Lipid-Lowering Therapy and Hemorrhagic Stroke Risk: Comparative Meta-Analysis of Statins and PCSK9 Inhibitors.

Background and Purpose: Statins were shown to increase hemorrhagic stroke (HS) in patients with a first cerebrovascular event in 2006 (SPARCL), likely due to off-target antithrombotic effects, but continued to sometimes be used in patients with elevated HS risk due to absence of alternative medications. Recently, the PCSK9Is (proprotein convertase subtilisin kexin 9 inhibitors) have become available as a potent lipid-lowering class with potentially less hemorrhagic propensity. Methods: We performed a systematic comparative meta-analysis assessing HS rates across all completed statin and PCSK9I randomized clinical trials with treatment >3 months, following PRISMA guidelines. In addition to HS rates across all trials, causal relation was probed by evaluating for dose-response relationships by medication (low versus high medication dose/potency) and by presence and type of preceding brain vascular events at inception (none versus ischemic stroke/transient ischemic attack versus HS). Results: The systematic review identified 36 statin randomized clinical trials (204 918 patients) and 5 PCSK9I randomized clinical trials (76 140 patients). Across all patient types and all medication doses/potencies, statins were associated with increased HS: relative risk 1.15, P=0.04; PCSK9Is were not (P=0.77). In the medication dose/potency analysis, higher dose/potency statins (7 trials, 62 204 patients) were associated with magnified HS risk: relative risk, 1.53; P=0.002; higher dose/potency PCSK9Is (1 trial, 27 564 patients) were not (P=0.99). In the type of index brain vascular injury analysis for statins (5 trials, 9772 patients), prior ischemic stroke/transient ischemic attack was associated with a magnified risk of HS: relative risk, 1.43; P=0.04; and index intracerebral hemorrhage was associated with an extremely high effect estimate of risk of recurrent HS: hazard ratio, 4.06. For PCSK9Is, prior ischemic stroke/transient ischemic attack (1 trial, 5337 patients) was not associated with increased HS risk (P=0.97). Conclusions: Statins increase the risk of HS in a medication dose- and type of index brain vascular injury-dependent manner; PCSK9Is do not increase HS risk. PCSK9Is may be a preferred lipid-lowering medication class in patients with elevated HS risk, including patients with prior HS.

Occipital Condyle Syndrome: A Red Flag for Malignancy. Comprehensive Literature Review and New Case Report.

OBJECTIVE: To perform a literature review of the epidemiology, clinical presentation, diagnostic evaluation, and clinical course of occipital condyle syndrome, including a new case report. BACKGROUND: Occipital condyle syndrome (OCS) is a rare clinical syndrome, consisting of unilateral occipital headache accompanied by ipsilateral hypoglossal palsy. This headache typically radiates to the temporal region, and is triggered by contralateral head rotation. It is usually associated with skull base metastasis, often unrevealed in basic neuroimaging studies. OCS might be the first manifestation of malignancy, and its unfamiliarity can lead to a delay in the diagnosis. METHODS: We performed a systematic literature review using PubMed and Embase for OCS, along with a new case report. RESULTS: A total of 35 cases (mean age 59 years, range 25-77), 24 (70%) men, presented typical unilateral headache followed by ipsilateral hypoglossal palsy from 0 to 150 days after headache presentation. In 16 patients (46%), initial neuroimaging studies were normal. OCS was due to skull base metastasis in 32 cases (91%). In 18 patients (51%), OCS was the first symptom of disease. CONCLUSIONS: OCS represents a warning sign and requires an exhaustive search for underlying neoplasm. An appropriate clinical evaluation can lead to an earlier diagnosis in patients with consistent headache.

Alberta Stroke Program Early CT Score applied to CT angiography source images is a strong predictor of futile recanalization in acute ischemic stroke.

