RESUMEN
OBJECTIVE: Outcome prognostication unbiased by early care limitations (ECL) is essential for guiding treatment in patients presenting with intracerebral hemorrhage (ICH). The aim of this study was to determine whether the max-ICH (maximally treated ICH) Score provides improved and clinically useful prognostic estimation of functional long-term outcomes after ICH. METHODS: This multicenter validation study compared the prognostication of the max-ICH Score versus the ICH Score regarding diagnostic accuracy (discrimination and calibration) and clinical utility using decision curve analysis. We performed a joint investigation of individual participant data of consecutive spontaneous ICH patients (n = 4,677) from 2 retrospective German-wide studies (RETRACE I + II; anticoagulation-associated ICH only) conducted at 22 participating centers, one German prospective single-center study (UKER-ICH; nonanticoagulation-associated ICH only), and 1 US-based prospective longitudinal single-center study (MGH; both anticoagulation- and nonanticoagulation-associated ICH), treated between January 2006 and December 2015. RESULTS: Of 4,677 included ICH patients, 1,017 (21.7%) were affected by ECL (German cohort: 15.6% [440 of 2,377]; MGH: 31.0% [577 of 1,283]). Validation of long-term functional outcome prognostication by the max-ICH Score provided good and superior discrimination in patients without ECL compared with the ICH Score (area under the receiver operating curve [AUROC], German cohort: 0.81 [0.78-0.83] vs 0.74 [0.72-0.77], p < 0.01; MGH: 0.85 [0.81-0.89] vs 0.78 [0.74-0.82], p < 0.01), and for the entire cohort (AUROC, German cohort: 0.84 [0.82-0.86] vs 0.80 [0.77-0.82], p < 0.01; MGH: 0.83 [0.81-0.85] vs 0.77 [0.75-0.79], p < 0.01). Both scores showed no evidence of poor calibration. The clinical utility investigated by decision curve analysis showed, at high threshold probabilities (0.8, aiming to avoid false-positive poor outcome attribution), that the max-ICH Score provided a clinical net benefit compared with the ICH Score (14.1 vs 2.1 net predicted poor outcomes per 100 patients). INTERPRETATION: The max-ICH Score provides valid and improved prognostication of functional outcome after ICH. The associated clinical net benefit in minimizing false poor outcome attribution might potentially prevent unwarranted care limitations in patients with ICH. ANN NEUROL 2021;89:474-484.
Asunto(s)
Hemorragia Cerebral/fisiopatología , Hemorragia Cerebral Intraventricular/fisiopatología , Estado Funcional , Factores de Edad , Anciano , Anciano de 80 o más Años , Anticoagulantes/efectos adversos , Área Bajo la Curva , Hemorragia Cerebral/inducido químicamente , Hemorragia Cerebral/diagnóstico por imagen , Hemorragia Cerebral/terapia , Hemorragia Cerebral Intraventricular/inducido químicamente , Hemorragia Cerebral Intraventricular/diagnóstico por imagen , Hemorragia Cerebral Intraventricular/terapia , Técnicas de Apoyo para la Decisión , Femenino , Alemania , Escala de Coma de Glasgow , Humanos , Masculino , Persona de Mediana Edad , Mortalidad , Pronóstico , Curva ROC , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Estados Unidos , Privación de TratamientoRESUMEN
OBJECTIVES: Up to 41% of intracerebral hemorrhages (ICH) are considered cryptogenic despite a thorough investigation to determine etiology. Certain over-the-counter supplements may increase proclivity to bleeding, and we hypothesize that specifically vitamin E may have an association with ICH and acutely elevated serum levels of α-tocopherol. Our aim is to report 3 cases of recently admitted patients with hypervitaminosis E and otherwise cryptogenic ICH. METHODS: At our institution between January and December 2018, 179 patients were admitted with ICH with 73 imputed to be "cryptogenic" (without clear etiology as per Structural vascular lesions, Medication, Amyloid angiopathy, Systemic disease, Hypertension, or Undetermined and Hypertension, Amyloid angiopathy, Tumor, Oral anticoagulants, vascular Malformation, Infrequent