Carmelo Graffagnino

Simvastatin Reduces Vasospasm After Aneurysmal Subarachnoid Hemorrhage: Results of a Pilot Randomized Clinical Trial

Background and Purpose— Cerebral vasospasm remains a major source of morbidity after aneurysmal subarachnoid hemorrhage (SAH). We demonstrate that simvastatin reduces serum markers of brain injury and attenuates vasospasm after SAH. Methods— Patients with angiographically documented aneurysmal SAH were randomized within 48 hours of symptom onset to receive either simvastatin (80 mg daily; n=19) or placebo (n=20) for 14 days. Plasma alanine aminotransferase, aspartate aminotransferase, and creatine phosphokinase were recorded weekly to evaluate laboratory evidence of hepatitis or myositis. Serum markers of brain injury were recorded daily. The primary end point of vasospasm was defined as clinical impression (delayed ischemic deficit not associated with rebleed, infection, or hydrocephalus) in the presence of ≥1 confirmatory radiographic test (angiography or transcranial Doppler demonstrating mean VMCA >160 m/sec). Results— There were no significant differences in laboratory-defined transaminitis or myositis between groups. No patients developed clinical symptoms of myopathy or hepatitis. Plasma von Willebrand factor and S100&bgr; were decreased 3 to 10 days after SAH (P<0.05) in patients receiving simvastatin versus placebo. Highest mean middle cerebral artery transcranial Doppler velocities were significantly lower in the simvastatin-treated group (103±41 versus 149±47; P<0.01). In addition, vasospasm was significantly reduced (P<0.05) in the simvastatin-treated group (5 of 19) compared with those who received placebo (12 of 20). Conclusion— The use of simvastatin as prophylaxis against delayed cerebral ischemia after aneurysmal SAH is a safe and well-tolerated intervention. Its use attenuates serum markers associated with brain injury and decreases the incidence of radiographic vasospasm and delayed ischemic deficit.

The importance of family history in cerebrovascular disease.

Background and Purpose The role of genetics in cerebrovascular disease remains controversial. The purpose of this study was to assess the influence of family history on atherothrombotic infarction or transient ischemic attack. Methods Ninety patients with stroke or transient ischemic attack and 90 age- and sex-matched community control subjects were studied prospectivery. Medical and family histories were obtained from all subjects, and a complete physical examination was performed. Results Eighty-five patients and 86 control subjects knew their family history for ischemic heart disease and stroke. A positive history for ischemic heart disease was present in 62 (73%) of the patients and 46 (53%) of the control subjects (P=.019), and a positive family history for stroke was present in 38 (47%) of the patients and 21 (24%) of the control subjects (P=.014). Conclusions Although a positive vascular family history was not an independent risk factor in a multivariate analysis, it was an excellent marker of the presence of other established vascular risk factors. Personal histories of ischemic heart disease, hypertension, and hyperlipidemia were found to be significant independent risk factors for stroke.

Intra-Arterial Thrombolytic Therapy in Peri-Coronary Angiography Ischemic Stroke

Background— Intra-arterial thrombolysis (IAT) for peri-coronary angiography (CA) stroke may be safe and efficacious. However, IAT may increase the risk of intracranial hemorrhage (ICH). Methods— A retrospective study was performed involving 3 university hospitals. All peri-CA IAT-treated cases were identified. Patient demographics, stroke severity, angiographic findings, thrombolytic use, modified Rankin Scale (mRS), ICH, and mortality were determined. Results— A total of 21 patients with post–left CA stroke were treated with IAT (mean age 71.8±12.3 years). Arterial occlusion was found in 14 (66.7%) and 7 (33.3%) of the anterior and posterior circulation, respectively. Mean time-to-therapy was 36±12 minutes from the time the neurological deficit was noted. mRS ≤2 occurred in 10 of 21 (48%) patients. Patients with younger age and shorter time-to-IAT had more complete arterial recanalization and clinical recovery. Symptomatic ICH occurred in 3 (14%) cases, and 4 (19%) patients died. Conclusions— Peri-CA IAT appears to be feasible and safe without increased risk of symptomatic ICH and death when compared with the previously reported IAT literature.

Transitional Care After Hospitalization for Acute Stroke or Myocardial Infarction: A Systematic Review

