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Meropenem penetration into the cerebrospinal fluid (CSF) is subject to high interindividual variability resulting in uncertain target attainment in CSF. Recently, several authors recommended administering meropenem as a continuous infusion (CI) to optimize CSF exposure. This study aimed to compare the concentrations and pharmacokinetics of meropenem in CSF after intermittent infusion (II) and CI. This prospective, observational study (NCT04426383) included critically ill patients with external ventricular drains who received either II or CI of meropenem. Meropenem pharmacokinetics in plasma and CSF were characterized using population pharmacokinetic modeling (NONMEM 7.5). The developed model was used to compare the concentration-time profile and probability of target attainment (PTA) between II and CI. A total of 16 patients (8 CI, 8 II; samples: nplasma = 243, nCSF = 263) were recruited, with nine patients (5 CI, 4 II) suffering from cerebral and seven patients from extracerebral infections. A one-compartment model described the plasma concentrations adequately. Meropenem penetration into the CSF (partition coefficient (KP), cCSF/cplasma) was generally low (6.0%), exhibiting substantial between-subject variability (coefficient of variation: 84.0%). There was no correlation between the infusion mode and KP, but interleukin (IL)-6 measured in CSF showed a strong positive correlation with KP (P < 0.001). Dosing simulations revealed no relevant differences in CSF concentrations and PTA in CSF between CI and II. Our study did not demonstrate increased penetration rates or higher concentrations of meropenem in the CSF with CI compared with II. CLINICAL TRIALS: This study is registered with ClinicalTrials.gov as NCT04426383.
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BACKGROUND: Cysto-ventricular catheters (CVC) have emerged as promising treatment option for cystic craniopharyngioma and arachnoid cysts, but their effectiveness in treating cysts originating from glioma or brain metastasis (BM) remains limited. This study aimed to analyze the efficacy of CVC in patients with glioma and BM as well as procedure-associated morbidity. METHODS: This single-center retrospective study included all patients treated with CVC placement for acquired space-occupying cysts deriving from previously treated glioma or BMs between 1/2010 and 12/2021. RESULTS: A total of 57 patients with a median age of 47 years (IQR 38-63) were identified. Focal neurological deficits were the predominant symptoms in 60% of patients (n = 34), followed by cephalgia in 14% (n = 8), and epileptic seizures in 21.1% (n = 12). Accurate CVC placement was achieved in all but one case requiring revision surgery due to malposition. Three months after CVC implantation, 70% of patients showed symptomatic improvement. Multivariate logistic regression analysis identified the development of space-occupying cysts later in the course of the disease (OR 1.014; p = 0.04) and a higher reduction of cyst-volume postoperatively (OR 1.055; p = 0.05) were significant predictors of postoperative symptomatic improvement following CVC placement. Local cyst recurrence was observed in three cases during follow-up MRI after an average time of 5 months (range 3-9 months). Further complications included secondary malresorptive hydrocephalus in three cases and meningeosis neoplastica in one patient. CONCLUSIONS: Stereotactic implantation of CVC is an efficient treatment option for patients suffering from symptomatic space-occupying cysts from BMs or glioma, independently from their CNS WHO grade. However, a vigilant approach is crucial regarding potential complications and treatment failures.
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Quistes Aracnoideos , Neoplasias Encefálicas , Glioma , Neoplasias Hipofisarias , Humanos , Adulto , Persona de Mediana Edad , Estudios Retrospectivos , Tomografía Computarizada por Rayos X , Neoplasias Encefálicas/cirugía , Glioma/diagnóstico por imagen , Glioma/cirugía , Quistes Aracnoideos/cirugía , CatéteresRESUMEN
OBJECTIVE: The best treatment strategies for cerebral arachnoid cysts (CAC) are still up for debate. In this study, we present CAC management, outcome data, and risk factors for recurrence after surgical treatment, focusing on microscopic/endoscopic approaches as compared to minimally invasive stereotactic procedures in children and adults. METHODS: In our single-institution retrospective database, we identified all patients treated surgically for newly diagnosed CAC between 2000 and 2022. Microscopic/endoscopic surgery (ME) aimed for safe cyst wall fenestration. Stereotactic implantation of an internal shunt catheter (STX) to drain CAC into the ventricles and/or cisterns was used as an alternative procedure in patients aged ≥ 3 years. Treatment decisions in favor of ME vs. STX were made by interdisciplinary consensus. The primary study endpoint was time to CAC recurrence (TTR). Secondary endpoints were outcome metrics including clinical symptoms and MR-morphological analyses. Data analysis included subdivision of the total cohort into three distinct age groups (AG1, < 6 years; AG2, 6-18 years; AG3, ≥ 18 years). RESULTS: Sixty-two patients (median age 26.5 years, range 0-82 years) were analyzed. AG1 included 15, AG2 10, and AG3 37 patients, respectively. The main presenting symptoms were headache and vertigo. In AG1 hygromas, an increase in head circumference and thinning of cranial calvaria were most frequent. Thirty-five patients underwent ME and 