causes, and Cryptogenic criteria). Of these, we found 3 (4.1%) clearly admitted to consistent use of vitamin E supplementation for which α-tocopherol levels were checked. We describe the clinical presentation and course of these patients and their etiologic and diagnostic evaluations including neuroimaging and α-tocopherol laboratory data. RESULTS: All patients in this series were consistently consuming higher than recommended doses of vitamin E and developed acute ICH. The first 2 patients both had subcortical (thalamic) intraparenchymal hemorrhages while the third had an intraventricular hemorrhage. Serum α-tocopherol levels in patient A, B, and C were elevated at 30.8, 46.7, and 23.3 mg/L, respectively (normal range 5.7-19.9 mg/L) with a mean of 33.6 mg/L. No clear alternate etiologies to their ICH could be conclusively determined despite thorough workups. CONCLUSIONS: In patients with cryptogenic ICH, clinicians should consider hypervitaminosis E and check serum α-tocopherol level during admission. Reviewing the patient's pharmacologic history, including over-the-counter supplements such as vitamin E, may help identify its association, and its avoidance in the future may mitigate risk. With its known vitamin K antagonism, hypo-prothrombinemic effect, cytochrome p-450 interaction, and antiplatelet activity, vitamin E may not be as benign as presumed. Its consumption in nonrecommended doses may increase ICH risk, which may be underestimated and under-reported.
Asunto(s)
Hemorragia Cerebral/inducido químicamente , Suplementos Dietéticos/envenenamiento , Accidente Cerebrovascular/inducido químicamente , Vitaminas/envenenamiento , alfa-Tocoferol/envenenamiento , Anciano , Hemorragia Cerebral/sangre , Hemorragia Cerebral/diagnóstico por imagen , Hemorragia Cerebral Intraventricular/sangre , Hemorragia Cerebral Intraventricular/inducido químicamente , Hemorragia Cerebral Intraventricular/diagnóstico por imagen , Humanos , Masculino , Persona de Mediana Edad , Ingesta Diaria Recomendada , Factores de Riesgo , Accidente Cerebrovascular/sangre , Accidente Cerebrovascular/diagnóstico por imagen , Vitaminas/sangre , alfa-Tocoferol/sangreRESUMEN
Neuroinflammation occurs after germinal matrix hemorrhage (GMH) and induces secondary brain injury. Interferon-α (IFN-α) has been shown to exert anti-inflammatory effects in infectious diseases via activating IFNAR and its downstream signaling. We aimed to investigate the anti-inflammatory effects of Recombinant human IFN-α (rh-IFN-α) and the underlying mechanisms in a rat GMH model. Two hundred and eighteen P7 rat pups of both sexes were subjected to GMH by an intraparenchymal injection of bacterial collagenase. Rh-IFN-α was administered intraperitoneally. Small interfering RNA (siRNA) of IFNAR, and siRNA of tumor necrosis factor receptor associated factor 3 (TRAF3) were administered through intracerebroventricular (i.c.v.) injections. JAK1 inhibitor ruxolitinib was given by oral lavage. Post-GMH evaluation included neurobehavioral function, Nissl staining, Western blot analysis, and immunofluorescence. Our results showed that endogenous IFN-α and phosphorylated IFNAR levels were increased after GMH. Administration of rh-IFN-α improved neurological functions, attenuated neuroinflammation, inhibited microglial activation, and ameliorated post-hemorrhagic hydrocephalus after GMH. These observations were concomitant with IFNAR activation, increased expression of phosphorylated JAK1, phosphorylated STAT1 and TRAF3, and decreased levels of phosphorylated NF-κB, IL-6 and TNF-α. Specifically, knockdown of IFNAR, JAK1 and TRAF3 abolished the protective effects of rh-IFN-α. In conclusion, our findings demonstrated that rh-IFN-α treatment attenuated neuroinflammation, neurological deficits and hydrocephalus formation through inhibiting microglial activation after GMH, which might be mediated by IFNAR/JAK1-STAT1/TRAF3/NF-κB signaling pathway. Rh-IFN-α may be a promising therapeutic agent to attenuate brain injury via its anti-inflammatory effect.
