Las hipersomnias: diagnóstico, clasificación y tratamiento

La hipersomnia o somnolencia diurna excesiva es una queja frecuente en la práctica neurológica y puede ser debida a múltiples trastornos. Puede definirse como la sensación subjetiva de sueño a una hora inapropiada. Hay que tener en cuenta que en ocasiones la hipersomnia no viene referida por el paciente como tal sino que lo que aqueja es cansancio o fatiga. Para abordar el diagnóstico de la hipersomnia es necesaria una historia clínica detallada. Un diagnóstico correcto permitirá un correcto abordaje terapéutico lo cual tiene una gran importancia dada la repercusión social y laboral de la hipersomnia. Dentro de los síndromes con somnolencia diurna excesiva podemos encontrar trastornos intrínsecos del sueño como la narcolepsia o hipersomnia secundaria a otras enfermedades o como efecto secundario de diversos fármacos

CM-352 Efficacy in a mouse model of anticoagulant-associated intracranial hemorrhage

Background: Intracranial hemorrhage (ICH) is one of the major devastating complications of anticoagulation. Matrix metalloproteinase (MMP) inhibition has been proposed as a novel pharmacological approach for ICH treatment. Objectives: We evaluated the effects of CM-352 (MMP-fibrinolysis inhibitor) in an experimental ICH model associated with oral anticoagulants as compared with clinically used prothrombin complex concentrate (PCC). Methods: ICH was induced by collagenase injection into the striatum of wild type (C57BL/6J) anticoagulated mice (warfarin or rivaroxaban) and Mmp10 -/- mice. Hematoma volume and neurological deficits were measured 24 hours later by diaminobenzidine staining and different behavioral tests. Circulating plasminogen activator inhibitor-1 (PAI-1) activity and interleukin-6 (IL-6) were measured in plasma samples and local inflammation was assessed by neutrophil infiltration. Finally, fibrinolytic effects of MMP-10 and rivaroxaban were evaluated by thromboelastometry and thrombin-activatable fibrinolysis inhibitor (TAFI) activation assays. Results: Only PCC reduced hemorrhage volume and improved functional outcome in warfarin-ICH, but both PCC and CM-352 treatments diminished hemorrhage volume (46%, p < 0.01 and 64%, p < 0.001, respectively) and ameliorated functional outcome in rivaroxaban-ICH. We further demonstrated that CM-352, but not PCC, decreased neutrophil infiltration in the hemorrhage area at 24 hours. The effect of CM-352 could be related to MMP-10 inhibition since Mmp10 -/- mice showed lower hemorrhage volume, better neurological score, reduced IL-6 levels and neutrophil infiltration, and increased PAI-1 after experimental ICH. Finally, we found that CM-352 reduced MMP-10 and rivaroxaban-related fibrinolytic effects in thromboelastometry and TAFI activation. Conclusion: CM-352 treatment, by diminishing MMPs and rivaroxaban-associated fibrinolytic effects, might be a novel antihemorrhagic strategy for rivaroxaban-associated ICH

RNU6-1 in circulating exosomes differentiates GBM from non-neoplastic brain lesions and PCNSL but not from brain metastases.

Background. Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Circulating biomarkers may assist in the processes of differential diagnosis and response assessment. GBM cells release extracellular vesicles containing a subset of proteins and nucleic acids. We previously demonstrated that exosomes isolated from the serum of GBM patients had an increased expression of RNU6-1 compared to healthy subjects. In this exploratory study, we investigated the role of this small noncoding RNA as a diagnostic biomarker for GBM versus other brain lesions with some potential radiological similarities. Methods. We analyzed the expression of RNU6-1 in circulating exosomes of GBM patients (n = 18), healthy controls (n = 30), and patients with subacute stroke (n = 30), acute/subacute hemorrhage (n = 30), acute demyelinating lesions (n = 18), brain metastases (n = 21), and primary central nervous system lymphoma (PCNSL; n = 12) using digital droplet PCR. Results. Expression of RNU6-1 was significantly higher in GBM patients than in healthy controls (P = .002). RNU6-1 levels were also significantly higher in exosomes from GBM patients than from patients with nonneoplastic lesions (stroke [P = .05], hemorrhage [P = .01], demyelinating lesions [P = .019]) and PCNSL (P = .004). In contrast, no significant differences were found between patients with GBM and brain metastases (P = .573). Receiver operator characteristic curve analyses supported the role of this biomarker in differentiating GBM from subacute stroke, acute/subacute hemorrhage, acute demyelinating lesions, and PCNSL (P < .05), but again not from brain metastases (P = .575)