27 STX, respectively; frequency did not differ between AGs. There were two (22.2%) periprocedural venous complications in infants (4- and 10-month-old) during an attempt at prepontine fenestration of a complex CAC, one with fatal outcome in a 10-month-old boy. Other complications included postoperative bleeding (2, 22.2%), CSF leaks (4, 44.4%), and meningitis (1, 11.1%). Overall, clinical improvement and significant volume reduction (p = 0.008) were seen in all other patients; this did not differ between AGs. Median follow-up for all patients was 25.4 months (range, 3.1-87.1 months). Recurrent cysts were seen in 16.1%, independent of surgical procedure used (p = 0.7). In cases of recurrence, TTR was 7.9 ± 12.7 months. Preoperative ventricular expansion (p = 0.03), paresis (p = 0.008), and age under 6 years (p = 0.03) were significant risk factors for CAC recurrence in multivariate analysis. CONCLUSIONS: In patients suffering from CAC, both ME and STX can improve clinical symptoms at low procedural risk, with equal extent of CAC volume reduction. However, in infants and young children, CAC are more often associated with severe clinical symptoms, stereotactic procedures have limited use, and microsurgery in the posterior fossa may bear the risk of severe venous bleeding.
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Quistes Aracnoideos , Niño , Lactante , Masculino , Adulto , Humanos , Preescolar , Recién Nacido , Adolescente , Adulto Joven , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Quistes Aracnoideos/diagnóstico por imagen , Quistes Aracnoideos/cirugía , Quistes Aracnoideos/complicaciones , Estudios Retrospectivos , Endoscopía/métodos , Ventriculostomía/métodos , Microcirugia/métodos , Resultado del TratamientoRESUMEN
BACKGROUND: The only established pharmacological treatment option improving outcomes for patients suffering from subarachnoid hemorrhage (SAH) is the L-type-calcium channel inhibitor nimodipine. However, the exact mechanisms of action of nimodipine conferring neuroprotection after SAH have yet to be determined. More recently, spasms of the cerebral microcirculation were suggested to play an important role in reduced cerebral perfusion after SAH and, ultimately, outcome. It is unclear whether nimodipine may influence microvasospasms and, thus, microcirculatory dysfunction. The aim of the current study was, therefore, to assess the effect of nimodipine on microvasospasms after experimental SAH. METHODS: Male C57Bl/6 N mice (n=3-5/group) were subjected to SAH using the middle cerebral artery perforation model. Six hours after SAH induction, a cranial window was prepared, and the diameter of cortical microvessels was assessed in vivo by 2-photon-microscopy before, during, and after nimodipine application. RESULTS: Nimodipine significantly reduced the number of posthemorrhagic microvasospasms. The diameters of nonspastic vessels were not affected. CONCLUSIONS: Our results show that nimodipine reduces the formation of microvasospasms, thus, shedding new light on the mode of action of a drug routinely used for the treatment of SAH for >3 decades. Furthermore, L-type Ca2+ channels may be involved in the pathophysiology of microvasospasm formation.
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Nimodipina , Hemorragia Subaracnoidea , Humanos , Animales , Ratones , Masculino , Nimodipina/farmacología , Nimodipina/uso terapéutico , Hemorragia Subaracnoidea/complicaciones , Hemorragia Subaracnoidea/tratamiento farmacológico , Microcirculación , Ratones Endogámicos C57BL , MicrovasosRESUMEN
BACKGROUND: Subarachnoid hemorrhage (SAH) is characterized by acute and delayed reductions of cerebral blood flow (CBF) caused, among others, by spasms of cerebral arteries and arterioles. Recently, the inactivation of perivascular macrophages (PVM) has been demonstrated to improve neurological outcomes after experimental SAH, but the underlying mechanisms of protection remain unclear. The aim of our exploratory study was, therefore, to investigate the role of PVM in the formation of acute microvasospasms after experimental SAH. METHODS: PVMs were depleted in 8- to 10-week-old male C57BL/6 mice (n=8/group) by intracerebroventricular application of clodronate-loaded liposomes and compared with mice with vehicle liposome injections. Seven days later, SAH was induced by filament perforation under continuous monitoring of CBF and intracranial pressure. Results were compared with sham-operated animals and animals who underwent SAH induction but no liposome injection (n=4/group each). Six hours after SAH induction or sham surgery, numbers of microvasospasms per volume of interest and % of affected pial and penetrating arterioles were examined in 9 standardized regions of interest per animal by in vivo 2-photon microscopy. Depletion of PVMs was proven by quantification of PVMs/mm3 identified by immunohistochemical staining for CD206 and Collagen IV. Statistical significance was tested with t tests for parametric data and Mann-Whitney U test for nonparametric data. RESULTS: PVMs were located around pial and intraparenchymal arterioles and were effectively depleted by clodronate from 671±28 to 46±14 PVMs/mm3 (P<0.001). After SAH, microvasospasms was observed in pial arteries and penetrating and precapillary arterioles and were accompanied by an increase to 1405±142 PVMs/mm3. PVM depletion significantly reduced the number of microvasospasms from 9 IQR 5 to 3 IQR 3 (P<0.001). CONCLUSIONS: Our results suggest that PVMs contribute to the formation of microvasospasms after experimental SAH.
