John R. Lynch

Aggressive medical treatment with or without stenting in high-risk patients with intracranial artery stenosis (SAMMPRIS): The final results of a randomised trial

BACKGROUND Early results of the Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis trial showed that, by 30 days, 33 (14·7%) of 224 patients in the stenting group and 13 (5·8%) of 227 patients in the medical group had died or had a stroke (percentages are product limit estimates), but provided insufficient data to establish whether stenting offered any longer-term benefit. Here we report the long-term outcome of patients in this trial. METHODS We randomly assigned (1:1, stratified by centre with randomly permuted block sizes) 451 patients with recent transient ischaemic attack or stroke related to 70-99% stenosis of a major intracranial artery to aggressive medical management (antiplatelet therapy, intensive management of vascular risk factors, and a lifestyle-modification programme) or aggressive medical management plus stenting with the Wingspan stent. The primary endpoint was any of the following: stroke or death within 30 days after enrolment, ischaemic stroke in the territory of the qualifying artery beyond 30 days of enrolment, or stroke or death within 30 days after a revascularisation procedure of the qualifying lesion during follow-up. Primary endpoint analysis of between-group differences with log-rank test was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT 00576693. FINDINGS During a median follow-up of 32·4 months, 34 (15%) of 227 patients in the medical group and 52 (23%) of 224 patients in the stenting group had a primary endpoint event. The cumulative probability of the primary endpoints was smaller in the medical group versus the percutaneous transluminal angioplasty and stenting (PTAS) group (p=0·0252). Beyond 30 days, 21 (10%) of 210 patients in the medical group and 19 (10%) of 191 patients in the stenting group had a primary endpoint. The absolute differences in the primary endpoint rates between the two groups were 7·1% at year 1 (95% CI 0·2 to 13·8%; p=0·0428), 6·5% at year 2 (-0·5 to 13·5%; p=0·07) and 9·0% at year 3 (1·5 to 16·5%; p=0·0193). The occurrence of the following adverse events was higher in the PTAS group than in the medical group: any stroke (59 [26%] of 224 patients vs 42 [19%] of 227 patients; p=0·0468) and major haemorrhage (29 [13%]of 224 patients vs 10 [4%] of 227 patients; p=0·0009). INTERPRETATION The early benefit of aggressive medical management over stenting with the Wingspan stent for high-risk patients with intracranial stenosis persists over extended follow-up. Our findings lend support to the use of aggressive medical management rather than PTAS with the Wingspan system in high-risk patients with atherosclerotic intracranial arterial stenosis. FUNDING National Institute of Neurological Disorders and Stroke (NINDS) and others.

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.

Simvastatin Increases Endothelial Nitric Oxide Synthase and Ameliorates Cerebral Vasospasm Resulting From Subarachnoid Hemorrhage

Background and Purpose— Endothelial nitric oxide synthase (eNOS) activity is decreased after subarachnoid hemorrhage (SAH). Simvastatin increases eNOS activity. We hypothesized that simvastatin would increase eNOS protein and ameliorate SAH-induced cerebral vasospasm. Methods— Mice were treated with subcutaneous simvastatin or vehicle for 14 days and then subjected to endovascular perforation of the right anterior cerebral artery or sham surgery. Three days later, neurological deficits were scored (5 to 27; 27=normal), and middle cerebral artery diameter and eNOS protein were measured. The study was repeated, but simvastatin treatment was started after SAH or sham surgery. Results— In SAH mice, simvastatin pretreatment increased middle cerebral artery diameter (SAH-simvastatin=74±22 &mgr;m, SAH-vehicle=52±18 &mgr;m, P =0.03; sham-simvastatin=102±8 &mgr;m, sham-vehicle=105±6 &mgr;m). Pretreatment reduced neurological deficits (SAH-simvastatin=25±2, SAH-vehicle=20±2, P =0.005; sham-simvastatin and sham-vehicle=27±0). Simvastatin pretreatment also increased eNOS protein. Simvastatin posttreatment caused a modest increase in middle cerebral artery diameter in SAH mice (SAH-simvastatin=56±12 &mgr;m, SAH-vehicle=45±4 &mgr;m, P =0.03; sham-simvastatin=92±13 &mgr;m, sham-vehicle=99±10 &mgr;m) and reduced neurological deficits (SAH-simvastatin=21±1, SAH-vehicle=19±2, P =0.009). Simvastatin posttreatment did not significantly increase eNOS protein. Conclusions— Simvastatin treatment before or after SAH attenuated cerebral vasospasm and neurological deficits in mice. The mechanism may be attributable in part to eNOS upregulation.

Anti-apoptotic MCL-1 localizes to the mitochondrial matrix and couples mitochondrial fusion to respiration

MCL-1, an anti-apoptotic BCL-2 family member that is essential for the survival of multiple cell lineages, is also among the most highly amplified genes in cancer. Although MCL-1 is known to oppose cell death, precisely how it functions to promote survival of normal and malignant cells is poorly understood. Here, we report that different forms of MCL-1 reside in distinct mitochondrial locations and exhibit separable functions. On the outer mitochondrial membrane, an MCL-1 isoform acts like other anti-apoptotic BCL-2 molecules to antagonize apoptosis, whereas an amino-terminally truncated isoform of MCL-1 that is imported into the mitochondrial matrix is necessary to facilitate normal mitochondrial fusion, ATP production, membrane potential, respiration, cristae ultrastructure and maintenance of oligomeric ATP synthase. Our results provide insight into how the surprisingly diverse salutary functions of MCL-1 may control the survival of both normal and cancer cells.

