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BACKGROUND: Vascular endothelial growth factor-A(165) (VEGF-A(165)) has been identified as a combination of two alternative splice variants: proangiogenic VEGF-A(165)a and antiangiogenic VEGF-A(165)b. Intracranial atherosclerotic disease (ICAD) and moyamoya disease (MMD) are two main types of intracranial arterial steno-occlusive disorders (ICASD) with distinct capacities for collateral formation. Recent studies indicate that VEGF-A(165) regulates collateral growth in ischemia. Therefore, we investigated if there is a distinctive composition of VEGF-A(165) isoforms in ICAD and MMD. METHODS: Sixty-six ICAD patients, six MMD patients, and five controls were enrolled in this prospective study. ICAD and MMD patients received intensive medical management upon enrollment. Surgery was offered to 9 ICAD patients who had recurrent ischemic events, 6 MMD patients, and 5 surgical controls without ICAD. VEGF-A(165)a and VEGF-A(165)b plasma levels were measured at baseline, within one week after patients having surgery, and at one, three, and six months after treatment. RESULTS: A significantly higher baseline VEGF-A(165)a/b ratio was observed in MMD compared to ICAD (p=0.016). The VEGF-A(165)a/b ratio increased significantly and rapidly after surgical treatment in ICAD (p=0.026) more so than in MMD and surgical controls. In patients with ICAD receiving intensive medical management, there was also an elevation of the VEGF-A(165)a/b ratio, but at a slower rate, reaching the peak at three months after initiation of treatment (baseline vs. three months VEGF-A(165)a/b ratio, p=0.028). CONCLUSIONS: Our study shows an increased VEGF-A(165)a/b ratio in MMD compared to ICAD, and suggests that both intensive medical management and surgical revascularization elevate the VEGF-A(165)a/b ratio in ICAD patients.

Background Non–vitamin K antagonist oral anticoagulant (NOAC) use has significantly reduced intracerebral hemorrhagic (ICH) risk compared with standard anticoagulant treatment. Hematoma expansion (HE) is a known predictor of mortality in warfarin-associated ICH. Little is known about HE in patients using NOACs. Methods We conducted a retrospective chart review of patients with ICH admitted to Cedars-Sinai Medical Center from October 2010 to June 2016. We identified patients with concomitant administration of an oral anticoagulant and collected data including evidence of HE on imaging and modified Rankin Scale (mRS) at discharge. We defined HE as relative (≥33% increase) or absolute expansion (≥12 mL). We compared outcomes of patients with and without HE. Results Out of 814 patients with ICH who were admitted, we identified 9 patients with recent NOAC use and 18 intentionally matched controls on warfarin. We found no significant differences in National Institutes of Health Stroke Scale or ICH score on presentation (median [interquartile range] 15 [5,21] versus 7 [1.25,19.5] [ P = .41] and 2 [1,4] versus 1 [1,3] [ P = .33]) between patients on NOACs and those on warfarin. Four out of the 9 patients on NOAC and 5 of the 18 patients on warfarin demonstrated HE, with no significant difference ( P = .42). There were no significant differences in mRS on discharge between groups ( P = .52). Conclusions In our coagulopathic NOAC patient population, HE occurs within 6 hours in 44% of patients. This case series did not have sufficient statistical power to detect significant differences between the groups. To our knowledge, this is one of the largest case series reporting on HE with concomitant NOAC use.

Effective therapy for acute ischemic stroke will require very rapid evaluation of patients so that treatment can begin soon enough to salvage injured but viable brain. Limited data suggest that neurons in the ischemic penumbra survive for a few hours, at the most. It is critical to know whether our medical system can overcome the many practical obstacles to ultra-rapid recognition,, transport, and treatment of stroke patients. We analyzed our patient recruitment into clinical treatment trials over time, attempting to identify strategies that improved recruitment. Specifically, we studied whether the imposition of an ultra-short time limit for treatment initiation, 3 h from stroke onset, impaired recruitment Prior to adopting the strict time limit, we enrolled about 0.4 patients per month per participating hospital. After adopting the limit, we enrolled about 0.7 patients per month per hospital. Our data indicate that patient recruitment may be maintained and even increased despite a demanding time limit for treatment. The data also suggest that a very short time window of survivability of the ischemic penumbra should not discourage efforts to develop new methods of salvaging brain, for we have shown that the medical delivery system in one county can be modified to allow ultra-rapid patient recognition, evaluation, and treatment.

