Moléculas inflamatorias y marcadores de lesión endotelial en la isquemia cerebral : participación en el deterioro neurológico y la transformación hemorrágiaca

Consultable des del TDXTítol obtingur de la portada digitalitzadaLos mecanismos implicados en el deterioro neurológico precoz (DNP) y en la transformación hemorrágica (TH) de la lesión isquémica cerebral no se conocen con exactitud. Estudios previos habían demostrado la asociación de niveles elevados de TNF-a e IL-6 con el DNP en pacientes con isquemia cerebral independientemente del mecanismo ictal. Sin embargo, los mecanismos relacionados con el DNP en pacientes con infarto lacunar no se conocían con exactitud. Con el objetivo de determinar si los mecanismos inflamatorios participaban en la progresión y el pronóstico funcional de estos pacientes se determinaron los niveles de TNF-a, IL-6 e ICAM-1 en el momento del ingreso en 113 pacientes con ictus lacunar de 14 pg/mL y de ICAM-1 > 208 pg/mL se asociaban de manera independiente tanto con el DNP como con el mal pronóstico funcional evaluado a los 3 meses. En cuanto a la TH, se había demostrado la asociación de niveles elevados de MMP-9 y la aparición de TH exclusivamente en pacientes con ictus de mecanismo cardioembólico por lo que se analizaron los niveles de esta molécula en 250 pacientes con ictus hemisférico de 14 pg/mL and ICAM-1 > 208 pg/mL were independently associated with both END and poor outcome at 3 months. On the other hand, the association between high levels of matrix metaloproteinase-9 (MMP-9) and secondary bleeding in patients with cardiembolic ischemic stroke had been already published. However, there were no data about the HT predictive capacity of MMP-9 in patients with other stroke subtypes. The association between high levels of MMP-9 and the development of HT was determined in 250 patients with hemispheric ischemic stroke within the first 24 hours of symptoms' onset. The results demonstrated that those patients with HT had significantly higher levels of MMP-9 at admission compared to those without secondary bleeding. Logistic regression analysis showed that MMP-9 levels ≥ 140 ng/mL were independently associated with HT after adjustment for potential confounders. Moreover, MMP-9 levels ≥ 140 ng/mL predicted the development of HT with a sensitivity, especificity, negative predictive value (NPV) and positive predictive value (PPV) of 87%, 90%, 61% and 97%, respectively. Finally, the association between the levels of cellular-Fibronectin (c-Fn), taken as a more specific marker of endothelial damage, and the development of HT in 87 patients who received thrombolytic treatment with rt-PA was evaluated. In order to compare the predictive capacity of MMP-9 and c-Fn levels, the levels of MMP-9 were also analyzed in this group of patients. The results demonstrated that patients with HT had significantly higher c-Fn as well as MMP-9 levels before the administration of the treatment. The levels of c-Fn were also higher in patients with symptomatic HT whereas no differences were found in MMP-9 levels between symptomatic and asymptomatic HT. Logistic regression analysis showed that c-Fn levels was the only variable associated with HT development after adjustment of potential confounders, which included MMP-9 levels. Levels of c-Fn ≥ 3.6 µg/mL predicted the development of hemorrhagic infarction type 2 and parenchymal hemorrhage (types of HT that has been reported to occur more often in patients treated with rt-PA) with a sensitivity of 100%, specificity of 96%, NPV of 44% and PPV of 100%, whereas the sensitivity, specificity, NPV and PPV of MMP-9 levels ≥ 140 ng/mL were 81%, 88%, 41% and 98%, respectively. These results were observed both in patients treated within 6 hours and within 3 hours from symptoms' onset. In conclusion, the results suggest that inflammation contributes to brain injury in patients with lacunar stroke and confirm that high plasma MMP-9 concentration is an independent predictor of HT in patients with acute ischemic stroke. Moreover, high plasma c-Fn levels are significantly associated with subsequent HT in stroke patients treated with rt-PA, so plasma c-Fn determinations might be useful in clinical practice to improve the risk/benefit ratio of thrombolytic treatment

Consensus document for lipid profile determination and reporting in Spanish clinical laboratories