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Hemorragia Subaracnoidea , Ratones , Masculino , Animales , Hemorragia Subaracnoidea/complicaciones , Ácido Clodrónico , Ratones Endogámicos C57BL , Arteriolas , Circulación Cerebrovascular/fisiología , Modelos Animales de EnfermedadRESUMEN
BACKGROUND: Subarachnoid hemorrhage (SAH) is characterized by an acute reduction of cerebral blood flow and subsequent cortical infarcts, but the underlying mechanisms are not well understood. Since pericytes regulate cerebral perfusion on the capillary level, we hypothesize that pericytes may reduce cerebral perfusion after SAH. METHODS: Pericytes and vessel diameters of cerebral microvessels were imaged in vivo using NG2 (neuron-glial antigen 2) reporter mice and 2-photon microscopy before and 3 hours after sham surgery or induction of SAH by perforating the middle cerebral artery with an intraluminal filament. Twenty-four hours after, SAH pericyte density was assessed by immunohistochemistry. RESULTS: SAH caused pearl-string-like constrictions of pial arterioles, slowed down blood flow velocity in pial arterioles by 50%, and reduced the volume of intraparenchymal arterioles and capillaries by up to 70% but did not affect pericyte density or induce capillary constriction by pericytes. CONCLUSIONS: Our results suggest that perfusion deficits after SAH are not induced by pericyte-mediated capillary constrictions.
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Pericitos , Hemorragia Subaracnoidea , Ratones , Animales , Pericitos/fisiología , Capilares , Hemorragia Subaracnoidea/complicaciones , Vasoconstricción/fisiología , PerfusiónRESUMEN
Vancomycin is a commonly used antibacterial agent in patients with primary central nervous system (CNS) infection. This study aims to examine predictors of vancomycin penetration into cerebrospinal fluid (CSF) in patients with external ventricular drainage and the feasibility of CSF sampling from the distal drainage port for therapeutic drug monitoring. Fourteen adult patients (9 with primary CNS infection) were treated with vancomycin intravenously. The vancomycin concentrations in blood and CSF (from proximal [CSF_P] and distal [CSF_D] drainage ports) were evaluated by population pharmacokinetics. Model-based simulations were conducted to compare various infusion modes. A three-compartment model with first-order elimination best described the vancomycin data. Estimated parameters included clearance (CL, 4.53 L/h), central compartment volume (Vc, 24.0 L), apparent CSF compartment volume (VCSF, 0.445 L), and clearance between central and CSF compartments (QCSF, 0.00322 L/h and 0.00135 L/h for patients with and without primary CNS infection, respectively). Creatinine clearance was a significant covariate on vancomycin CL. CSF protein was the primary covariate to explain the variability of QCSF. There was no detectable difference between the data for sampling from the proximal and the distal port. Intermittent infusion and continuous infusion with a loading dose reached the CSF target concentration faster than continuous infusion only. All infusion schedules reached similar CSF trough concentrations. Beyond adjusting doses according to renal function, starting treatment with a loading dose in patients with primary CSF infection is recommended. Occasionally, very high and possibly toxic doses would be required to achieve adequate CSF concentrations, which calls for more investigation of direct intraventricular administration of vancomycin. (This study has been registered at ClinicalTrials.gov under registration no. NCT04426383).
