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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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Cistos Aracnóideos , Neoplasias Encefálicas , Glioma , Neoplasias Hipofisárias , Humanos , Adulto , Pessoa de Meia-Idade , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , Neoplasias Encefálicas/cirurgia , Glioma/diagnóstico por imagem , Glioma/cirurgia , Cistos Aracnóideos/cirurgia , CatéteresRESUMO
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 Subaracnóidea , Humanos , Animais , Camundongos , Masculino , Nimodipina/farmacologia , Nimodipina/uso terapêutico , Hemorragia Subaracnóidea/complicações , Hemorragia Subaracnóidea/tratamento farmacológico , Microcirculação , Camundongos Endogâmicos C57BL , MicrovasosRESUMO
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 Subaracnóidea , Camundongos , Animais , Pericitos/fisiologia , Capilares , Hemorragia Subaracnóidea/complicações , Vasoconstrição/fisiologia , PerfusãoRESUMO
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 , Neuroendoscopia , Terceiro Ventrículo , Humanos , Masculino , Feminino , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Ventriculostomia/efeitos adversos , Resultado do Tratamento , Estudos Retrospectivos , Terceiro Ventrículo/cirurgia , Neuroendoscopia/efeitos adversos , Hidrocefalia/etiologia , Hidrocefalia/cirurgia , Hidrocefalia/diagnósticoRESUMO
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 Subaracnóidea/metabolismo , Vasoespasmo Intracraniano/metabolismo , Animais , Dioxanos/farmacologia , Antagonistas do Receptor de Endotelina A/farmacologia , Endotelina-1/metabolismo , Masculino , Camundongos , Microscopia de Fluorescência por Excitação Multifotônica , Piridinas/farmacologia , Pirimidinas/farmacologia , Hemorragia Subaracnóidea/tratamento farmacológico , Hemorragia Subaracnóidea/fisiopatologia , Sulfonamidas/farmacologia , Tetrazóis/farmacologia , Vasoespasmo Intracraniano/tratamento farmacológico , Vasoespasmo Intracraniano/fisiopatologiaRESUMO
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 , Mutação , Regiões Promotoras Genéticas , Telomerase/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Feminino , Humanos , Masculino , Neoplasias Meníngeas/mortalidade , Neoplasias Meníngeas/patologia , Neoplasias Meníngeas/cirurgia , Meningioma/mortalidade , Meningioma/patologia , Meningioma/cirurgia , Pessoa de Meia-Idade , Gradação de Tumores , Prognóstico , Estudos RetrospectivosRESUMO
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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Arteríolas/fisiologia , Isquemia Encefálica/prevenção & controle , Circulação Colateral/fisiologia , Óxido Nítrico/uso terapêutico , Acidente Vascular Cerebral/prevenção & controle , Vasodilatação/fisiologia , Administração por Inalação , Animais , Arteríolas/efeitos dos fármacos , Encéfalo/irrigação sanguínea , Isquemia Encefálica/patologia , Isquemia Encefálica/fisiopatologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Circulação Colateral/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Neurônios/patologia , Óxido Nítrico/administração & dosagem , Óxido Nítrico/farmacologia , Fluxo Sanguíneo Regional/efeitos dos fármacos , Fluxo Sanguíneo Regional/fisiologia , Ovinos , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/fisiopatologia , Vasodilatação/efeitos dos fármacosRESUMO
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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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.
Assuntos
Edema Encefálico , Lesões Encefálicas Traumáticas , Enxaqueca com Aura , Animais , Edema Encefálico/genética , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/genética , Canais de Cálcio Tipo N/genética , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Enxaqueca com Aura/genética , Mutação , Convulsões/genéticaRESUMO
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.