Las enfermedades cardiovasculares (ECV) siguen siendo la principal causa de muerte en nuestro país. El control adecuado de las alteraciones del metabolismo lipídico es un reto clave en prevención cardiovascular que está lejos de alcanzarse en la práctica clínica real. Existe una gran heterogeneidad en los informes del metabolismo lipídico de los laboratorios clínicos españoles, lo que puede contribuir al mal control del mismo. Por ello, un grupo de trabajo de las principales sociedades científicas implicadas en la atención de los pacientes de riesgo vascular hemos elaborado este documento con una propuesta básica de consenso sobre la determinación del perfil lipídico básico en prevención cardiovascular, recomendaciones para su realización y unificación de criterios para incorporar los objetivos de control lipídico adecuados al riesgo vascular de los pacientes en los informes de laboratorio.Cardiovascular diseases (CVD) continue to be the main cause of death in our country. Adequate control of lipid metabolism disorders is a key challenge in cardiovascular prevention that is far from being achieved in real clinical practice. There is a great heterogeneity in the reports of lipid metabolism from Spanish clinical laboratories, which may contribute to its poor control. For this reason, a working group of the main scientific societies involved in the care of patients at vascular risk, has prepared this document with a consensus proposal on the determination of the basic lipid profile in cardiovascular prevention, recommendations for its realization and unification of criteria to incorporate the lipid control goals appropriate to the vascular risk of the patients in the laboratory reports

Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data

Background: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers. Methods: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0–1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0–2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4–6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903. Findings: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10–2·03]; p=0·011), with low heterogeneity across studies (I2=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05–1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06–2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4–6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52–1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03–4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [<1%], adjusted OR 5·58 [1·22–25·50]; p=0·024). Interpretation: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death. Funding: None

Moléculas inflamatorias y marcadores de lesión endotelial en la isquemia cerebral: participación en el deterioro neurológico y la transformación hemorrágica

Los mecanismos implicados en el deterioro neurológico precoz (DNP) y en la transformación hemorrágica (TH) de la lesión isquémica cerebral no se conocen con exactitud. Estudios previos habían demostrado la asociación de niveles elevados de TNF-a e IL-6 con el DNP en pacientes con isquemia cerebral independientemente del mecanismo ictal. Sin embargo, los mecanismos relacionados con el DNP en pacientes con infarto lacunar no se conocían con exactitud. Con el objetivo de determinar si los mecanismos inflamatorios participaban en la progresión y el pronóstico funcional de estos pacientes se determinaron los niveles de TNF-a, IL-6 e ICAM-1 en el momento del ingreso en 113 pacientes con ictus lacunar de 14 pg/mL y de ICAM-1 > 208 pg/mL se asociaban de manera independiente tanto con el DNP como con el mal pronóstico funcional evaluado a los 3 meses. En cuanto a la TH, se había demostrado la asociación de niveles elevados de MMP-9 y la aparición de TH exclusivamente en pacientes con ictus de mecanismo cardioembólico por lo que se analizaron los niveles de esta molécula en 250 pacientes con ictus hemisférico de 14 pg/mL and ICAM-1 > 208 pg/mL were independently associated with both END and poor outcome at 3 months. On the other hand, the association between high levels of matrix metaloproteinase-9 (MMP-9) and secondary bleeding in patients with cardiembolic ischemic stroke had been already published. However, there were no data about the HT predictive capacity of MMP-9 in patients with other stroke subtypes. The association between high levels of MMP-9 and the development of HT was determined in 250 patients with hemispheric ischemic stroke within the first 24 hours of symptoms' onset. The results demonstrated that those patients with HT had significantly higher levels of MMP-9 at admission compared to those without secondary bleeding. Logistic regression analysis showed that MMP-9 levels ≥ 140 ng/mL were independently associated with HT after adjustment for potential confounders. Moreover, MMP-9 levels ≥ 140 ng/mL predicted the development of HT with a sensitivity, especificity, negative predictive value (NPV) and positive predictive value (PPV) of 87%, 90%, 61% and 97%, respectively. Finally, the association between the levels of cellular-Fibronectin (c-Fn), taken as a more specific marker of endothelial damage, and the development of HT in 87 patients who received thrombolytic treatment with rt-PA was evaluated. In order to compare the predictive capacity of MMP-9 and c-Fn levels, the levels of MMP-9 were also analyzed in this group of patients. The results demonstrated that patients with HT had significantly higher c-Fn as well as MMP-9 levels before the administration of the treatment. The levels of c-Fn were also higher in patients with symptomatic HT whereas no differences were found in MMP-9 levels between symptomatic and asymptomatic HT. Logistic regression analysis showed that c-Fn levels was the only variable associated with HT development after adjustment of potential confounders, which included MMP-9 levels. Levels of c-Fn ≥ 3.6 µg/mL predicted the development of hemorrhagic infarction type 2 and parenchymal hemorrhage (types of HT that has been reported to occur more often in patients treated with rt-PA) with a sensitivity of 100%, specificity of 96%, NPV of 44% and PPV of 100%, whereas the sensitivity, specificity, NPV and PPV of MMP-9 levels ≥ 140 ng/mL were 81%, 88%, 41% and 98%, respectively. These results were observed both in patients treated within 6 hours and within 3 hours from symptoms' onset. In conclusion, the results suggest that inflammation contributes to brain injury in patients with lacunar stroke and confirm that high plasma MMP-9 concentration is an independent predictor of HT in patients with acute ischemic stroke. Moreover, high plasma c-Fn levels are significantly associated with subsequent HT in stroke patients treated with rt-PA, so plasma c-Fn determinations might be useful in clinical practice to improve the risk/benefit ratio of thrombolytic treatment