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Infecciones del Sistema Nervioso Central , Vancomicina , Adulto , Humanos , Antibacterianos/farmacocinética , Infecciones del Sistema Nervioso Central/tratamiento farmacológico , Drenaje , Plasma , Vancomicina/farmacocinéticaRESUMEN
BACKGROUND: Intracranial tumors can cause obstructive hydrocephalus (OH). Most often, symptomatic treatment is pursued through ventriculoperitoneal shunt (VS) or endoscopic third ventriculostomy (ETV). In this study, we propose stereotactic third ventriculostomy with internal shunt placement (sTVIP) as an alternative treatment option and assess its safety and efficacy. METHODS: In this single-center, retrospective analysis, clinical symptoms, procedure-related complications, and revision-free survival of all patients with OH due to tumor formations treated by sTVIP between January 2010 and December 2021 were evaluated. RESULTS: Clinical records of thirty-eight patients (11 female, 27 male) with a mean age of 40 years (range 5-88) were analyzed. OH was predominantly (in 92% of patients) caused by primary brain tumors (with exception of 3 cases with metastases). Following sTVIP, 74.2% of patients experienced symptomatic improvement. Preoperative headache was a significant predictor of postoperative symptomatic improvement (OR 26.25; 95% CI 4.1-521.1; p = 0.0036). Asymptomatic hemorrhage was detected along the stereotactic trajectory in 2 cases (5.3%). One patient required local revision due to CSF fistula (2.6%); another patient had to undergo secondary surgery to connect the catheter to a valve/abdominal catheter due to CSF malabsorption. However, in the remaining 37 patients, shunt independence was maintained during a median follow-up period of 12 months (IQR 3-32 months). No surgery-related mortality was observed. CONCLUSIONS: sTVIP led to a significant symptom control and was associated with low operative morbidity, along with a high rate of ventriculoperitoneal shunt independency during the follow-up period. Therefore, sTVIP constitutes a highly effective and minimally invasive treatment option for tumor-associated obstructive hydrocephalus, even in cases with a narrow prepontine interval.
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Hidrocefalia , Neuroendoscopía , Tercer Ventrículo , Humanos , Masculino , Femenino , Preescolar , Niño , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Ventriculostomía/efectos adversos , Resultado del Tratamiento , Estudios Retrospectivos , Tercer Ventrículo/cirugía , Neuroendoscopía/efectos adversos , Hidrocefalia/etiología , Hidrocefalia/cirugía , Hidrocefalia/diagnósticoRESUMEN
BACKGROUND AND PURPOSE: Subarachnoid hemorrhage (SAH) is associated with acute and delayed cerebral ischemia resulting in high acute mortality and severe chronic neurological deficits. Spasms of the pial and intraparenchymal microcirculation (microvasospasms) contribute to acute cerebral ischemia after SAH; however, the underlying mechanisms remain unknown. We hypothesize that free iron (Fe3+) released from hemolytic red blood cells into the subarachnoid space may be involved in microvasospasms formation. METHODS: Male C57BL/6 mice (n=8/group) received 200 mg/kg of the iron scavenger deferoxamine or vehicle intravenously and were then subjected to SAH by filament perforation. Microvasospasms of pial and intraparenchymal vessels were imaged three hours after SAH by in vivo 2-photon microscopy. RESULTS: Microvasospasms occurred in all investigated vessel categories down to the capillary level. Deferoxamine significantly reduced the number of microvasospasms after experimental SAH. The effect was almost exclusively observed in larger pial arterioles (>30 µm) covered with blood. CONCLUSIONS: These results provide proof-of-principle evidence that Fe3+ is involved in the formation of arteriolar microvasospasms after SAH and that arteriolar and capillary microvasospasms are triggered by different mechanisms. Deciphering the mechanisms of Fe3+-induced microvasospasms may result in novel therapeutic strategies for SAH patients.
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Hierro/metabolismo , Hemorragia Subaracnoidea/complicaciones , Hemorragia Subaracnoidea/metabolismo , Vasoespasmo Intracraneal/etiología , Vasoespasmo Intracraneal/metabolismo , Animales , Arteriolas , Isquemia Encefálica/etiología , Isquemia Encefálica/metabolismo , Capilares , Deferoxamina/farmacología , Masculino , Ratones Endogámicos C57BL , Sideróforos/farmacologíaRESUMEN
Subarachnoid hemorrhage (SAH) is associated with acute and delayed cerebral ischemia. We suggested spasms of pial arterioles as a possible mechanism; however, it remained unclear whether and how pial microvasospasms (MVSs) induce cerebral ischemia. Therefore, we used in vivo deep tissue imaging by two-photon microscopy to investigate MVSs together with the intraparenchymal microcirculation in a clinically relevant murine SAH model. Male C57BL/6 mice received a cranial window. Cerebral vessels and leukocytes were labelled with fluorescent dyes and imaged by in vivo two-photon microscopy before and three hours after SAH induced by filament perforation. After SAH, a large clot formed around the perforation site at the skull base, and blood distributed along the perivascular space of the middle cerebral artery up to the cerebral cortex. Comparing the cerebral microvasculature before and after SAH, we identified three different patterns of constrictions: pearl string, global, and bottleneck. At the same time, the volume of perfused intraparenchymal vessels and blood flow velocity in individual arterioles were significantly reduced by more than 60%. Plugging of capillaries by leukocytes was observed but infrequent. The current study demonstrates that perivascular blood is associated with spasms of pial arterioles and that these spasms result in a significant reduction in cortical perfusion after SAH. Thus, the pial microvasospasm seems to be an important mechanism by which blood in the subarachnoid space triggers cerebral ischemia after SAH. Identifying the mechanisms of pial vasospasm may therefore result in novel therapeutic options for SAH patients.
