Decreased sodium permeability across the blood-brain barrier occurs in streptozotocin-treated rat... more Decreased sodium permeability across the blood-brain barrier occurs in streptozotocin-treated rats after 2 weeks of diabetes. To establish whether this is a phenomenon specific for cations, the blood-brain barrier permeability for sodium, potassium and calcium was studied with an arterial integral uptake technique. Experiments were performed in control rats and, after two weeks after diabetes induction, in untreated streptozotocin-diabetic rats and in insulin-treated streptozotocin rats. In untreated diabetes, the neocortical blood-brain barrier permeability for sodium decreased by 35% (5.2 +/- 1.7 vs 3.4 +/- 1.1 10(-5).cm3.s-1.g-1) and potassium permeability by 39% (19.8 +/- 5.7 vs 12.1 +/- 3.9 10(-5).cm3.s-1.g-1), whereas no differences in calcium permeability occurred. Insulin treatment was associated with an increase in the blood-brain barrier permeability to sodium (4.8 +/- 1.0 10(-5).cm3.s-1.g-1) as compared to untreated diabetes (3.4 +/- 1.1 10(-5).cm3.s-1.g-1). It is concluded that the observed changes in sodium and potassium permeability cannot be caused by electrostatic membrane changes. More specific abnormalities of the transport of sodium and potassium across the blood-brain barrier are likely to occur; disturbances in the sodium-potassium-pump activity could account for such alterations.
Journal of Neurology Neurosurgery and Psychiatry, Nov 1, 2010
To highlight the group of hydrocephalus patients known to have a long history of shunt revisions ... more To highlight the group of hydrocephalus patients known to have a long history of shunt revisions and refractory chronic headache. When a shunt in perfect working order has no effect on headache, other causes of headache should be investigated. In this paper, patients with medication overuse headache are identified and the positive effect of medication withdrawal are described. Patients with hydrocephalus and shunt referred from the neurosurgical department to the Danish Headache Centre were identified. In all cases, over- and underdrainage was ruled out prior to referral. Six patients with medication overuse headache were documented and their charts were reviewed retrospectively with specific attention to: shunt revisions, inpatient and outpatient contacts, headache data and medication use before and after withdrawal of analgesic medication overuse. A marked reduction in shunt revisions and inpatient contacts in five out of six patients was found and a reduction in outpatient contacts in four out of six patients. Furthermore, an improvement in headache intensity was found in three out of six patients and a reduction in duration was found in two out of six patients. This study indicates that it is important to identify shunt patients with persistent chronic headache from causes other than shunt malfunction. By reducing their analgesic intake, it is possible to reduce headaches, the number of surgical interventions and hospital contacts. Hopefully this will raise awareness and lead to further research on the subject.
We currently do not have sufficient knowledge regarding appropriate boundaries between "norm... more We currently do not have sufficient knowledge regarding appropriate boundaries between "normal" and "abnormal" intracranial pressure (ICP) in humans. Our objective in this study was to quantify the effects of postural changes on ICP in normal and ill subjects. As a model for normal patients, we included adult patients scheduled for complete removal of a solitary, clearly demarcated, small brain tumor and performed long-term ICP monitoring using a telemetric device. The ill subjects included required invasive ICP monitoring as part of their diagnostic workup or monitoring of the effect of shunt treatment at our department. All patients were included prospectively for a session of monitored changes in body posture. In our preliminary results from 19 patients, we were able to statistically distinguish between patient groups and assumed body postures, highlighting the need for the further characterization of the effects of postural changes on ICP to inform diagnostic...
Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery, Jan 3, 2016
Confusion has surrounded the description of post-operative mutism and associated morbidity in ped... more Confusion has surrounded the description of post-operative mutism and associated morbidity in pediatric patients with cerebellar tumors for years. The heterogeneity of definitions and diagnostic features has hampered research progress within the field, and to date, no international guidelines exist on diagnosis, prevention, treatment, or follow-up of this debilitating condition. An international group of clinicians and researchers from multiple relevant disciplines recently formed a cohesive panel to formulate a new working definition and agree upon standardized methods for diagnosis and follow-up. Consensus was obtained using the modified nominal group technique, involving four rounds of online Delphi questionnaires interspersed with a structured consensus conference with lectures, group work, and open discussion sessions. A new, proposed definition of "post-operative pediatric CMS" was formed, preliminary recommendations for diagnostic and follow-up procedures were creat...