RNU6-1 in circulating exosomes differentiates GBM from non-neoplastic brain lesions and PCNSL but not from brain metastases.

Background. Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Circulating biomarkers may assist in the processes of differential diagnosis and response assessment. GBM cells release extracellular vesicles containing a subset of proteins and nucleic acids. We previously demonstrated that exosomes isolated from the serum of GBM patients had an increased expression of RNU6-1 compared to healthy subjects. In this exploratory study, we investigated the role of this small noncoding RNA as a diagnostic biomarker for GBM versus other brain lesions with some potential radiological similarities. Methods. We analyzed the expression of RNU6-1 in circulating exosomes of GBM patients (n = 18), healthy controls (n = 30), and patients with subacute stroke (n = 30), acute/subacute hemorrhage (n = 30), acute demyelinating lesions (n = 18), brain metastases (n = 21), and primary central nervous system lymphoma (PCNSL; n = 12) using digital droplet PCR. Results. Expression of RNU6-1 was significantly higher in GBM patients than in healthy controls (P = .002). RNU6-1 levels were also significantly higher in exosomes from GBM patients than from patients with nonneoplastic lesions (stroke [P = .05], hemorrhage [P = .01], demyelinating lesions [P = .019]) and PCNSL (P = .004). In contrast, no significant differences were found between patients with GBM and brain metastases (P = .573). Receiver operator characteristic curve analyses supported the role of this biomarker in differentiating GBM from subacute stroke, acute/subacute hemorrhage, acute demyelinating lesions, and PCNSL (P < .05), but again not from brain metastases (P = .575)

MRI predicts intracranial hemorrhage in patients who receive long-term oral anticoagulation

OBJECTIVE: We tested the hypothesis that the risk of intracranial hemorrhage (ICH) in patients with cardioembolic ischemic stroke who are treated with oral anticoagulants (OAs) can be predicted by evaluating surrogate markers of hemorrhagic-prone cerebral angiopathies using a baseline MRI. METHODS: Patients were participants in a multicenter and prospective observational study. They were older than 64 years, had a recent cardioembolic ischemic stroke, and were new users of OAs. They underwent a baseline MRI analysis to evaluate microbleeds, white matter hyperintensities, and cortical superficial siderosis. We collected demographic variables, clinical characteristics, risk scores, and therapeutic data. The primary endpoint was ICH that occurred during follow-up. We performed bivariate and multivariate Cox regression analyses. RESULTS: We recruited 937 patients (aged 77.6 +/- 6.5 years; 47.9% were men). Microbleeds were detected in 207 patients (22.5%), moderate/severe white matter hyperintensities in 419 (45.1%), and superficial siderosis in 28 patients (3%). After a mean follow-up of 23.1 +/- 6.8 months, 18 patients (1.9%) experienced an ICH. In multivariable analysis, microbleeds (hazard ratio 2.7, 95% confidence interval [CI] 1.1-7, p = 0.034) and moderate/severe white matter hyperintensities (hazard ratio 5.7, 95% CI 1.6-20, p = 0.006) were associated with ICH (C index 0.76, 95% CI 0.66-0.85). Rate of ICH was highest in patients with both microbleed and moderate/severe WMH (3.76 per 100 patient-years, 95% CI 1.62-7.4). CONCLUSION: Patients taking OAs who have advanced cerebral small vessel disease, evidenced by microbleeds and moderate to severe white matter hyperintensities, had an increased risk of ICH. Our results should help to determine the risk of prescribing OA for a patient with cardioembolic stroke. CLINICALTRIALSGOV IDENTIFIER: NCT02238470