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Lesões Encefálicas/patologia , Isquemia Encefálica/patologia , Microvasos/patologia , Óxido Nítrico Sintase Tipo III/fisiologia , Óxido Nítrico/metabolismo , Hemorragia Subaracnóidea/patologia , Vasoespasmo Intracraniano/patologia , Animais , Lesões Encefálicas/etiologia , Lesões Encefálicas/metabolismo , Isquemia Encefálica/etiologia , Isquemia Encefálica/metabolismo , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Knockout , Microcirculação , Hemorragia Subaracnóidea/complicações , Hemorragia Subaracnóidea/metabolismo , Vasoespasmo Intracraniano/etiologia , Vasoespasmo Intracraniano/metabolismoRESUMO
Traumatic brain injury (TBI) causes long-lasting neurodegeneration and cognitive impairments; however, the underlying mechanisms of these processes are not fully understood. Acid-sensing ion channels 1a (ASIC1a) are voltage-gated Na+- and Ca2+-channels shown to be involved in neuronal cell death; however, their role for chronic post-traumatic brain damage is largely unknown. To address this issue, we used ASIC1a-deficient mice and investigated their outcome up to 6 months after TBI. ASIC1a-deficient mice and their wild-type (WT) littermates were subjected to controlled cortical impact (CCI) or sham surgery. Brain water content was analyzed 24 h and behavioral outcome up to 6 months after CCI. Lesion volume was assessed longitudinally by magnetic resonance imaging and 6 months after injury by histology. Brain water content was significantly reduced in ASIC1a-/- animals compared to WT controls. Over time, ASIC1a-/- mice showed significantly reduced lesion volume and reduced hippocampal damage. This translated into improved cognitive function and reduced depression-like behavior. Microglial activation was significantly reduced in ASIC1a-/- mice. In conclusion, ASIC1a deficiency resulted in reduced edema formation acutely after TBI and less brain damage, functional impairments, and neuroinflammation up to 6 months after injury. Hence, ASIC1a seems to be involved in chronic neurodegeneration after TBI.
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Canais Iônicos Sensíveis a Ácido/deficiência , Dano Encefálico Crônico/etiologia , Dano Encefálico Crônico/patologia , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/patologia , Animais , Dano Encefálico Crônico/psicologia , Lesões Encefálicas Traumáticas/psicologia , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Transgênicos , Atividade MotoraRESUMO
Many compounds tested for a possible neuroprotective effect after traumatic brain injury (TBI) are not readily soluble and therefore organic solvents need to be used as a vehicle. It is, however, unclear whether these organic solvents have intrinsic pharmacological effects on secondary brain damage and may therefore interfere with experimental results. Thus, the aim of the current study was to evaluate the effect of four widely used organic solvents, dimethylsulfoxide (DMSO), Miglyol 812 (Miglyol®), polyethyleneglycol 40 (PEG 40), and N-2-methyl-pyrrolidone (NMP) on outcome after TBI in mice. A total of 143 male C57Bl/6 mice were subjected to controlled cortical impact (CCI). Contusion volume, brain edema formation, and neurological function were assessed 24 h after TBI. Test substances or saline were injected intraperitoneally (i.p.) 10 min before CCI. DMSO, Miglyol, and PEG 40 had no effect on post-traumatic contusion volume after CCI; NMP, however, significantly reduced contusion volume and brain edema formation at different concentrations. The use of DMSO, Miglyol, and PEG 40 is unproblematic for studies investigating neuroprotective treatment strategies as they do not influence post-traumatic brain damage. NMP seems to have an intrinsic neuroprotective effect that should be considered when using this agent in pharmacological experiments; further, a putative therapeutic effect of NMP needs to be elucidated in future studies.
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CO2-reactivity and neurovascular coupling are sequentially lost within the first 24 h after subarachnoid hemorrhage (SAH). Whether and when these impairments recover is not known. Therefore, we investigated the reactivity of pial and intraparenchymal vessels by in vivo two-photon microscopy one month after experimental SAH. C57BL/6 mice were subjected to either sham surgery or SAH by filament perforation. One month later, cerebral blood flow following CO2-challenge and forepaw stimulation was assessed by laser Doppler fluxmetry. Diameters of pial and intraparenchymal arterioles were quantified by in vivo two-photon microscopy. One month after SAH, pial and parenchymal vessels dilated in response to CO2. Neurovascular coupling was almost completely absent after SAH: vessel diameter did not change upon forepaw stimulation compared to a 20% increase in sham-operated mice. The current results demonstrate that neurovascular function differentially recovers after SAH: while CO2-reactivity normalizes within one month after SAH, neurovascular coupling is still absent. These findings show an acute and persistent loss of neurovascular coupling after SAH that may serve as a link between early brain injury and delayed cerebral ischemia, two distinct pathophysiological phenomena after SAH that were so far believed not to be directly related.