INTRODUCTION: Reliable predictors of poor clinical outcome despite successful revascularization might help select patients with acute ischemic stroke for thrombectomy. We sought to determine whether baseline Alberta Stroke Program Early CT Score (ASPECTS) applied to CT angiography source images (CTA-SI) is useful in predicting futile recanalization. METHODS: Data are from the FUN-TPA study registry (ClinicalTrials.gov; NCT02164357) including patients with acute ischemic stroke due to proximal arterial occlusion in anterior circulation, undergoing reperfusion therapies. Baseline non-contrast CT and CTA-SI-ASPECTS, time-lapse to image acquisition, occurrence, and timing of recanalization were recorded. Outcome measures were NIHSS at 24 h, symptomatic intracranial hemorrhage, modified Rankin scale score, and mortality at 90 days. Futile recanalization was defined when successful recanalization was associated with poor functional outcome (death or disability). RESULTS: Included were 110 patients, baseline NIHSS 17 (IQR 12; 20), treated with intravenous thrombolysis (IVT; 45 %), primary mechanical thrombectomy (MT; 16 %), or combined IVT + MT (39 %). Recanalization rate was 71 %, median delay of 287 min (225; 357). Recanalization was futile in 28 % of cases. In an adjusted model, baseline CTA-SI-ASPECTS was inversely related to the odds of futile recanalization (OR 0.5; 95 % CI 0.3-0.7), whereas NCCT-ASPECTS was not (OR 0.8; 95 % CI 0.5-1.2). A score ≤5 in CTA-SI-ASPECTS was the best cut-off to predict futile recanalization (sensitivity 35 %; specificity 97 %; positive predictive value 86 %; negative predictive value 77 %). CONCLUSIONS: CTA-SI-ASPECTS strongly predicts futile recanalization and could be a valuable tool for treatment decisions regarding the indication of revascularization therapies.

Effect of anticoagulation on cardioembolic stroke severity, outcomes and response to intravenous thrombolysis.

Our objective was to evaluate the effect of anticoagulation on cardioembolic stroke (CS) severity, outcomes, and response to intravenous thrombolysis (IVT). Observational study of CS patients admitted to a Stroke Center (2010-2013). The sample was classified into three groups based on pre-stroke oral anticoagulants (OAC) treatment (all acenocumarol) and the international normalized ratio (INR) on admission: (1) non-anticoagulated or anticoagulated patients with INR <1.5, (2) anticoagulated with INR 1.5-1.9 and (3) anticoagulated with INR ≥2. We compared demographic data, vascular risk factors, symptomatic intracranial hemorrhage, severity on admission (NIHSS) and 3 month outcomes (mRS). Overall 475 patients were included, 47.2 % male, mean age 75.5 (SD 10.7) years old, 31.8 % were on OAC. 76 % belonged to the INR <1.5 group, 13.3 % to the INR 1.5-1.9 and 10.5 % to the INR >2. 35 %of patients received IVT. Multivariate analyses showed that an INR ≥2 on admission was a factor associated with a higher probability of mild stroke (NIHSS <10) (OR 2.026, 95 % CI 1.006-4.082). Previous OAC in general (OR 2.109, 95 % CI 1.173-3.789) as well as INR 1.5-1.9 (OR 3.676, 95 % CI 1.510-8.946) were associated with favorable outcomes (mRS ≤2). OAC was not related to stroke outcomes in the subgroup of IVT patients. Therapeutic OAC levels are associated with lesser CS severity, and prior OAC treatment with favorable outcomes. In this study, OAC are not related with response to IVT.

Comparison between xenogeneic and allogeneic adipose mesenchymal stem cells in the treatment of acute cerebral infarct: proof of concept in rats.

BACKGROUND: Rat adipose tissue-derived-mesenchymal stem cells (rAD-MSCs) have proven to be safe in experimental animal models of stroke. However, in order to use human AD-MSCs (hAD-MSCs) as a treatment for stroke patients, a proof of concept is needed. We analyzed whether the xenogeneic hAD-MSCs were as safe and effective as allogeneic rAD-MSCs in permanent Middle Cerebral Artery Occlusion (pMCAO) in rats. METHODS: Sprague-Dawley rats were randomly divided into three groups, which were intravenously injected with xenogeneic hAD-MSCs (2 × 10(6)), allogeneic rAD-MSCs (2 × 10(6)) or saline (control) at 30 min after pMCAO. Behavior, cell implantation, lesion size and cell death were evaluated. Brain markers such as GFAP (glial fibrillary acid protein), VEGF (vascular endothelial growth factor) and SYP (synaptophysin) and tumor formation were analyzed. RESULTS: Compared to controls, recovery was significantly better at 24 h and continued to be so at 14 d after IV administration of either hAD-MSCs or rAD-MSCs. No reduction in lesion size or migration/implantation of cells in the damaged brain were observed in the treatment groups. Nevertheless, cell death was significantly reduced with respect to the control group in both treatment groups. VEGF and SYP levels were significantly higher, while those of GFAP were lower in the treated groups. At three months, there was no tumor formation. CONCLUSIONS: hAD-MSCs and rAD-MSCs were safe and without side effects or tumor formation. Both treatment groups showed equal efficacy in terms of functional recovery and decreased ischemic brain damage (cell death and glial scarring) and resulted in higher angiogenesis and synaptogenesis marker levels.