The mechanisms underlying secondary or delayed cell death following traumatic brain injury are po... more The mechanisms underlying secondary or delayed cell death following traumatic brain injury are poorly understood. Recent evidence from experimental models suggests that widespread neuronal loss is progressive and continues in selectively vulnerable brain regions for months to years after the initial insult. The mechanisms underlying delayed cell death are believed to result, in part, from the release or activation of endogenous "autodestructive" pathways induced by the traumatic injury. The development of sophisticated neurochemical, histopathological and molecular techniques to study animal models of TBI have enabled researchers to begin to explore the cellular and genomic pathways that mediate cell damage and death. This new knowledge has stimulated the development of novel therapeutic agents designed to modify gene expression, synthesis, release, receptor or functional activity of these pathological factors with subsequent attenuation of cellular damage and improvement in behavioral function. This article represents a compendium of recent studies suggesting that modification of post-traumatic neurochemical and cellular events with targeted pharmacotherapy can promote functional recovery following traumatic injury to the central nervous system.
Implant infection and obstruction are major complications for ventriculoperitoneal shunts in pati... more Implant infection and obstruction are major complications for ventriculoperitoneal shunts in patients with post-haemorrhagic hydrocephalus. In an effort to (1) reduce the incidence of these complications, (2) reduce the rate of shunt failure and (3) shorten the duration of neurosurgical hospitalisation, we have implemented valveless ventriculoperitoneal shunts at our department for adult patients with post-haemorrhagic hydrocephalus and haemorrhagic cerebrospinal fluid at the time of shunt insertion. All adult patients (>18 years old) treated for post-haemorrhagic hydrocephalus with ventriculoperitoneal shunting at our institution from 1 January 2008 to 31 December 2014 were included in this retrospective population-based consecutive cohort study. Data were collected by retrospectively reviewing medical records. We compared two different shunt modalities (valveless vs valve-regulated), analysing frequencies of complications, shunt survival and duration of neurosurgical hospitalis...
... T. Gudrunardottir .A. Sehested .K. Schmiegelow (*) Department of Pediatrics, University Hospi... more ... T. Gudrunardottir .A. Sehested .K. Schmiegelow (*) Department of Pediatrics, University Hospital Rigshospitalet, Copenhagen, Denmark e-mail: kschmiegelow@rh.dk ... methods of monitoring the acute and late sequelae of posterior fossa surgery, that is now recognized to ...
American journal of physiology. Regulatory, integrative and comparative physiology, Jan 14, 2015
We evaluated postural effects on intracranial pressure (ICP) and cerebral perfusion pressure (CPP... more We evaluated postural effects on intracranial pressure (ICP) and cerebral perfusion pressure (CPP: mean arterial pressure (MAP) - ICP) in neurosurgical patients undergoing 24-hour ICP monitoring as part of their diagnostic workup. We identified 9 patients (5 women, age 44±20 yrs.; mean±SD) who were "as normal as possible" i.e. without indication for neurosurgical intervention (e.g. focal lesions, global edema, abnormalities in ICP-profile or cerebrospinal fluid dynamics). ICP (tip-transducer probe, Raumedic) in the brain parenchyma (N=7) or in the lateral ventricles (N=2) and cardiovascular variables (Nexfin) were determined from 20° head-down tilt to standing up. Compared to the supine position, ICP increased during 10° and 20° of head-down tilt (from 9.4±3.8 to 14.3±4.7 and 19±4.7 mmHg, P<0.001). Conversely, 10° and 20° head-up tilt reduced ICP to 4.8±3.6 and 1.3±3.6 mmHg and ICP reached -2.4±4.2 mmHg when standing up (P<0.05). Concordant changes in MAP maintained ...
For decades, the preferred and almost sole method for measurement of gene expression has been RT-... more For decades, the preferred and almost sole method for measurement of gene expression has been RT-qPCR. The method is robust, inexpensive, and well-studied; however, PCR is also quite laborious and vulnerable to contamination. As part of an investigation of VEGF-A gene expression in meningiomas, an alternative and less laborious method for gene expression analysis based on branched DNA hybridization and chemiluminescence (Lumistar) was tested. Albeit the two methods differ, in principle, cellular mRNA-concentration is measured with both. Because they both determine gene expression via the measurement of mRNA-concentration, they were expected to be comparable. The aim of the present study was to compare Lumistar to the traditional RT-qPCR approach in a routine laboratory setting, where there is emphasis on rapid analysis response. Meningioma (n = 10) and control brain tissue (n = 5) samples were collected and VEGF-A and GAPDH mRNA were quantified using both RT-qPCR and Lumistar. Furth...