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Acoplamento Neurovascular/fisiologia , Hemorragia Subaracnóidea/fisiopatologia , Animais , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Increasing clinical and experimental evidence suggests that traumatic brain injury (TBI) is associated with progressive histopathological damage. The aim of the current study was to characterize the time course of motor function, memory performance, and depression-like behavior up to 1 year after experimental TBI, and to correlate these changes to histopathological outcome. Male C57BL/6N mice underwent controlled cortical impact (CCI) or sham operation, and histopathological outcome was evaluated 15 min, 24 h, 1 week, or 1, 3, 6, or 12 months thereafter (n = 12 animals per time point). Motor function, depression-like behavior, and memory function were evaluated concomitantly, and magnetic resonance imaging (MRI) was repeatedly performed. Naïve mice (n = 12) served as an unhandled control group. Injury volume almost doubled within 1 year after CCI (p = 0.008) and the ipsilateral hemisphere became increasingly atrophic (p < 0.0001). Progressive tissue loss was observed in the corpus callosum (p = 0.007) and the hippocampus (p = 0.004) together with hydrocephalus formation (p < 0.0001). Motor function recovered partially after TBI, but 6 months after injury progressive depression-like behavior (p < 0.0001) and loss of memory function (p < 0.0001) were observed. The present study demonstrates that delayed histopathological damage that occurs over months after brain injury is followed by progressive depression and memory loss, changes also observed after TBI in humans. Hence, experimental TBI models in mice replicate long-term sequelae of brain injury such as post-traumatic dementia and depression.
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Lesões Encefálicas Traumáticas/patologia , Disfunção Cognitiva/patologia , Depressão/patologia , Progressão da Doença , Animais , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/etiologia , Depressão/diagnóstico por imagem , Depressão/etiologia , Imageamento por Ressonância Magnética/tendências , Transtornos da Memória/diagnóstico por imagem , Transtornos da Memória/etiologia , Transtornos da Memória/patologia , Camundongos , Fatores de TempoRESUMO
Epidemiological studies suggest that pharmacological reduction of systemic hypertension lowers incidence and severity of stroke. However, whether the reduction of blood pressure per se or the compounds used to reduce hypertension are responsible for this effect received little attention. In the current study we therefore aimed to investigate whether Aliskiren, a renin-inhibitor used to treat arterial hypertension, may improve outcome in a mouse model of ischemic stroke when applied centrally and in a dose not affecting blood pressure. Male C57BL/6 mice received 0.6, 2.0, or 6.0 µg Aliskiren or vehicle by intracerebroventricular injection as a pre-treatment and were then subjected to 60 min of middle cerebral artery occlusion (MCAo). Infarct volume, brain edema formation, mortality, antioxidant effects, and functional outcome were assessed up to seven days after MCAo. Central administration of Aliskiren (0.6 or 2.0 µg) had no effect on systemic blood pressure but significantly reduced infarct volume and brain edema formation, blunted mortality, and improved neurological outcome up to 1 week after MCAo. Due to the central and prophylactic administration of the compound, we cannot make any conclusions about the potency of Aliskiren for acute stroke treatment, however, our study clearly demonstrates, that in addition to lowering blood pressure Aliskiren seems to have a direct neuroprotective effect. Hence, renin-inhibitors may be an effective addition to prophylactic treatment regimens in stroke patients.