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Encéfalo/irrigación sanguínea , Leucocitos/patología , Microvasos/patología , Hemorragia Subaracnoidea/patología , Vasoespasmo Intracraneal/patología , Animales , Encéfalo/patología , Circulación Cerebrovascular , Microscopía Intravital , Masculino , Ratones Endogámicos C57BL , Microscopía de Fluorescencia por Excitación MultifotónicaRESUMEN
BACKGROUND AND PURPOSE: Perturbations in cerebral microcirculation (eg, microvasospasms) and reduced neurovascular communication determine outcome after subarachnoid hemorrhage (SAH). ET-1 (endothelin-1) and its receptors have been implicated in the pathophysiology of large artery spasms after SAH; however, their role in the development of microvascular dysfunction is currently unknown. Here, we investigated whether inhibiting ETA (endothelin A) receptors can reduce microvasospasms after experimentally induced SAH. METHODS: SAH was induced in male C57BL/6 mice by filament perforation of the middle cerebral artery. Three hours after SAH, a cranial window was prepared and the pial and parenchymal cerebral microcirculation was measured in vivo using two-photon microscopy before, during, and after administration of the ETA receptor inhibitor clazosentan. In separate experiments, the effect of clazosentan treatment on neurological outcome was measured 3 days after SAH. RESULTS: Clazosentan treatment had no effect on the number or severity of SAH-induced cerebral microvasospasms nor did it affect neurological outcome. CONCLUSIONS: Our results indicate that ETA receptors, which mediate large artery spasms after SAH, do not seem to play a role in the development of microarterial spasms, suggesting that posthemorrhagic spasms are mediated by distinct mechanisms in large and small cerebral vessels. Given that cerebral microvessel dysfunction is a key factor for outcome after SAH, further research into the mechanisms that underlie posthemorrhagic microvasospasms is urgently needed.
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Receptor de Endotelina A/metabolismo , Hemorragia Subaracnoidea/metabolismo , Vasoespasmo Intracraneal/metabolismo , Animales , Dioxanos/farmacología , Antagonistas de los Receptores de la Endotelina A/farmacología , Endotelina-1/metabolismo , Masculino , Ratones , Microscopía de Fluorescencia por Excitación Multifotónica , Piridinas/farmacología , Pirimidinas/farmacología , Hemorragia Subaracnoidea/tratamiento farmacológico , Hemorragia Subaracnoidea/fisiopatología , Sulfonamidas/farmacología , Tetrazoles/farmacología , Vasoespasmo Intracraneal/tratamiento farmacológico , Vasoespasmo Intracraneal/fisiopatologíaRESUMEN
INTRODUCTION: Transcriptional activating mutations in the promoter region of the telomerase reverse transcriptase (TERT) gene occur at high frequency in various types of solid tumors and have also been reported for meningiomas. Especially for atypical and anaplastic meningiomas, the prognostic relevance of TERT promoter mutation is yet unclear. The present study aimed to analyze the frequency of TERT promoter mutation and define its long-term prognostic significance beyond clinical and histological factors in a cohort of meningiomas WHO grade II and III. METHODS: Patients undergoing surgical resection of aggressive meningiomas were included. Analysis for C228T and C250T mutation in the TERT promoter region was performed using PCR method. Patients were stratified into two groups (TERT mutated vs. TERT wild type). Univariate analysis was conducted using molecular and histological factors. RESULTS: 87 patients with atypical (N = 72) and anaplastic meningiomas (N = 15) were included in the study. TERT promoter region was found to be mutated in 4 WHO grade II and 2 WHO grade III meningiomas. TERT promoter mutation was associated with shorter progression free survival than TERT wild type meningiomas (median PFS 12.5 vs. 26 months, p = .004). In the univariate analysis, TERT promoter mutation had a strong prognostic value on overall survival (p = .009) and progression free survival. CONCLUSIONS: Presence of TERT promoter mutation is associated with shorter progression free survival and overall survival in meningiomas WHO grade II and III. In these tumors, TERT promoter mutation should be considered as a clinically relevant prognostic factor to identify high risk patients.