Journal of neurosurgical anesthesiology, Jan 4, 2015
Delayed cerebral ischemia (DCI) is a serious and frequent complication following subarachnoid hem... more Delayed cerebral ischemia (DCI) is a serious and frequent complication following subarachnoid hemorrhage. Treatments with convincing effect are lacking and the pathophysiology behind DCI remains poorly understood. Neuropeptide Y (NPY) is a potent endogenous vasoconstrictor and a role of NPY in the development of DCI has been proposed. This study investigated the relationship between plasma-NPY and cerebral blood flow (CBF), cerebral vasospasm, DCI, and clinical outcome. In 90 patients with subarachnoid hemorrhage, NPY was measured in peripheral blood days 2 to 11. Any occurrence of DCI was recorded and CBF was quantified day 3 and day 8 using computed tomography (CT) perfusion. CT angiography was performed day 8. Clinical outcome was assessed after 3 months. No correlation was found between plasma-NPY and CBF or angiographic vasospasm. The correlation between reduced plasma-NPY and DCI reached borderline statistical significance (P=0.05). Increased levels of NPY measured on days 2 t...
Delayed ischemic neurological deficits (DINDs) are a major contributing factor for poor outcome i... more Delayed ischemic neurological deficits (DINDs) are a major contributing factor for poor outcome in patients with subarachnoid hemorrhage. In this trial, we investigated the therapeutic potential of prostacyclin, an endogen substance with known effect on vascular tone and blood flow regulation, on factors related to DIND. This trial is a single-center, randomized, blinded, clinical, pilot trial with 3 arms. Ninety patients were randomized to continuous infusion of prostacyclin 1 ng/kg per minute, prostacyclin 2 ng/kg per minute, or placebo. The intervention was initiated day 5 after subarachnoid hemorrhage and discontinued day 10. Primary outcome was the difference in change from baseline in global cerebral blood flow. Secondary outcome measures were occurrence of DIND, angiographic vasospasm, and clinical outcome at 3 months. No statistically significant difference in change of global cerebral blood flow was found between the intervention groups. The observed incidence of DIND and a...
One of the main causes of mortality and morbidity following subarachnoid hemorrhage (SAH) is the ... more One of the main causes of mortality and morbidity following subarachnoid hemorrhage (SAH) is the development of cerebral vasospasm, a frequent complication arising in the weeks after the initial bleeding. Despite extensive research, no effective treatment of vasospasm exists to date. Prostacyclin is a potent vasodilator and inhibitor of platelet aggregation. In vitro models have shown a relaxing effect of prostacyclin after induced contraction in cerebral arteries, and a recent pilot trial showed a positive effect on cerebral vasospasm in a clinical setting. No randomized clinical trials have investigated the possible pharmacodynamic effects of prostacyclin on the human brain following SAH. This trial is a single centre, randomized, placebo-controlled, parallel group, double blinded, clinical pilot trial. A total of 90 patients with SAH will be randomized to one of three intervention arms: epoprostenol at 1 ng/kg/min, epoprostenol at 2 ng/kg/min, or placebo in addition to the standa...
Decreased sodium permeability across the blood-brain barrier occurs in streptozotocin-treated rat... more Decreased sodium permeability across the blood-brain barrier occurs in streptozotocin-treated rats after 2 weeks of diabetes. To establish whether this is a phenomenon specific for cations, the blood-brain barrier permeability for sodium, potassium and calcium was studied with an arterial integral uptake technique. Experiments were performed in control rats and, after two weeks after diabetes induction, in untreated streptozotocin-diabetic rats and in insulin-treated streptozotocin rats. In untreated diabetes, the neocortical blood-brain barrier permeability for sodium decreased by 35% (5.2 +/- 1.7 vs 3.4 +/- 1.1 10(-5).cm3.s-1.g-1) and potassium permeability by 39% (19.8 +/- 5.7 vs 12.1 +/- 3.9 10(-5).cm3.s-1.g-1), whereas no differences in calcium permeability occurred. Insulin treatment was associated with an increase in the blood-brain barrier permeability to sodium (4.8 +/- 1.0 10(-5).cm3.s-1.g-1) as compared to untreated diabetes (3.4 +/- 1.1 10(-5).cm3.s-1.g-1). It is concluded that the observed changes in sodium and potassium permeability cannot be caused by electrostatic membrane changes. More specific abnormalities of the transport of sodium and potassium across the blood-brain barrier are likely to occur; disturbances in the sodium-potassium-pump activity could account for such alterations.