Intravenous thrombolysis in stroke patients under 55 years of age: is there a different effect according to etiology and severity?

The effect of intravenous thrombolysis (IVT) according to etiology and stroke severity in young patients with ischemic stroke (IS) has not been described previously. To analyze the effect of IVT in young patients with IS according to etiological subtype and stroke severity. Observational study with inclusion of IS patients under 55 years of age (2007-2012). Two groups were compared according to IVT treatment. Favorable outcomes were defined as 3 months modified Rankin Scale ≤2. Multivariate analyses were performed to determine those factors independently associated with favorable outcomes, and subgroup analyses were conducted to assess the effect of IVT according to etiological stroke subtype and severity on admission, adjusted for other prognostic variables. We evaluated 262 patients. 63 (24%) received IVT. The mean age and the sex distribution were similar in the IVT treated and the non-treated groups. Multivariate analyses showed that IVT was associated with a higher probability of favorable outcome (OR, 95% CI: 4.652, 1.294-16.722) whereas artery dissection (OR, 95% CI: 0.191, 0.056-0.654) and NIHSS (OR, 95% CI: 0.727, 0.664-0.797) were associated with a lower probability of a favorable outcome. The subgroup analysis showed that the beneficial effect of IVT on outcomes was significant in moderate-severe strokes (NIHSS ≥8) (OR, 95% CI: 3.782, 1.095-13.069) and in cardioembolism (OR, 95% CI: 41.887, 1.001-1751.596). In IS patients under 55 years of age, those with moderate-severe strokes benefit more from IVT than those with mild strokes. Cardioembolic infarctions may benefit more from IV tPA than other etiologies.

Acute ischemic stroke patients with diabetes should not be excluded from intravenous thrombolysis.

The benefit of intravenous thrombolysis (IVT) has been questioned for patients with diabetes mellitus (DM) in cases of acute ischemic stroke (IS). Our objective was to analyze the differences in outcome according to prior diagnosis of DM and the use or not of IVT. Observational study with inclusion of consecutive IS patients admitted to an stroke unit. Demographic data, vascular risk factors, comorbidity, stroke severity and 3-month follow-up outcome (modified Rankin Scale) were compared according to prior diagnosis of DM and the use or not of IVT. A total of 1,139 IS patients were admitted; 283 (24.8%) patients had a diagnosis of DM, and 261 were IVT treated (23.2% of the group without DM and 21.9% of the DM group). The IVT-treated patients with DM were older, had more comorbidities and had higher glucose levels on admission than those without DM and than IVT-treated patients. No significant differences in stroke severity, hemorrhagic transformation, in-hospital mortality or outcome at 3 months were found. The logistic regression analysis showed that stroke severity was associated with a higher risk of a poor outcome in IVT-treated patients, with no significant effect from DM after adjustment for confounders. Moreover, IVT was independently associated with a lower risk of poor outcome in DM patients (OR 0.49; 95% CI 0.31-0.76; P = .002). DM patients should not be excluded from IVT, because DM is not associated with a poor outcome after IVT and this treatment is clearly beneficial for DM patients as compared with DM patients not treated with IVT.

Mechanical thrombectomy in patients with medical contraindications for intravenous thrombolysis: a prospective observational study.