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Although changes of cerebral blood flow (CBF) in and around traumatic contusions are well documented, the role of CBF for the delayed death of neuronal cells in the traumatic penumbra ultimately resulting in secondary contusion expansion remains unclear. The aim of the current study was therefore to investigate the relationship between changes of CBF and progressive peri-contusional cell death following traumatic brain injury (TBI). CBF and contusion size were measured in C57Bl6 mice under continuous on-line monitoring of (ETp)CO2 before, and at 15 min and 24 h following controlled cortical impact by 14C-iodoantipyrine autoradiography (IAP-AR; n = 5-6 per group) and by Nissl staining, respectively. Contused and ischemic (CBF < 10%) tissue volumes were calculated and compared over time. Cortical CBF in not injured mice varied between 69 and 93 mL/100mg/min depending on the anatomical location. Fifteen minutes after trauma, CBF decreased in the whole brain by approximately 50% (39 +/- 18 mL/100mg/min; p < 0.05), except in contused tissue where it fell by more than 90% (3 +/- 2 mL/100mg/min; p < 0.001). Within 24 h after TBI, CBF recovered to normal values in all brain areas except the contusion where it remained reduced by more than 90% (p < 0.001). Contusion volume expanded from 24.9 to 35.5 mm3 (p < 0.01) from 15 min to 24 h after trauma (+43%), whereas the area of severe ischemia (CBF < 10%) showed only a minimal (+13%) and not significant increase (22.3 to 25.1 mm3). The current data therefore suggest that the delayed secondary expansion of a cortical contusion following traumatic brain injury may not be caused by a reduction of CBF alone.
Assuntos
Antipirina/análogos & derivados , Autorradiografia/métodos , Lesões Encefálicas/diagnóstico por imagem , Lesões Encefálicas/fisiopatologia , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Circulação Cerebrovascular , Animais , Anti-Inflamatórios não Esteroides , Biomarcadores , Encéfalo/irrigação sanguínea , Infarto Encefálico/diagnóstico por imagem , Infarto Encefálico/fisiopatologia , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/fisiopatologia , Radioisótopos de Carbono , Artérias Cerebrais/diagnóstico por imagem , Artérias Cerebrais/fisiopatologia , Modelos Animais de Doenças , Progressão da Doença , Fluxometria por Laser-Doppler , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microcirculação/diagnóstico por imagem , Microcirculação/fisiopatologia , Degeneração Neural/diagnóstico por imagem , Degeneração Neural/etiologia , Degeneração Neural/fisiopatologia , Cintilografia , Recuperação de Função Fisiológica , Coloração e Rotulagem , Fatores de TempoRESUMO
MicroRNAs (miRNAs) were recently identified as important regulators of gene expression under a wide range of physiological and pathophysiological conditions. Thus, they may represent a novel class of molecular targets for the management of traumatic brain injury (TBI). In this study, we investigated the temporal profile of miRNA expression during the development of secondary brain damage after experimental TBI. For this purpose, we used a controlled cortical impact model in C57Bl/6 mice (n = 6) to induce a cortical contusion and analyzed miRNA expression in the traumatized cortex by microarray analysis during the development of secondary contusion expansion-i.e., at 1, 6, and 12 h after TBI. Of a total 780 mature miRNA sequences analyzed, 410 were detected in all experimental groups. Of these, 158 miRNAs were significantly upregulated or downregulated in TBI compared with sham-operated animals, and 52 miRNAs increased more than twofold. We validated the upregulation of five of the most differentially expressed miRNAs (miR-21*, miR-144, miR-184, miR-451, miR-2137) and the downregulation of four of the most differentially expressed miRNAs (miR-107, miR-137, miR-190, miR-541) by quantitative polymerase chain reaction (qPCR). miR-2137, the most differentially expressed miRNA after TBI, was further investigated by in situ hybridization and was found to be upregulated in neurons within the traumatic penumbra. This study gives a comprehensive picture of miRNA expression levels during secondary contusion expansion after TBI and may pave the way for the identification of novel targets for the management of brain trauma.