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Neoplasias Meníngeas/genética , Meningioma/genética , Mutación , Regiones Promotoras Genéticas , Telomerasa/genética , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Femenino , Humanos , Masculino , Neoplasias Meníngeas/mortalidad , Neoplasias Meníngeas/patología , Neoplasias Meníngeas/cirugía , Meningioma/mortalidad , Meningioma/patología , Meningioma/cirugía , Persona de Mediana Edad , Clasificación del Tumor , Pronóstico , Estudios RetrospectivosRESUMEN
RATIONALE: Stroke is the third most common cause of death in industrialized countries. The main therapeutic target is the ischemic penumbra, potentially salvageable brain tissue that dies within the first few hours after blood flow cessation. Hence, strategies to keep the penumbra alive until reperfusion occurs are needed. OBJECTIVE: To study the effect of inhaled nitric oxide on cerebral vessels and cerebral perfusion under physiological conditions and in different models of cerebral ischemia. METHODS AND RESULTS: This experimental study demonstrates that inhaled nitric oxide (applied in 30% oxygen/70% air mixture) leads to the formation of nitric oxide carriers in blood that distribute throughout the body. This was ascertained by in vivo microscopy in adult mice. Although under normal conditions inhaled nitric oxide does not affect cerebral blood flow, after experimental cerebral ischemia induced by transient middle cerebral artery occlusion it selectively dilates arterioles in the ischemic penumbra, thereby increasing collateral blood flow and significantly reducing ischemic brain damage. This translates into significantly improved neurological outcome. These findings were validated in independent laboratories using two different mouse models of cerebral ischemia and in a clinically relevant large animal model of stroke. CONCLUSIONS: Inhaled nitric oxide thus may provide a completely novel strategy to improve penumbral blood flow and neuronal survival in stroke or other ischemic conditions.
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Arteriolas/fisiología , Isquemia Encefálica/prevención & control , Circulación Colateral/fisiología , Óxido Nítrico/uso terapéutico , Accidente Cerebrovascular/prevención & control , Vasodilatación/fisiología , Administración por Inhalación , Animales , Arteriolas/efectos de los fármacos , Encéfalo/irrigación sanguínea , Isquemia Encefálica/patología , Isquemia Encefálica/fisiopatología , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Circulación Colateral/efectos de los fármacos , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Animales , Neuronas/patología , Óxido Nítrico/administración & dosificación , Óxido Nítrico/farmacología , Flujo Sanguíneo Regional/efectos de los fármacos , Flujo Sanguíneo Regional/fisiología , Ovinos , Accidente Cerebrovascular/patología , Accidente Cerebrovascular/fisiopatología , Vasodilatación/efectos de los fármacosRESUMEN
The kallikrein-kinin system is one of the first inflammatory pathways to be activated following traumatic brain injury (TBI) and has been shown to exacerbate brain edema formation in the acute phase through activation of bradykinin 2 receptors (B2R). However, the influence of B2R on chronic post-traumatic damage and outcome is unclear. In the current study, we assessed long-term effects of B2R-knockout (KO) after experimental TBI. B2R KO mice (heterozygous, homozygous) and wild-type (WT) littermates (n = 10/group) were subjected to controlled cortical impact (CCI) TBI. Lesion size was evaluated by magnetic resonance imaging up to 90 days after CCI. Motor and memory function were regularly assessed by Neurological Severity Score, Beam Walk, and Barnes maze test. Ninety days after TBI, brains were harvested for immunohistochemical analysis. There was no difference in cortical lesion size between B2R-deficient and WT animals 3 months after injury; however, hippocampal damage was reduced in B2R KO mice (p = 0.03). Protection of hippocampal tissue was accompanied by a significant improvement of learning and memory function 3 months after TBI (p = 0.02 WT vs. KO), whereas motor function was not influenced. Scar formation and astrogliosis were unaffected, but B2R deficiency led to a gene-dose-dependent attenuation of microglial activation and a reduction of CD45+ cells 3 months after TBI in cortex (p = 0.0003) and hippocampus (p < 0.0001). These results suggest that chronic hippocampal neurodegeneration and subsequent cognitive impairment are mediated by prolonged neuroinflammation and B2R. Inhibition of B2R may therefore represent a novel strategy to reduce long-term neurocognitive deficits after TBI.