Despite the increasing use of thrombolytic therapy for acute ischemic stroke, hemorrhagic transformation remains a significant complication. Transformation appears to occur more frequently with age, diabetes, and hypertension, but clinical data are mixed. In addition to risk factors, matrix metalloproteinase expression mediates hemorrhage. We sought to test the effects of age, hypertension, and matrix metalloproteinases during recombinant tissue plasminogen activator (rt-PA) treatment in a standard model of filament occlusion of the middle cerebral artery.We compared young and aged rats who were genetically predisposed to hypertension to similar and dissimilar strains to separate the effect of hypertension and age.Hemorrhagic transformation occurred significantly more frequently in chronically hypertensive animals-23 of 53 (44%) compared to 2 of 23 (9%) normotensive, genetically similar rats (Chi-square; P.001; Mantel-Haenszel common odds ratio estimate 12.33 [95% confidence interval 2.7-57.0]). Hemorrhage rates were comparable in aged and young chronically hypertensive animals. Induced acute hypertension during reperfusion did not appear to alter rates of transformation. In hypertensive (n = 26) compared to genetically similar normotensive (n = 12) animals, rt-PA treatment increased mortality to 35% from 0% (Chi-square; P.05), while hemorrhage occurred in 50% of the rt-PA-treated hypertensive subjects compared to 8% of the normotensive animals (Chi-square; P.05). Two different inhibitors of matrix metalloproteinases significantly reduced mortality but not hemorrhage rates.Our data suggest for the first time an effect of chronic hypertension separate from age on the risk of hemorrhagic transformation. In addition, inhibitors of matrix metalloproteinases may protect the neurovascular unit directly, even without reducing hemorrhage risk. These findings will require additional research.

In 1995 two studies by the National Institute of Neurological Disorders and Stroke (NINDS) proved that intravenous tissue plasminogen activator (t-PA) was superior to placebo in patients with stroke of less than 3 hours' duration. The recently published European Cooperative Acute Stroke Study (ECASS) III introduced new patient selection criteria and treatment between 3 and 4.5 hours. Using these criteria, t-PA was shown effective at the later time window. Both analyses used the 3-month modified Rankin scale (mRS) score as main primary outcome. We sought to study the effect of applying the ECASS III selection criteria to the original NINDS cohort.We analyzed the subgroup of patients from NINDS sample who matched the ECASSS III criteria. We examined 3-month outcomes adjusted and unadjusted for confounding factors.The NINDS t-PA study included 624 patients. A total of 200 in the t-PA-treated group and 199 in the placebo group were selected after applying ECASS III criteria. Of these selected patients, 52% in the t-PA group versus 31% had mRS score of 0 or 1 at 3 months (P.001). The unadjusted odds ratio for t-PA treatment versus placebo on day-90 mRS score 0 to 1 versus 2 to 6 was 2.45 (95% confidence interval: 1.63-3.69). When adjusted for baseline National Institutes of Health Stroke Scale score, smoking status, time to treatment, and history of hypertension, the odds ratio was 2.14 (95% confidence interval: 1.34-3.41) (P.001).Using the ECASS III criteria in patients treated in less than 3 hours, 52% of t-PA-treated patients had a favorable outcome at 3 months.