Asunto(s)
Hemorragia Cerebral Intraventricular/inmunología , Interferón-alfa/metabolismo , Neuroinmunomodulación/fisiología , Animales , Animales Recién Nacidos , Lesiones Encefálicas/metabolismo , Hemorragia Cerebral Intraventricular/inducido químicamente , Hemorragia Cerebral Intraventricular/fisiopatología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Proteínas I-kappa B/metabolismo , Inflamación/metabolismo , Interferón-alfa/farmacología , Interferón-alfa/fisiología , Janus Quinasa 1/metabolismo , Janus Quinasa 1/fisiología , Masculino , Microglía/metabolismo , FN-kappa B/inmunología , FN-kappa B/metabolismo , Neuroinmunomodulación/inmunología , Ratas , Ratas Sprague-Dawley , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT1/fisiología , Transducción de Señal/efectos de los fármacos , Factor 3 Asociado a Receptor de TNF/metabolismoRESUMEN
Intraventricular hemorrhage (IVH) leads to reduced myelination and astrogliosis of the white matter in premature infants. No therapeutic strategy exists to minimize white matter injury in survivors with IVH. Epidermal growth factor (EGF) enhances myelination, astrogliosis, and neurologic recovery in animal models of white matter injury. Here, we hypothesized that recombinant human (rh) EGF treatment would enhance oligodendrocyte precursor cell (OPC) maturation, myelination, and neurological recovery in preterm rabbits with IVH. In addition, rhEGF would promote astrogliosis by inducing astroglial progenitor proliferation and GFAP transcription. We tested these hypotheses in a preterm rabbit model of IVH and evaluated autopsy samples from human preterm infants. We found that EGF and EGFR expression were more abundant in the ganglionic eminence relative to the cortical plate and white matter of human infants and that the development of IVH reduced EGF levels, but not EGFR expression. Accordingly, rhEGF treatment promoted proliferation and maturation of OPCs, preserved myelin in the white matter, and enhanced neurological recovery in rabbits with IVH. rhEGF treatment inhibited Notch signaling, which conceivably contributed to OPC maturation. rhEGF treatment contributed to astrogliosis by increasing astroglial proliferation and upregulating GFAP as well as Sox9 expression. Hence, IVH results in a decline in EGF expression; and rhEGF treatment preserves myelin, restores neurological recovery, and exacerbates astrogliosis by inducing proliferation of astrocytes and enhancing transcription of GFAP and Sox9 in pups with IVH. rhEGF treatment might improve the neurological outcome of premature infants with IVH. GLIA 2016;64:1987-2004.
Asunto(s)
Astrocitos/efectos de los fármacos , Hemorragia Cerebral Intraventricular/complicaciones , Hemorragia Cerebral Intraventricular/patología , Factor de Crecimiento Epidérmico/farmacología , Gliosis/etiología , Vaina de Mielina/metabolismo , Factores de Edad , Animales , Animales Recién Nacidos , Astrocitos/ultraestructura , Encéfalo/embriología , Encéfalo/crecimiento & desarrollo , Encéfalo/patología , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Hemorragia Cerebral Intraventricular/inducido químicamente , Modelos Animales de Enfermedad , Embrión de Mamíferos , Regulación de la Expresión Génica/fisiología , Proteína Ácida Fibrilar de la Glía/metabolismo , Humanos , Recién Nacido , Recien Nacido Prematuro , Antígeno Ki-67/metabolismo , Factor de Transcripción 2 de los Oligodendrocitos/metabolismo , Oligodendroglía/patología , Oligodendroglía/ultraestructura , Conejos , Transducción de Señal/fisiologíaAsunto(s)
Anticoagulantes/efectos adversos , Factores de Coagulación Sanguínea/uso terapéutico , Hemorragia Cerebral Intraventricular/terapia , Desamino Arginina Vasopresina/uso terapéutico , Hemostáticos/uso terapéutico , Hemorragia Intracraneal Traumática/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/efectos adversos , Anciano , Anciano de 80 o más Años , Aspirina/efectos adversos , Hemorragia Cerebral Traumática/etiología , Hemorragia Cerebral Traumática/terapia , Hemorragia Cerebral Intraventricular/inducido químicamente , Clopidogrel/efectos adversos , Femenino , Fracturas Óseas/complicaciones , Hematoma/etiología , Hematoma/terapia , Hematoma Intracraneal Subdural/etiología , Hematoma Intracraneal Subdural/terapia , Humanos , Relación Normalizada Internacional , Hemorragia Intracraneal Traumática/etiología , Masculino , Persona de Mediana Edad , Huesos Pélvicos/lesiones , Pirazoles/efectos adversos , Piridonas/efectos adversos , Estudios Retrospectivos , Rivaroxabán/efectos adversos , Hemorragia Subaracnoidea Traumática/etiología , Hemorragia Subaracnoidea Traumática/terapia , Trombosis/inducido químicamente , Trombosis/epidemiología , Warfarina/efectos adversosRESUMEN