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Introduction: In patients with severe aneurysmal subarachnoid hemorrhage (SAH) deep sedation is often used early in the course of the disease in order to control brain edema formation and thus intracranial hypertension. However, some patients do not reach an adequate sedation depth despite high doses of common intravenous sedatives. Balanced sedation protocols incorporating low-dose volatile isoflurane administration might improve insufficient sedation depth in these patients. Methods: We retrospectively analyzed ICU patients with severe aneurysmal SAH who received isoflurane in addition to intravenous anesthetics in order to improve insufficient sedation depth. Routinely recorded data from neuromonitoring, laboratory and hemodynamic parameters were compared before and up to 6 days after initiation of isoflurane. Results: Sedation depth measured using the bispectral index improved in thirty-six SAH patients (-15.16; p = 0.005) who received additional isoflurane for a mean period of 9.73 ± 7.56 days. Initiation of isoflurane sedation caused a decline in mean arterial pressure (-4.67 mmHg; p = 0.014) and cerebral perfusion pressure (-4.21 mmHg; p = 0.013) which had to be balanced by increased doses of vasopressors. Patients required increased minute ventilation in order to adjust for the increase in PaCO2 (+2.90 mmHg; p < 0.001). We did not detect significant increases in mean intracranial pressure. However, isoflurane therapy had to be terminated prematurely in 25% of the patients after a median of 30 h due to episodes of intracranial hypertension or refractory hypercapnia. Discussion: A balanced sedation protocol including isoflurane is feasible for SAH patients experiencing inadequately shallow sedation. However, therapy should be restricted to patients without impaired lung function, hemodynamic instability and impending intracranial hypertension.
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Introduction: One of the major goals of neurointensive care is to prevent secondary injuries following aSAH. Bed rest and patient immobilization are practiced in order to decrease the risk of DCI. Research question: To explore the current practices in place concerning the management of patients with aSAH, specifically, protocols and habits regarding restrictions of mobilization and HOB positioning. Material and methods: A survey was designed, modified, and approved by the panel of the Trauma & Critical Care section of the EANS to cover the practice of restrictions of patient mobilization and HOB positioning in patients with aSAH. Results: Twenty-nine physicians from 17 countries completed the questionnaire. The majority (79.3%) stated that non-secured aneurysm and the presence of an EVD were the factors related to the establishment of restriction of mobilization. The average duration of the restriction varied widely ranging between 1 and 21 days. The presence of an EVD (13.8%) was found to be the main reason to recommend restriction of HOB elevation. The average duration of restriction of HOB positioning ranged between 3 and 14 days. Rebleeding or complications related to CSF over-drainage were found to be related to these restrictions. Discussion and conclusion: Restriction of patient mobilization regimens vary widely in Europe. Current limited evidence does not support an increased risk of DCI rather the early mobilization might be beneficial. Large prospective studies and/or the initiative of a RCT are needed to understand the significance of early mobilization on the outcome of patients with aSAH.
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Patients suffering from familial hemiplegic migraine type 1 (FHM1) may have a disproportionally severe outcome after head trauma, but the underlying mechanisms are unclear. Hence, we subjected knock-in mice carrying the severer S218L or milder R192Q FHM1 gain-of-function missense mutation in the CACNA1A gene that encodes the α1A subunit of neuronal voltage-gated CaV2.1 (P/Q-type) calcium channels and their wild-type (WT) littermates to experimental traumatic brain injury (TBI) by controlled cortical impact and investigated cortical spreading depolarizations (CSDs), lesion volume, brain edema formation, and functional outcome. After TBI, all mutant mice displayed considerably more CSDs and seizures than WT mice, while S218L mutant mice had a substantially higher mortality. Brain edema formation and the resulting increase in intracranial pressure were more pronounced in mutant mice, while only S218L mutant mice had larger lesion volumes and worse functional outcome. Here, we show that gain of CaV2.1 channel function worsens histopathological and functional outcome after TBI in mice. This phenotype was associated with a higher number of CSDs, increased seizure activity, and more pronounced brain edema formation. Hence, our results suggest increased susceptibility for CSDs and seizures as potential mechanisms for bad outcome after TBI in FHM1 mutation carriers.