Assuntos
Contusão Encefálica/genética , Contusão Encefálica/metabolismo , MicroRNAs/biossíntese , MicroRNAs/genética , Lobo Parietal/metabolismo , Animais , Contusão Encefálica/patologia , Lesões Encefálicas Traumáticas/genética , Lesões Encefálicas Traumáticas/metabolismo , Lesões Encefálicas Traumáticas/patologia , Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Lobo Parietal/patologia , Fatores de TempoRESUMO
OBJECT Treatment of skull base lesions is complex and usually requires a multidisciplinary approach. In meningioma, which is the most common tumor entity in this region, resection is considered to be the most important therapeutic step to avoid tumor recurrence. However, resection of skull base lesions with orbital or optic nerve involvement poses a challenge due to their anatomical structure and their proximity to eloquent areas. Therefore the main goal of surgery should be to achieve the maximum extent of resection while preserving neurological function. In the postoperative course, medical and radiotherapeutic strategies may then be successfully used to treat possible tumor residues. Methods to safely improve the extent of resection in skull base lesions therefore are desirable. The current study reports the authors' experience with the use of intraoperative CT (iCT) combined with neuronavigation with regard to feasibility and possible benefits of the method. METHODS Those patients with tumorous lesions in relationship to the orbit, sphenoid wing, or cavernous sinus who were surgically treated between October 2008 and December 2013 using iCT-based neuronavigation and in whom an intraoperative scan was obtained for control of resection were included. In all cases a second iCT scan was performed under sterile conditions after completion of navigation-guided microsurgical tumor resection. The surgical strategy was adapted accordingly; if necessary, resection was continued. RESULTS Twenty-three patients (19 with WHO Grade I meningioma and 4 with other lesions) were included. The most common clinical symptoms were loss of visual acuity and exophthalmus. Intraoperative control of resection by iCT was successfully obtained in all cases. Intraoperative imaging changed the surgical approach in more than half (52.2%) of these patients, either because iCT demonstrated unexpected residual tumor masses or because the second scan revealed additional tumor tissue that was not detected in the first scan due to overlay by osseous tumor parts; in these cases resection was continued. In the remaining cases resection was concluded as planned because iCT verified the surgeon's microscopic estimation of tumor resection status. Postoperative visual outcome was favorable in more than 80% of patients. CONCLUSIONS Intraoperative CT allows control of resection in case of uncertainty and can help to improve the extent of maximal safe resection, especially in case of osseous tumor parts and masses within the orbit.
Assuntos
Neoplasias Meníngeas/patologia , Neoplasias Meníngeas/cirurgia , Meningioma/patologia , Meningioma/cirurgia , Microcirurgia/métodos , Neoplasia Residual/patologia , Neoplasia Residual/cirurgia , Neuronavegação/métodos , Neoplasias Orbitárias/patologia , Neoplasias Orbitárias/cirurgia , Neoplasias da Base do Crânio/patologia , Neoplasias da Base do Crânio/cirurgia , Cirurgia Assistida por Computador/métodos , Tomografia Computadorizada por Raios X/métodos , Adulto , Feminino , Humanos , Período Intraoperatório , Masculino , Pessoa de Meia-Idade , Reoperação , Sensibilidade e EspecificidadeRESUMO
Microthrombus formation and bleeding worsen the outcome after traumatic brain injury (TBI). The aim of the current study was to characterize these processes in the brain parenchyma after experimental TBI and to determine the involvement of coagulation factor XI (FXI). C57BL/6 mice (n = 101) and FXI-deficient mice (n = 15) were subjected to controlled cortical impact (CCI). Wild-type mice received an inhibitory antibody against FXI (14E11) or control immunoglobulin G 24 h before or 30 or 120 min after CCI. Cerebral microcirculation was visualized in vivo by 2-photon microscopy 2-3 h post-trauma and histopathological outcome was assessed after 24 h. TBI induced hemorrhage and microthrombus formation in the brain parenchyma (p < 0.001). Inhibition of FXI activation or FXI deficiency did not reduce cerebral thrombogenesis, lesion volume, or hemispheric swelling. However, it also did not increase intracranial hemorrhage. Formation of microthrombosis in the brain parenchyma after TBI is independent of the intrinsic coagulation cascade since it was not reduced by inhibition of FXI. However, since targeting FXI has well-established antithrombotic effects in humans and experimental animals, inhibition of FXI could represent a reasonable strategy for the prevention of deep venous thrombosis in immobilized patients with TBI.