BACKGROUND Transitional care is a time-limited service to prevent discontinuous care and adverse outcomes, including rehospitalization. PURPOSE To describe transitional care interventions and evidence of benefit or harm in patients hospitalized for acute stroke or myocardial infarction (MI). DATA SOURCES Cumulative Index to Nursing and Allied Health Literature, MEDLINE, Cochrane Database of Systematic Reviews, and EMBASE, supplemented with manual searches of reference lists of relevant studies and review articles (January 2000 to March 2012). STUDY SELECTION 6 reviewers screened 5857 citations to identify English-language reports of trials or observational studies that compared transitional care with usual care among adults hospitalized for stroke or MI and that reported patient, caregiver, process, or systems outcomes within 1 year of hospital discharge. DATA EXTRACTION Data on study design, quality, population, intervention characteristics, and patient- and system-level outcomes were extracted by 3 reviewers and confirmed by 1 additional reviewer. DATA SYNTHESIS 62 articles representing 44 studies of transitional care for either acute stroke (27 studies) or MI (17 studies). Four intervention types were studied: hospital-initiated support (n = 14), patient and family education (n = 7), community-based support (n = 20), and chronic disease management (n = 3). Most studies (68%) were of fair quality. Overall, moderate-strength evidence showed that hospital-initiated support reduced length of stay for patients who had a stroke, and low-strength evidence showed that it reduced mortality for patients who had an MI. Evidence about benefits of other interventions and harms from transitional care services was insufficient. LIMITATIONS Few studies had high-quality research designs. The usual care comparator was often poorly defined. Applicability to U.S. clinical practice was limited; only 6 studies were conducted in the United States. CONCLUSION Available evidence shows that hospital-initiated transitional care can improve some outcomes in adults hospitalized for stroke or MI. Finding additional transitional care interventions that improve functional outcomes and prevent rehospitalizations and adverse events is a high priority for the growing population of patients who have an MI or a stroke. PRIMARY FUNDING SOURCE Agency for Healthcare Research and Quality.

Effect of apolipoprotein E genotype on in-hospital mortality following intracerebral haemorrhage

Objective– To determine the relationship between the apolipoprotein E (APOE) ε4 allele and in‐hospital mortality from intracerebral haemorrhage (ICH). Material and methods ‐‐ Patients admitted to two acute stroke units with ICH were prospectively evaluated and APOE genotyped. In‐hospital survival was recorded in 176 patients. Results– There were 85 men and 91 women, mean age 68 years. Fifty‐two (30%) of the 176 patients died in hospital. After adjusting for sex, age, hospital, and race, increased age (P = 0.009) and the presence of the APOEε4 allele (P = 0.026) significantly reduced in‐hospital survival. Conclusion– The APOEε4 allele in this population may be associated with poor survival following ICH.

De Novo Cerebral Arteriovenous Malformation: Case Report

OBJECTIVE AND IMPORTANCE Arteriovenous malformations (AVMs) are generally thought to have a congenital cause. This is the first report of an angiographically proven de novo cerebral AVM in an adult patient without previous vascular abnormality. CLINICAL PRESENTATION A 26-year-old African-American woman developed multiple cranial nerve deficits and ataxia over the course of a few days after a streptococcal throat infection. T2-weighted magnetic resonance imaging scans revealed a hyperintense signal in the midbrain with extension into the diencephalon. A cerebral angiogram performed at that time to exclude vasculitis revealed normal cerebral vasculature. The patient was treated with corticosteroids, and symptoms resolved. Subsequently, at the age of 32, this patient presented with a severe headache and emesis, but with no focal neurological deficit. INTERVENTION The patient’s cranial computed tomographic and magnetic resonance imaging scans revealed a right posterior temporal intraparenchymal hemorrhage, and cerebral angiography revealed a new 3- by 2-cm AVM. The patient underwent microsurgical resection of the AVM and associated hematoma. Postoperative angiography revealed no evidence of residual AVM. CONCLUSION This study details the case of a woman who developed a de novo cerebral AVM during a 6-year period. This report challenges the conventional belief that all AVMs have a congenital cause.

Hemicraniectomy and Durotomy Upon Deterioration From Infarction-Related Swelling Trial: Randomized Pilot Clinical Trial

Background and Purpose— Hemicraniectomy and Durotomy Upon Deterioration From Infarction-Related Swelling Trial (HeADDFIRST) was a randomized pilot study to obtain information necessary to design a Phase III trial to evaluate the benefit of surgical decompression for brain swelling from large supratentorial cerebral hemispheric infarction. Methods— All patients with stroke were screened for eligibility (age 18–75 years, National Institutes of Health Stroke Scale ≥18 with Item 1a<2 [responsive to minor stimulation], and CT demonstrating unilateral, complete middle cerebral artery territory infarction by specific imaging criteria). All enrolled patients were treated using a standardized medical treatment protocol. Those with both ≥4 mm of pineal shift and deterioration in level of arousal or ≥7.5 mm of anteroseptal shift within 96 hours of stroke onset were randomized to continued medical treatment only or medical treatment plus surgery. Death at 21 days was the primary outcome measure. Results— Among 4909 screened patients, only 66 (1.3%) patients were eligible for HeADDFIRST. Forty patients were enrolled, and 26 patients developed the requisite brain swelling for randomization. All who failed to meet randomization criteria were alive at 21 days. Mortality at 21 and 180 days was 40% (4/10) in the medical treatment only and 21% (3/14) and 36% (5/14) in the medical treatment plus surgery arms, respectively. Conclusions— HeADDFIRST randomization criteria effectively distinguished low from high risk of death from large supratentorial cerebral hemispheric infarction. Lower mortality in the medical treatment only group than in other published trials suggests a possible benefit to standardizing medical management. These results can inform the interpretation of recently completed European trials concerning patient selection and medical management. Clinical Trial Registration— This trial was not registered because enrollment began before July 1, 2005.

