated with ischemic stroke (37/93 vs. 47/200; OR 2.23, 95% CI 1.26–3.96 and 17/93 vs.16/200; OR 2.45, 95% IC 1.11–5.39, respectively). Stratifying for stroke subtypes, acute IE significantly and independently increased the risk of atherothrombotic (OR 5.72, 95% CI 2.14–15.25) and cardioembolic stroke (OR 3.02, 95%CI 1.20–7.63). Conclusions: Acute IE increase the risk of acute ischemic stroke of atherothrombotic and cardioembolic type independently of other predisposing factors. Implications for daily clinical practice, in relation to prevention and treatment of IE in patients at risk, have to be explored.

Failure of radiation therapy for brain involvement in Erdheim Chester disease.

A patient with suprasellar and brain stem involvement in Erdheim Chester disease (ECD) underwent magnetic resonance (MR) imaging and proton MR spectroscopy (1H MRS) of the ventral pons before and 1, 4 and 18 months after external whole-brain (24 Gy) radiotherapy. By revealing a decrease of the N-acetyl-aspartate/choline ratio in the pons, 1H MR spectroscopy anticipated lesions growth on MR imaging. In line with the results in four patients reported in the literature, our observation indicates that external radiation therapy is not effective for intracranial involvement in ECD.

Intravenous Tirofiban With Intra-Arterial Urokinase and Mechanical Thrombolysis in Stroke Preliminary Experience in 11 Cases

Background and Purpose— To evaluate preliminarily efficacy and safety of intravenous tirofiban combined with mechanical clot disruption and urokinase in patients with stroke attributable to major cerebral artery occlusion. Methods— Eleven consecutive patients with stroke attributable to acute occlusion of a major cerebral artery were treated with an intravenous bolus injection of the platelet glycoprotein IIb/IIIa antagonist tirofiban combined with heparin and by endovascular procedures including mechanical thrombolysis and locally delivered urokinase. Of the 11 cases, 9 involved angioplasty and 2 only microcatheter and microguidewire manipulation. Results— There were 7 patients with internal carotid or middle cerebral artery occlusion treated within 6 hours and 4 patients with basilar artery occlusion treated within 12 hours of symptom onset. Median National Institutes of Health Stroke Scale (NIHSS) score on admission was 20. After the interventional procedure, vessel recanalization was partial (thrombolysis in myocardial infarction grade flow 2 [TIMI 2]) in 7 patients and absent or insufficient in 4 patients. Twenty-four hours after the procedure, all the patients but 1 improved substantially, and on control angiography, the occluded vessel was totally patent (TIMI 3) in 10 of the 11 patients. One patient with partial recanalization did not improve and died 3 months later from pulmonary embolism. Neither a symptomatic intracerebral hemorrhage nor systemic bleedings requiring blood transfusion occurred in any patient. At discharge, median NIHSS score was 2. The 3-month outcome was excellent in 8 patients (modified Rankin Scale [mRS] 0 to 1), good in 2 patients (mRS 2), and poor in 1 patient (mRS 6). Conclusions— The combination of intravenous tirofiban with intra-arterial mechanical clot disruption and urokinase may be successful in reopening an occluded major cerebral vessel without increasing the hemorrhagic risk and with good functional outcome. This strategy cannot be recommended as the systematic treatment of stroke attributable to major cerebral artery occlusion until tested in a controlled study design.