Inhibidores de la proproteína convertasa subtilisina/kexina tipo 9 (iPCSK9) en la prevención secundaria de episodios vasculares en pacientes con ictus isquémico: Documento de consenso y aplicaciones prácticas

Introducción Los pacientes, tras un ictus o un ataque isquémico transitorio, presentan un riesgo muy elevado de sufrir nuevos episodios vasculares. La reducción del nivel de colesterol unido a lipoproteínas de baja densidad (cLDL) reduce la incidencia de nuevos episodios, si bien una proporción importante de pacientes no alcanza los objetivos terapéuticos recomendados con los tratamientos hipolipemiantes actuales. El objetivo de este documento de consenso es actualizar el papel de los inhibidores de la proproteína convertasa subtilisina/kexina tipo 9 (iPCSK9; alirocumab y evolocumab) en la prevención secundaria de episodios vasculares en pacientes con ictus isquémico previo. Métodos Se realizó una revisión bibliográfica para identificar las principales evidencias sobre el uso de iPCSK9 en estos pacientes y los objetivos terapéuticos recomendados de cLDL. Los resultados se discutieron en 2 reuniones de consenso, que constituyeron la base para la elaboración del documento. Conclusiones Los iPSCSK9 son eficaces en la reducción del riesgo vascular en prevención secundaria y, específicamente, evolocumab ha demostrado esta reducción en pacientes con ictus isquémico previo. Ambos fármacos han demostrado un buen perfil de seguridad, incluso en pacientes que alcanzaron un nivel de cLDL < 20 mg/dL. En este sentido, en el subestudio de episodios neurocognitivos con evolocumab no se observó ninguna señal de empeoramiento de la función cognitiva en pacientes con nivel muy bajo de cLDL. Con base en estas evidencias, en el documento se presentan recomendaciones prácticas sobre el uso de iPCSK9 para la prevención secundaria y seguimiento de episodios vasculares en pacientes con ictus isquémico previo

Acute damage to the posterior limb of the internal capsule on diffusion tensor tractography as an early imaging predictor of motor outcome after stroke

BACKGROUND AND PURPOSE: Early prediction of motor outcome is of interest in stroke management. We aimed to determine whether lesion location at DTT is predictive of motor outcome after acute stroke and whether this information improves the predictive accuracy of the clinical scores. MATERIALS AND METHODS: We evaluated 60 consecutive patients within 12 hours of middle cerebral artery stroke onset. We used DTT to evaluate CST involvement in the motor cortex and premotor cortex, centrum semiovale, corona radiata, and PLIC and in combinations of these regions at admission, at day 3, and at day 30. Severity of limb weakness was assessed by using the motor subindex scores of the National Institutes of Health Stroke Scale (5a, 5b, 6a, 6b). We calculated volumes of infarct and fractional anisotropy values in the CST of the pons. RESULTS: Acute damage to the PLIC was the best predictor associated with poor motor outcome, axonal damage, and clinical severity at admission (P < .001). There was no significant correlation between acute infarct volume and motor outcome at day 90 (P = .176, r = 0.485). The sensitivity, specificity, and positive and negative predictive values of acute CST involvement at the level of the PLIC for motor outcome at day 90 were 73.7%, 100%, 100%, and 89.1%, respectively. In the acute stage, DTT predicted motor outcome at day 90 better than the clinical scores (R2 = 75.50, F = 80.09, P < .001). CONCLUSIONS: In the acute setting, DTT is promising for stroke mapping to predict motor outcome. Acute CST damage at the level of the PLIC is a significant predictor of unfavorable motor outcom

Quantification of thrombus Hounsfield units on noncontrast CT predicts stroke subtype and early recanalization after intravenous recombinant tissue plasminogen activator