Detection of atrial fibrillation (AF) after ischemic stroke is important because anticoagulation is indicated to reduce the risk of recurrent stroke. However, no consensus exists about the optimum method for detecting underlying paroxysmal AF not apparent on presentation with stroke. The aim of this study was to characterize the rate, timing, and predictors of delayed detection of AF after stroke.The Virtual International Stroke Trials Archive provided data from 3464 patients in the placebo arms of 4 clinical trials of therapies for acute ischemic stroke. Patients who had AF by history or on the baseline electrocardiogram were excluded. Electrocardiograms were obtained routinely and as clinically indicated. The time to detection of AF was evaluated using Kaplan-Meier survival statistics. Cox proportional hazards analysis was used to evaluate risk factors for AF.Among 2504 qualifying patients, AF was detected in 174 (6.9%; 95% confidence interval [CI] 6.0%-8.0%). In 68% of patients, AF was detected more than 48 hours after presentation. Detection of AF was associated with increasing age (hazard ratio [HR] 1.6/decade; 95% CI 1.4-1.9; P.005), female sex (HR 1.7; CI 1.2-2.4; P.005), congestive heart failure (HR 1.9; CI 1.1-3.4; P = .02), and the absence of hypertension (HR 1.6; CI 1.1-2.2; P = .01).Delayed detection of AF was common in this large cohort of patients carefully monitored after ischemic stroke. Current methods of screening may fail to detect underlying paroxysmal AF in a substantial proportion of patients.

During cerebral ischemia, there is excessive activity of excitatory amino acids, especially glutamate. Activation of glutamate receptors leads to a marked increase in intracellular calcium, which in turn leads to activation of intracellular enzymes and neuronal death--the so-called excitotoxic cascade. The calcium antagonist nimodipine, which acts at L-type calcium channels, was tested for a putative neuroprotectant effect in patients with acute ischemic stroke, but no beneficial effect was demonstrated. Glutamate receptors are attractive targets for neuroprotectant drugs because glutamate plays a central role in the excitotoxic cascade. Clinical trials of NMDA (N-methyl-D-aspartate) antagonists have been disappointing, however, and psychiatric side effects seem to be a general problem with this class of drug. Another strategy proposed for interfering with NMDA receptor function is the infusion of magnesium. The NMDA receptor is normally blocked by magnesium ions and will only respond to glutamate when this magnesium-induced block is removed on depolarization. A large clinical trial to investigate possible neuroprotection by magnesium is underway. The NMDA receptor also has a glycine-binding site and a polyamine-binding site, and the cation channel will only open in response to glutamate if glycine and polyamines are already bound to these obligatory modulatory sites. Gavestinel is selective for the glycine-binding site, and eliprodil for the polyamine site, but large international clinical trials have failed to find any beneficial effects in patients with acute ischemic stroke. Neurotoxic free radicals are also generated during cerebral ischemia. Laboratory stroke models suggest that free radical scavengers might be effective neuroprotectants. One of these, NXY-059, was effective in several animal studies, and preliminary studies in human subjects show that plasma concentrations that are neuroprotective in animal models can be achieved and are well tolerated. Lubeluzole interferes with the glutamate-induced neuronal damage mediated through the formation of nitric oxide. However, a meta-analysis of all clinical trials of lubeluzole was unable to detect a neuroprotectant effect of the drug. There is now some evidence that, in addition to necrosis, some neurons die as a result of apoptosis after cerebral ischemia. Several drugs that interfere with the apoptosis cascade, for example, caspase inhibitors, are under investigation. Clomethiazole ('ZENDRA'; a trademark, the property of the AstraZeneca group of companies) is also undergoing a second large clinical trial in patients with major ischemic strokes. This drug's mechanism of action is not completely clear, but it is known to activate a nonbenzodiazepine site on the GABA(A) (gamma-aminobutyric acid) receptor. This causes increased chloride conductance and hyperpolarization. In vitro clomethiazole inhibits ischemia-induced glutamate efflux from cerebral neurons. The first large controlled trial showed it to be well tolerated and suggested a clinically significant effect in patients with deficits of a major stroke.