Statin Use and Sex-Specific Stroke Outcomes in Patients With Vascular Disease

Background and Purpose— Although statins reduce the risk of stroke in patients with coronary heart disease, possible differing effects of statins on stroke outcomes based on sex remain uncertain. We investigated the relationships between statin use and sex-specific stroke incidence, severity, and mortality. Methods— Data from 3 trials of oral glycoprotein IIb/IIIa inhibitors (first and second Sibrafiban versus aspirin to Yield Maximum Protection from ischemic Heart events postacute cOroNary sYndromes [SYMPHONY] and Blockade of the glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion [BRAVO]) were pooled and stroke outcomes compared among 8191 baseline statin users versus 14 752 nonusers. Time-to-event data were modeled with proportional hazards regression. Stroke severity was assessed retrospectively with the Canadian Neurological Scale (CNS) based on records with scoreable neurological examinations. Results— A total of 217 subjects had strokes (0.95%). Statin users had a lower risk of stroke in unadjusted (hazard ratio [HR], 0.69; 95% CI, 0.51 to 0.92) and risk-adjusted models (HR, 0.72; 95% CI, 0.53 to 0.97). There was no difference in stroke mortality with statin use (P=0.8). CNS scores could be assigned to 106 of the subjects, with no difference in severity among statin users and nonusers (median CNS=10.5 in users versus CNS=9.75 in nonusers; P=0.14). Women had more severe strokes than men (median CNS=10.5 in men versus 9.5 in women; Poisson regression P=0.035). Women had more severe strokes after adjustment for statin use (P=0.03) and the combination of statin use, atrial fibrillation, and age (P=0.03). Conclusions— In patients included in these clinical trials of oral glycoprotein IIb/IIIa inhibitors, statin use is associated with a reduced risk of stroke but not severity or mortality. Women had more severe strokes than men, a difference that was not explained by baseline characteristics or statin use.

Cystatin C Mutation in an Elderly Man With Sporadic Amyloid Angiopathy and Intracerebral Hemorrhage

BACKGROUND Cerebral amyloid angiopathy (CAA) with intracerebral hemorrhage (ICH) occurs both sporadically and as a result of mutations in either cystatin C or the amyloid precursor protein. ICH due to cystatin C mutations typically occurs in young people of Icelandic origin. CASE DESCRIPTION We report a case of sporadic CAA with ICH in an elderly Croatian man with a mutation in cystatin C identical to that found in Icelandic hereditary cerebral hemorrhage with amyloidosis. CONCLUSIONS This is the first case report of sporadic CAA associated with the same mutation causing hereditary cerebral hemorrhage with amyloidosis of the Icelandic type. Sporadic CAA may thus be associated with genetic mutations in some patients. The frequency of these mutations is yet to be determined.

Dose-Finding, Safety, and Tolerability Study of an Oral Platelet Glycoprotein IIb/IIIa Inhibitor, Lotrafiban, in Patients With Coronary or Cerebral Atherosclerotic Disease

BACKGROUND Antiplatelet therapy is the mainstay of the treatment and secondary prevention of cardiovascular and cerebrovascular ischemic events. We assessed the safety, tolerability, and pharmacodynamics of lotrafiban, an oral platelet glycoprotein IIb/IIIa inhibitor, as a secondary prevention strategy in patients with cerebrovascular or cardiovascular disease. METHODS AND RESULTS Overall, 451 patients with a recent cardiovascular or cerebrovascular acute ischemic event were randomized in a double-blind fashion to 1 of 5 dosing regimens for 12 weeks: placebo or 5, 20, 50, or 100 mg lotrafiban, both twice daily with 300 to 325 mg/d aspirin. The primary end point was the incidence and tolerability of major and minor bleeding during treatment. Secondary end points included inhibition of platelet aggregation and clinical events. The placebo and lotrafiban 5-mg groups had similarly low rates of minor and major bleeding, but the 100-mg arm was terminated early because of excess major bleeding. Protocol-defined thrombocytopenia (<100 000 platelets/microL) occurred in 5 lotrafiban-treated patients (1.4%, 95% CI 0.2% to 2.7%) and 1 placebo patient (1.1%, 95% CI 0% to 3.1%). Three lotrafiban-treated patients had a nadir platelet count <20 000/microL (0.9%, 95% CI 0% to 1.8%). Lotrafiban produced dose-dependent inhibition of platelet aggregation; 5 mg lotrafiban did not differ significantly from placebo, whereas 100 mg inhibited aggregation by nearly 100%. CONCLUSIONS -Lotrafiban provides dose-dependent platelet inhibition when administered to a range of patients with atherosclerosis. The level of platelet inhibition appears to correlate with bleeding risk and drug tolerability.