BACKGROUND AND PURPOSE: The present study was conducted with the objective of evaluating the safety of primary mechanical thrombectomy (MT) in patients with large vessel occlusion (LVO) stroke and comorbidities that preclude treatment with IV thrombolysis (IVT), compared with patients who received standard IVT treatment followed by MT. Secondary objectives were to analyse the recanalization rate and outcomes. METHODS: A prospective observational multicenter study (FUN-TPA) that recruited patients treated within 4.5 hours of symptom onset was performed. Treatments were IVT followed by MT if occlusion persisted, or primary MT when IVT was contraindicated. Outcome measures were procedural complications, symptomatic intracranial hemorrhage (SICH), recanalization rate, National Institutes of Health Stroke Scale (NIHSS) score at 7 days, modified Rankin Scale (mRS) score and mortality at 90 days. RESULTS: Of 131 patients, 21 (16%) had medical contraindications for IVT and were treated primarily with MT whereas 110 (84%) underwent IVT, followed by MT in 53 cases (40%). The recanalization rate and procedural complications were similar in the two groups. There were no SICHs after primary MT vs 3 (6%) after IVT+MT. Nine patients (43%) in the primary MT group achieved independence (mRS 0-2) compared with 36 (68%) in the IVT+MT group (p=0.046). Mortality rates in the two groups were 14% (n=3) vs 4% (n=2) (p=0.13). Adjusted ORs for independence in patients receiving standard IVT+MT vs MT in patients with medical contraindications for IVT were 2.8 (95% CI 0.99 to 7.98) and 0.24 (95% CI 0.04 to 1.52) for mortality. CONCLUSIONS: MT is safe in patients with potential comorbidity-derived risks that preclude IVT. MT should be offered, aiming for prompt recanalization, to patients with LVO stroke unsuitable for IVT. TRIAL REGISTRATION NUMBER: NCT02164357; Results.

DCE-MRI blood-brain barrier assessment in acute ischemic stroke.

OBJECTIVE: To quantitatively evaluate blood-brain barrier changes in ischemic stroke patients using dynamic contrast-enhanced (DCE) MRI. METHODS: We examined 54 stroke patients (clinicaltrials.gov NCT00715533, NCT02077582) in a 3T MRI scanner within 48 hours after symptom onset. Twenty-eight patients had a follow-up examination on day 5-7. DCE T1 mapping and Patlak analysis were employed to assess BBB permeability changes. RESULTS: Median stroke Ktrans values (0.7 × 10-3 min-1 [interquartile range (IQR) 0.4-1.8] × 10-3 min-1) were more than 3-fold higher compared to median mirror Ktrans values (0.2 × 10-3 min-1, IQR 0.1-0.7 × 10-3 min-1, p < 0.001) and further increased at follow-up (n = 28, 2.3 × 10-3 min-1, IQR 0.8-4.6 × 10-3 min-1, p < 0.001). By contrast, mirror Ktrans values decreased over time with a clear interaction of timepoint and stroke/mirror side (p < 0.001). Median stroke Ktrans values were 2.5 times lower than in hemorrhagic transformed regions (0.7 vs 1.8 × 10-3 min-1; p = 0.055). There was no association between stroke Ktrans values and the delay from symptom onset to baseline examination, age, and presence of hyperintense acute reperfusion marker. CONCLUSION: BBB in acute stroke patients can be successfully assessed quantitatively. The decrease of BBB permeability in unaffected regions at follow-up may be an indicator of global BBB leakage even in vessel territories remote from the index infarct.

Can we improve the early detection of atrial fibrillation in a stroke unit? Detection rate of a monitor with integrated detection software.

INTRODUCTION: It is unknown whether monitors that include atrial fibrillation recognition software (AF-RS) increase the rate of early atrial fibrillation (AF) detection in acute stroke. We aimed to evaluate the AF detection rate of an AF-RS monitor and compare it with standard monitoring. METHODS: This was a retrospective, single-centre observational study conducted on consecutive patients with acute transient ischaemic attack or brain infarction attended in a stroke unit (SU) with six beds. Five beds had a standard monitor with a three-lead electrocardiogram (ECG)-tracing monitor that did not automatically detect AF, and one bed had a 12-lead ECG monitor with integrated AF-RS. All patients were monitored for at least 24 h and underwent a daily ECG during their stay in the SU. In case of unknown stroke aetiology, the patients underwent 24 h Holter monitoring. RESULTS: A total of 76 patients were included: 59 patients in the standard monitor group and 17 patients in the AF-RS monitor group. The mean age was 72.11 (±13.09) years, and 59.2% were men. A total of 20 new cases of AF were identified. The AF-RS monitor showed a higher rate of AF detection than the standard devices (57.1% vs 7.7%, p=0.031). The AF-RS monitor showed sensitivity, specificity, positive predictive value, and negative predictive values of 57.1%, 100%, 100% and 76.9%, respectively. For the standard monitors, these values were 7.7%, 100%, 100% and 79.3%, respectively. CONCLUSION: The monitor with AF-RS demonstrated a higher detection rate for AF than standard ECG monitoring in acute stroke patients in a SU.

Is diabetes an independent risk factor for in-hospital complications after a stroke? ？.