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Edema Encefálico , Lesiones Traumáticas del Encéfalo , Migraña con Aura , Animales , Edema Encefálico/genética , Lesiones Traumáticas del Encéfalo/complicaciones , Lesiones Traumáticas del Encéfalo/genética , Canales de Calcio Tipo N/genética , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Migraña con Aura/genética , Mutación , Convulsiones/genéticaRESUMEN
BACKGROUND: We demonstrated experimentally that inhaled nitric oxide (iNO) dilates hypoperfused arterioles, increases tissue perfusion, and improves neurological outcome following subarachnoid hemorrhage (SAH) in mice. We performed a prospective pilot study to evaluate iNO in patients with delayed cerebral ischemia after SAH. METHODS: SAH patients with delayed cerebral ischemia and hypoperfusion despite conservative treatment were included. iNO was administered at a maximum dose of 40 ppm. The response to iNO was considered positive if: cerebral artery diameter increased by 10% in digital subtraction angiography (DSA), or tissue oxygen partial pressure (PtiO2) increased by > 5 mmHg, or transcranial doppler (TCD) values decreased more than 30 cm/sec, or mean transit time (MTT) decreased below 6.5 secs in CT perfusion (CTP). Patient outcome was assessed at 6 months with the modified Rankin Scale (mRS). RESULTS: Seven patients were enrolled between February 2013 and September 2016. Median duration of iNO administration was 23 h. The primary endpoint was reached in all patients (five out of 17 DSA examinations, 19 out of 29 PtiO2 time points, nine out of 26 TCD examinations, three out of five CTP examinations). No adverse events necessitating the cessation of iNO were observed. At 6 months, three patients presented with a mRS score of 0, one patient each with an mRS score of 2 and 3, and two patients had died. CONCLUSION: Administration of iNO in SAH patients is safe. These results call for a larger prospective evaluation.
RESUMEN
OBJECTIVE: The CACNA1A gene encodes the pore-forming subunit of neuronal Ca(V)2.1 Ca2+ channels. In patients, the S218L CACNA1A mutation causes a dramatic hemiplegic migraine syndrome that is associated with ataxia, seizures, and severe, sometimes fatal, brain edema often triggered by only a mild head trauma. METHODS: We introduced the S218L mutation into the mouse Cacna1a gene and studied the mechanisms for the S218L syndrome by analyzing the phenotypic, molecular, and electrophysiological consequences. RESULTS: Cacna1a(S218L) mice faithfully mimic the associated clinical features of the human S218L syndrome. S218L neurons exhibit a gene dosage-dependent negative shift in voltage dependence of Ca(V)2.1 channel activation, resulting in enhanced neurotransmitter release at the neuromuscular junction. Cacna1a(S218L) mice also display an exquisite sensitivity to cortical spreading depression (CSD), with a vastly reduced triggering threshold, an increased propagation velocity, and frequently multiple CSD events after a single stimulus. In contrast, mice bearing the R192Q CACNA1A mutation, which in humans causes a milder form of hemiplegic migraine, typically exhibit only a single CSD event after one triggering stimulus. INTERPRETATION: The particularly low CSD threshold and the strong tendency to respond with multiple CSD events make the S218L cortex highly vulnerable to weak stimuli and may provide a mechanistic basis for the dramatic phenotype seen in S218L mice and patients. Thus, the S218L mouse model may prove a valuable tool to further elucidate mechanisms underlying migraine, seizures, ataxia, and trauma-triggered cerebral edema.
Asunto(s)
Canales de Calcio Tipo P/genética , Canales de Calcio Tipo P/metabolismo , Canales de Calcio Tipo Q/genética , Canales de Calcio Tipo Q/metabolismo , Depresión de Propagación Cortical/genética , Depresión de Propagación Cortical/fisiología , Trastornos Migrañosos/genética , Trastornos Migrañosos/fisiopatología , Animales , Encéfalo/fisiopatología , Canales de Calcio Tipo N , Modelos Animales de Enfermedad , Femenino , Predisposición Genética a la Enfermedad , Masculino , Potenciales de la Membrana/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Mutación Missense , Unión Neuromuscular/fisiopatología , Neuronas/fisiología , Neurotransmisores/metabolismo , SíndromeRESUMEN
The first few hours and days after subarachnoid hemorrhage (SAH) are characterized by cerebral ischemia, spasms of pial arterioles, and a significant reduction of cerebral microperfusion, however, the mechanisms of this early microcirculatory dysfunction are still unknown. Endothelial nitric oxide production is reduced after SAH and exogenous application of NO reduces post-hemorrhagic microvasospasm. Therefore, we hypothesize that the endothelial NO-synthase (eNOS) may be involved in the formation of microvasospasms, microcirculatory dysfunction, and unfavorable outcome after SAH. SAH was induced in male eNOS deficient (eNOS-/-) mice by endovascular MCA perforation. Three hours later, the cerebral microcirculation was visualized using in vivo 2-photon-microscopy. eNOS-/- mice had more severe SAHs, more severe ischemia, three time more rebleedings, and a massively increased mortality (50 vs. 0%) as compared to wild type (WT) littermate controls. Three hours after SAH eNOS-/- mice had fewer perfused microvessels and 40% more microvasospasms than WT mice. The current study indicates that a proper function of eNOS plays a key role for a favorable outcome after SAH and helps to explain why patients suffering from hypertension or other conditions associated with impaired eNOS function, have a higher risk of unfavorable outcome after SAH.