Novel Diagnostic Test for Acute Stroke

Background and Purpose— The absence of a widely available and sensitive diagnostic test for acute cerebral ischemia remains a significant limitation in the diagnosis and management of stroke. The objective of this study was to examine the feasibility of developing a diagnostic panel of blood-borne biochemical markers of cerebral ischemia. Methods— Serial blood samples were obtained from patients (n=65 with suspected ischemic stroke, n=157 control subjects) presenting to an academic medical center emergency department. We analyzed 26 blood-borne markers believed to play a role in the ischemic cascade and created a 3-variable logistic regression model to predict the clinical diagnosis of stroke, defined as persistent neurological symptoms of cerebral ischemia lasting >24 hours. Results— Of the 26 blood-borne markers analyzed, univariate logistic analysis revealed that 4 were highly correlated with stroke (P <0.001): a marker of glial activation (S100&bgr;), 2 markers of inflammation (matrix metalloproteinase-9 and vascular cell adhesion molecule), and 1 marker of thrombosis (von Willebrand factor). When the outcome level was set to a cutoff of P =0.1, our logistic model provided a sensitivity and specificity of 90% for predicting stroke. Conclusions— A panel of blood-borne biochemical markers may be helpful in identifying patients with acute cerebral ischemia who could benefit from urgent care. Such a test may also be helpful in identifying stroke patients in the prehospital setting so that they could be fast-tracked to an institution equipped to care for patients with acute stroke.

Apolipoprotein E modulates glial activation and the endogenous central nervous system inflammatory response

Apolipoprotein E (apoE) is a 299 amino acid protein that is associated with risk of developing Alzheimers Disease (AD) and outcome after acute brain injury. To investigate the possibility that apoE modulates glial activation we studied the effect of endogenous apoE on inflammatory gene regulation in vitro and in vivo. Our results indicate that apoE downregulates CNS production of TNFalpha, Il-1beta, and Il-6 mRNA following stimulation with lipopolysaccharide (LPS). This effect of endogenous apoE on inflammatory gene regulation appears to be specific, and may account for the biological role that apoE plays in acute and chronic human neurological disease.

Xenon Attenuates Cardiopulmonary Bypass–induced Neurologic and Neurocognitive Dysfunction in the Rat

Background With clinical data suggesting a role for excitatory amino acid neurotransmission in the pathogenesis of cardiopulmonary bypass (CPB)–associated brain injury, the current study was designed to determine whether xenon, an N-methyl-d-aspartate receptor antagonist, would attenuate CPB-induced neurologic and neurocognitive dysfunction in the rat. Methods Following surgical preparation, rats were randomly divided into four groups: (1) sham rats were cannulated but did not undergo CPB; (2) CPB rats were subjected to 60 min of CPB using a membrane oxygenator receiving a gas mixture of 30% O2, 65% N2, and 5% CO2; (3) CPB + MK801 rats received MK801 (0.15 mg/kg intravenous) 15 min prior to 60 min of CPB with the same gas mixture; and (4) CPB + xenon rats underwent 60 min of CPB using an oxygenator receiving 30% O2, 60% xenon, 5% N2, and 5% CO2. Following CPB, the rats recovered for 12 days, during which they underwent standardized neurologic and neurocognitive testing (Morris water maze). Results The sham and CPB + xenon groups had significantly better neurologic outcome compared to both the CPB and CPB + MK801 groups on postoperative days 1 and 3 (P < 0.05). Compared to the CPB group, the sham, CPB + MK801, and CPB + xenon groups had better neurocognitive outcome on postoperative days 3 and 4 (P < 0.001). By the 12th day, the neurocognitive outcome remained significantly better in the CPB + xenon group compared to the CPB group (P < 0.01). Conclusion These data indicate that CPB-induced neurologic and neurocognitive dysfunction can be attenuated by the administration of xenon, potentially related to its neuroprotective effect via N-methyl-d-aspartate receptor antagonism.

Simvastatin and atorvastatin improve behavioral outcome, reduce hippocampal degeneration, and improve cerebral blood flow after experimental traumatic brain injury.