BACKGROUND: Patients with diabetes mellitus (DM) are more likely to develop in-hospital complications (IHCs) than patients without DM. In addition, they have poorer outcomes after an ischemic stroke (IS). Our goal was to evaluate whether the increase in risk for the development of IHCs in patients with IS is due to DM per se, to poor metabolic control of the DM or to glucose levels on admission. METHODS: An observational study that included 1137 consecutive IS patients admitted to a stroke unit. Demographic data, vascular risk factors, stroke severity, on-admission glycemia and IHC were compared between patients with and without DM. Multivariate logistic regression analyses were performed to identify factors associated with IHCs. RESULTS: Of all included patients, 283 (24.8%) had a previous diagnosis of DM. These patients were older and had higher comorbidity, with no differences in stroke severity. They presented on-admission glycemia ≥155 mg/dL more often and suffered IHCs more frequently (24% versus 17.7%, P = 0.034). However, after adjusting for baseline differences, DM was not associated with the development of any IHC, whereas on-admission glycemia ≥155 mg/dL (odds ratio: 1.959; 95% CI 1.276-3.009; P = 0.002) and stroke severity (odds ratio: 1.141; 95% CI 1.109-1.173; P < 0.001) were the primary predictors of the development of IHCs. CONCLUSIONS: Although IS patients with DM more often suffered IHCs, previous diagnosis of DM is not per se associated with the risk of IHCs. Stroke severity and on-admission glycemia ≥155 mg/dL were the most significant predictors for the development of IHCs.

The effect of telestroke systems among neighboring hospitals: more and better? The Madrid Telestroke Project.

A telestroke system was established between a community hospital lacking an on-call neurologist and a comprehensive stroke center only 13 km away. Our goal was to analyze the impact of telestroke on the number of intravenous thrombolysis (IVT), door-to-needle times and stroke outcomes. An observational before-and-after study of patients with acute ischemic stroke (IS) who were attended in a community hospital during the 2 years before the telestroke system was implemented (pre-telestroke group) and the first 2 years after telestroke was established (telestroke group). The number of IVT, the door-to-needle time (min), the outcomes [modified Rankin Scale (mRS)] and the safety (mortality and hemorrhagic transformations) were compared between groups. During the pre-telestroke years, 259 patients with IS were attended (28 phone activations), 12 of whom received IVT (4.7 %). During the telestroke years, 225 patients with IS were attended (42 telestroke activations), of whom 18 (8 %) received IVT. The door-to-needle times were lower in the telestroke group [median interquartile range: 66 (54) vs. 143.5 (48) min, P < 0.0001]. The safety was similar in both groups; however, the 3-month mRS scores were lower in the telestroke group (P = 0.049). The multiple linear regression analysis showed a negative association between telestroke and door-to-needle time [ß-coefficient (SE) = -59.089 (14.461)], adjusted for confounders. In conclusion, telestroke systems are effective, even between nearby hospitals, shortening door-to-needle time and improving stroke outcomes.

Treatment with statins and ischemic stroke severity: does the dose matter?

OBJECTIVE: To examine the effects of pretreatment with statins at high doses (40 mg of rosuvastatin or 80 mg of any other statin) and low to moderate doses (<40 mg of rosuvastatin or <80 mg of any other statin) on ischemic stroke (IS) severity in clinical practice. METHODS: Observational study of IS admissions to our stroke unit over a 3-year period (2008-2010). Mild stroke severity was defined as NIH Stroke Scale score ≤5 on admission. Multivariable regression models and matched propensity score analyses were used to quantify the association of statin pretreatment at high and low to moderate doses with mild stroke severity. RESULTS: Of the 969 IS patients, 23% were taking low to moderate doses and 4.1% were taking high doses of statins prior to the stroke. Statins were associated with lower NIHSS scores on admission (median [interquartile range] 4 [9] for nonstatin patients, 4 [9] for low to moderate doses of statins, and 2 [4] for high doses of statins; p = 0.010). After multivariable adjustment, pretreatment with statins was associated with a higher probability of mild stroke severity in the unmatched analysis (odds ratio [OR] = 1.637, 95% confidence interval [CI] 1.156-2.319 for the low to moderate doses and OR = 3.297, 95% CI 1.480-7.345 for the high doses of statins) as well as in the propensity score matched analysis (OR = 2.023, 95% CI 1.248-3.281 for the low to moderate doses and OR = 3.502, 95% CI 1.477-8.300 for the high doses of statins). CONCLUSION: Pretreatment with statins is associated with lower stroke severity, at high as well as at low to moderate doses.