Relieving neonatal pain is essential for the management of premature infants. Morphine is the most frequently used analgesic in neonatal intensive care. Here we report the relationship between early morphine infusion and the composite outcome of intraventricular hemorrhage and/or death in intubated premature infants. Infants (gestational age ≤ 32 weeks and birth weight < 1,500 g) intubated on admission were retrospectively evaluated in a large tertiary neonatal intensive care unit. Modified log-Poisson regression with robust variance estimator and Cox regression was applied to adjust the relative risk for infants' outcomes. Of 420 premature infants, 230 (54.7%) received continuous morphine infusion in the first 72 h. Of these, 153 were < 28 gestational weeks; of the 190 patients who did not receive morphine, 63 were < 28 gestational weeks. The analysis revealed that infants < 28 gestational weeks who received morphine were significantly associated with an increased risk for IVH and/or death [adjusted relative risk (aRR) 1.37, 95% confidence interval (CI) 1.1-1.71)], and mortality (aRR 1.83, 95% CI 1.17-2.89). Moreover, in infants < 28 gestational weeks, survival was low in those infants who were exposed to morphine infusion in the first 72 h (hazard ratio 2.11; 95% CI 1.19-3.73). Early morphine infusion is associated with an increased risk for IVH and/or death; however, further studies are required to verify our findings.
Asunto(s)
Hemorragia Cerebral Intraventricular/mortalidad , Enfermedades del Prematuro/tratamiento farmacológico , Recien Nacido Prematuro , Morfina/efectos adversos , Analgésicos Opioides/efectos adversos , Hemorragia Cerebral Intraventricular/inducido químicamente , Hemorragia Cerebral Intraventricular/epidemiología , Hemorragia Cerebral Intraventricular/patología , Femenino , Humanos , Incidencia , Recién Nacido , Enfermedades del Prematuro/patología , Masculino , Pronóstico , Estudios Retrospectivos , Arabia Saudita/epidemiología , Tasa de SupervivenciaRESUMEN
Neuroinflammation significantly contributes to brain injury and neurological deterioration following intracerebral hemorrhage (ICH). MicroRNA-152(miR-152) was reported to be downregulated in ICH patients and to possess anti-inflammatory properties in other diseases. In this study, we aimed to explore the role of miR-152 in ICH, and the underlying mechanisms, using a collagenase-induced rat ICH model and hemin-exposure as a cell model. We first confirmed that miR-152 was consistently downregulated in both models. Overexpression of miR-152 in microglial BV2 cells reduced hemin-induced inflammatory response and reactive oxygen species (ROS) generation, thus protecting co-cultured neuronal HT22 cells. Moreover, overexpression of miR-152 by intracerebroventricular lentivirus injection in ICH rats significantly alleviated neurodecifits, brain edema, and hematoma. These changes were associated with a marked reduction in ICH-induced neuronal death, as detected by co-staining of NeuN and TUNEL, and ICH-induced neuroinflammation, as revealed by inflammatory cytokine levels as well as by the number of Iba1 positive-stained cells in the perihematomal region. Mechanistically, miR-152 significantly inhibited ICH-induced TXNIP expression, and its overexpression blocked the interaction between TXNIP and NOD-like receptor pyrin domain containing 3(NLRP3), thus inhibiting NLRP3-driven inflammasome activation to attenuate neuroinflammation in vivo and in vitro. Moreover, the results of si-TXNIP transfection further confirmed that TXNIP inhibition was involved in the reduction of NLRP3 inflammasome activation by the overexpression of miR-152. Collectively, the present study demonstrates that miR-152 confers protection against ICH-induced neuroinflammation and brain injury by inhibiting TXNIP-mediated NLRP3 inflammasome activation, indicating a potential strategy for ICH treatment.