BACKGROUND AND PURPOSE: Little is known about the factors that determine recanalization after intravenous thrombolysis. We assessed the value of thrombus Hounsfield unit quantification as a predictive marker of stroke subtype and MCA recanalization after intravenous rtPA treatment. MATERIALS AND METHODS: NCCT scans and CTA were performed on patients with MCA acute stroke within 4.5 hours of symptom onset. Demographics, stroke severity, vessel hyperattenuation, occlusion site, thrombus length, and time to thrombolysis were recorded. Stroke origin was categorized as LAA, cardioembolic, or indeterminate according to TOAST criteria. Two blinded neuroradiologists calculated the Hounsfield unit values for the thrombus and contralateral MCA segment. We used ROC curves to determine the rHU cutoff point to discriminate patients with successful recanalization from those without. We assessed the accuracy (sensitivity, specificity, and positive and negative predictive values) of rHU in the prediction of recanalization. RESULTS: Of 87 consecutive patients, 45 received intravenous rtPA and only 15 (33.3%) patients had acute recanalization. rHU values and stroke mechanism were the highest predictive factors of recanalization. The Matthews correlation coefficient was highest for rHU (0.901). The sensitivity, specificity, and positive and negative predictive values for lack of recanalization after intravenous rtPA for rHU ≤ 1.382 were 100%, 86.67%, 93.75%, and 100%, respectively. LAA thrombi had lower rHU than cardioembolic and indeterminate stroke thrombi (P = .004). CONCLUSIONS: The Hounsfield unit thrombus measurement ratio can predict recanalization with intravenous rtPA and may have clinical utility for endovascular treatment decision making

Impact of COVID-19 outbreak on ischemic stroke admissions and in-hospital mortality in North-West Spain

Background and purpose Spain has been one of the countries heavily stricken by COVID-19. But this epidemic has not affected all regions equally. We analyzed the impact of the COVID-19 pandemic on hospital stroke admissions and in-hospital mortality in tertiary referral hospitals from North-West Spain.Methods Spanish multicenter retrospective observational study based on data from tertiary hospitals of the NORDICTUS network. We recorded the number of patients admitted for ischemic stroke between 30 December 2019 and 3 May 2020, the number of IVT and EVT procedures, and in-hospital mortality.Results In the study period, 2737 patients were admitted with ischemic stroke. There was a decrease in the weekly mean admitted patients during the pandemic (124 vs. 173, p<0.001). In-hospital mortality of stroke patients increased significantly (9.9% vs. 6.5%, p = 0.003), but there were no differences in the proportion of IVT (17.3% vs. 16.1%, p = 0.405) or EVT (22% vs. 23%, p = 0.504).Conclusion We found a decrease in the number of ischemic stroke admissions and an increase in in-hospital mortality during the COVID-19 epidemic in this large study from North-West Spain. There were regional changes within the network, not fully explained by the severity of the pandemic in different regions.Peer reviewe

Wallerian degeneration in the corticospinal tract evaluated by diffusion tensor imaging correlates with motor deficit 30 days after middle cerebral artery ischemic stroke

BACKGROUND AND PURPOSE: The quantification and clinical significance of WD in CSTs following supratentorial stroke are not well understood. We evaluated the anisotropy by using DTI and signalintensity changes on conventional MR imaging in the CST to determine whether these findings are correlated with limb motor deficit in patients with MCA ischemic stroke. MATERIALS AND METHODS: We studied 60 patients within 12 hours of stroke onset. At admission, day 3, and day 30 of evolution, patients underwent multimodal MR imaging, including DTI sequences. We assessed the severity of limb weakness by using the motor subindex scores (5a, 5b, 6a, 6b) of the m-NIHSS and established 3 groups: I (m-NIHSS scores of 0), II (m-NIHSS, 1-4), and III (m-NIHSS, 5-8). FA values and rFAs were measured on the affected and the unaffected CSTs in the pons. RESULTS: FA values for the CST were significantly lower on the affected side compared with the unaffected side only at day 30 (P < .001), and the rFA was significantly correlated with the motor deficit at day 30 (P < .001; r=-0.793). The sensitivity, specificity, and positive and negative predictive values for motor deficit by rFA < 0.925 were 95.2%, 94.9%, 90.9%, and 97.4%, respectively. CONCLUSIONS: WD in the CST revealed by DTI correlates with motor deficit 30 days after MCA ischemic stroke. This study highlights the utility of imaging follow-up at 30 days and the potential of DTI as a surrogate marker in clinical trial