The treatment of traumatic brain injury (TBI) remains limited, and aside from surgical hematoma evacuation, clinical management is largely supportive and directed toward management of cerebral edema and intracranial hypertension. Secondary neuronal injury caused by ischemia and the development of cerebral edema may occur in the subacute phase, with intracranial pressures often peaking in the first several days following injury. Because inflammation contributes significantly to the pathophysiology of cerebral ischemia and endothelial dysfunction underlies the development of cerebral edema, therapeutic strategies that target the post-traumatic inflammatory cascade and reduce endothelial dysfunction hold enormous potential to improve clinical outcomes after TBI. Statins inhibit inflammation by suppressing inflammatory cytokine release, and by interfering with multiple steps of leukocyte recruitment and migration into the CNS. In this study, we demonstrate that treatment with atorvastatin and simvastatin markedly reduced functional neurological deficits after traumatic brain injury in mice. These effects were accompanied by histological reduction in degenerating hippocampal neurons and suppression of inflammatory cytokine mRNA expression in brain parenchyma. Furthermore, statin treatment improved cerebral hemodynamics following head injury. Thus, the administration of statins may represent a viable therapeutic strategy in the acute treatment of closed head injury.

Interventional Acute Ischemic Stroke Therapy With Intracranial Self-Expanding Stent

Background and Purpose— Rapid and safe recanalization of occluded intracranial arteries in acute ischemic stroke (AIS) is challenging. Newly available self-expanding intracranial atherosclerotic stents (SEIS), which can be deployed rapidly and safely, make acute stenting an option for treating AIS. We present the feasibility of this technique. Methods— A retrospective analysis evaluated procedural protocols and clinical response to treatment in patients with AIS treated with SEIS. Descriptive statistics are presented with initial and follow-up National Institutes of Health Stroke Scale and modified Rankin Score. Results— Nine patients with AIS underwent acute SEIS placement. There was successful deployment of the Neuroform (n=4) and Wingspan (n=4/5) stents in the M1/M2 (n=5) and M3 (n=1) middle cerebral artery segments, intracranial internal carotid artery (one of 2), and intracranial vertebrobasilar junction (one). Mean time of SEIS deployment from AIS onset was 5.1 hours. Complete (Thrombolysis in Cerebral Ischemia/Thrombolysis in Myocardial Ischemia 3) and partial/complete (Thrombolysis in Cerebral Ischemia/Thrombolysis in Myocardial Ischemia 2 or 3) recanalization occurred in 67% and 89%, respectively. One intracranial hemorrhage (11%) and one acute in-stent thrombosis (successfully treated with abciximab and balloon angioplasty) occurred. Stroke-related mortality occurred in 3 of 9 (33%) patients and survivors had modified Rankin Score ≤2. Follow-up angiography (mean, 8 months; range, 2 to 14 months) in 4 of 9 patients showed no stent restenosis. Conclusions— This preliminary experience with SEIS in refractory AIS demonstrated the technical feasibility and high rate of recanalization with acute stenting. Long-term safety and strategies to limit in-stent thrombosis and optimize periprocedural management are crucial before initiating future randomized efficacy studies with SEIS in AIS refractory to standard therapy.

Correlation of serum brain natriuretic peptide with hyponatremia and delayed ischemic neurological deficits after subarachnoid hemorrhage.

OBJECTIVE:Serum brain natriuretic peptide (BNP) is elevated after subarachnoid hemorrhage (SAH), causes diuresis and natriuresis (cerebral salt wasting), and may exacerbate delayed ischemic neurological deficits. We examined the temporal relationship between serum BNP elevation, hyponatremia, and the onset of delayed ischemic neurological deficits and determined whether serum BNP levels correlated with the 2-week outcome after SAH. METHODS:Serum BNP and sodium were measured prospectively every 12 hours for 14 days in 40 consecutive patients admitted with SAH. All patients remained euvolemic, underwent transcranial Doppler assessment every 48 hours, and underwent angiography at the onset of delayed neurological deficits. New-onset neurological deficits were attributed to vasospasm only in the absence of other causes and when supported by transcranial Doppler or cerebral angiography. RESULTS:Sixteen patients (40%) experienced symptomatic cerebral vasospasm after SAH. A more than threefold increase in admission serum BNP was associated with the onset of hyponatremia (P <0.05). Mean BNP levels were similar between vasospasm and nonvasospasm patients fewer than 3 days after SAH (126 ± 39 pg/ml versus 154 ± 40 pg/ml; P = 0.61) but were elevated in the vasospasm cohort 4 to 6 days after SAH (285 ± 67 pg/ml versus 116 ± 30 pg/ml; P < 0.01), 7 to 9 days after SAH (278 ± 72 pg/ml versus 166 ± 45 pg/ml; P < 0.01), and 9 to 12 days after SAH (297 ± 83 pg/ml versus 106 ± 30 pg/ml; P < 0.01). BNP level remained independently associated with vasospasm adjusting for Fisher grade and Hunt and Hess grade (odds ratio, 1.28; 95% confidence interval, 1.1–1.6). In patients in whom vasospasm developed, mean serum BNP increased 5.4-fold within 24 hours after vasospasm onset and 11.2-fold the first 3 days after vasospasm onset. Patients with increasing BNP levels from admission demonstrated no change (0 ± 3) in Glasgow Coma Scale score 2 weeks after SAH versus a 3.0 ± 2 (P < 0.05) improvement in Glasgow Coma Scale score in patients without increasing serum BNP levels. CONCLUSION:Increasing serum BNP levels independently were associated with hyponatremia, significantly increased the first 24 hours after onset of delayed ischemic neurological deficits, and predicted the 2-week Glasgow Coma Scale score.