Asunto(s)
Proteínas Portadoras/genética , Proteínas de Ciclo Celular/genética , Hemorragia Cerebral Intraventricular/genética , Inflamasomas/inmunología , MicroARNs/metabolismo , Tiorredoxinas/genética , Animales , Proteínas Portadoras/metabolismo , Proteínas de Ciclo Celular/metabolismo , Línea Celular , Hemorragia Cerebral Intraventricular/inducido químicamente , Hemorragia Cerebral Intraventricular/inmunología , Hemorragia Cerebral Intraventricular/patología , Ventrículos Cerebrales/inmunología , Ventrículos Cerebrales/patología , Técnicas de Cocultivo , Modelos Animales de Enfermedad , Regulación hacia Abajo/inmunología , Técnicas de Silenciamiento del Gen , Hemina/inmunología , Humanos , Inflamasomas/metabolismo , Inyecciones Intraventriculares , Masculino , Ratones , MicroARNs/agonistas , MicroARNs/antagonistas & inhibidores , Colagenasa Microbiana/administración & dosificación , Colagenasa Microbiana/toxicidad , Microglía , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Neuronas , Unión Proteica/genética , Unión Proteica/inmunología , ARN Interferente Pequeño/metabolismo , Ratas , Tiorredoxinas/metabolismoRESUMEN
BACKGROUND: As intraventricular thrombolysis for intraventricular hemorrhage (IVH) has developed over the last 2 decades, hemorrhagic complications have remained a concern despite general validation of its safety in controlled trials in the Clot Lysis: Evaluation of Accelerated Resolution of Intraventricular Hemorrhage Phase III (CLEAR-IVH) program. OBJECTIVE: To analyze factors associated with symptomatic bleeding following IVH with and without thrombolysis in conjunction with the recently completed CLEAR III trial. METHODS: We reviewed safety reports on symptomatic bleeding events reported during the first year after randomization among subjects enrolled in the CLEAR III trial. Clinical and imaging data were retrieved through the trial database as part of ongoing quality and safety monitoring. A posthoc root-cause analysis was performed to identify potential factors predisposing to rebleeding in each case. Cases were classified according to onset of rebleeding (during dosing, early after dosing and delayed), the pattern of bleeding, and treatment rendered (alteplase vs saline). RESULTS: Twenty subjects developed a secondary symptomatic intracranial hemorrhage constituting 4% of subjects. Symptomatic rebleeding events occurred during the dosing protocol (n = 9, 67% alteplase), early after the protocol (n = 5, 40% alteplase), and late (n = 6, 0% alteplase). Catheter-related hemorrhages were the most common (n = 7, 35%) followed by expansion or new intraventricular (n = 6, 30%) and intracerebral (n = 5, 25%) hemorrhages. Symptomatic hemorrhages during therapy resulted from a combination of treatment- and patient-related factors and were at most partially attributable to alteplase. Rebleeding after the dosing protocol primarily reflected patients' risk factors. CONCLUSION: Intraventricular thrombolysis marginally increases the overall risk of symptomatic hemorrhagic complications after IVH, and only during the treatment phase.