Journal of Neurology Neurosurgery and Psychiatry, Nov 1, 2010
To highlight the group of hydrocephalus patients known to have a long history of shunt revisions ... more To highlight the group of hydrocephalus patients known to have a long history of shunt revisions and refractory chronic headache. When a shunt in perfect working order has no effect on headache, other causes of headache should be investigated. In this paper, patients with medication overuse headache are identified and the positive effect of medication withdrawal are described. Patients with hydrocephalus and shunt referred from the neurosurgical department to the Danish Headache Centre were identified. In all cases, over- and underdrainage was ruled out prior to referral. Six patients with medication overuse headache were documented and their charts were reviewed retrospectively with specific attention to: shunt revisions, inpatient and outpatient contacts, headache data and medication use before and after withdrawal of analgesic medication overuse. A marked reduction in shunt revisions and inpatient contacts in five out of six patients was found and a reduction in outpatient contacts in four out of six patients. Furthermore, an improvement in headache intensity was found in three out of six patients and a reduction in duration was found in two out of six patients. This study indicates that it is important to identify shunt patients with persistent chronic headache from causes other than shunt malfunction. By reducing their analgesic intake, it is possible to reduce headaches, the number of surgical interventions and hospital contacts. Hopefully this will raise awareness and lead to further research on the subject.
We currently do not have sufficient knowledge regarding appropriate boundaries between "norm... more We currently do not have sufficient knowledge regarding appropriate boundaries between "normal" and "abnormal" intracranial pressure (ICP) in humans. Our objective in this study was to quantify the effects of postural changes on ICP in normal and ill subjects. As a model for normal patients, we included adult patients scheduled for complete removal of a solitary, clearly demarcated, small brain tumor and performed long-term ICP monitoring using a telemetric device. The ill subjects included required invasive ICP monitoring as part of their diagnostic workup or monitoring of the effect of shunt treatment at our department. All patients were included prospectively for a session of monitored changes in body posture. In our preliminary results from 19 patients, we were able to statistically distinguish between patient groups and assumed body postures, highlighting the need for the further characterization of the effects of postural changes on ICP to inform diagnostic...
Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery, Jan 3, 2016
Confusion has surrounded the description of post-operative mutism and associated morbidity in ped... more Confusion has surrounded the description of post-operative mutism and associated morbidity in pediatric patients with cerebellar tumors for years. The heterogeneity of definitions and diagnostic features has hampered research progress within the field, and to date, no international guidelines exist on diagnosis, prevention, treatment, or follow-up of this debilitating condition. An international group of clinicians and researchers from multiple relevant disciplines recently formed a cohesive panel to formulate a new working definition and agree upon standardized methods for diagnosis and follow-up. Consensus was obtained using the modified nominal group technique, involving four rounds of online Delphi questionnaires interspersed with a structured consensus conference with lectures, group work, and open discussion sessions. A new, proposed definition of "post-operative pediatric CMS" was formed, preliminary recommendations for diagnostic and follow-up procedures were creat...
The mechanisms underlying secondary or delayed cell death following traumatic brain injury are po... more The mechanisms underlying secondary or delayed cell death following traumatic brain injury are poorly understood. Recent evidence from experimental models suggests that widespread neuronal loss is progressive and continues in selectively vulnerable brain regions for months to years after the initial insult. The mechanisms underlying delayed cell death are believed to result, in part, from the release or activation of endogenous &quot;autodestructive&quot; pathways induced by the traumatic injury. The development of sophisticated neurochemical, histopathological and molecular techniques to study animal models of TBI have enabled researchers to begin to explore the cellular and genomic pathways that mediate cell damage and death. This new knowledge has stimulated the development of novel therapeutic agents designed to modify gene expression, synthesis, release, receptor or functional activity of these pathological factors with subsequent attenuation of cellular damage and improvement in behavioral function. This article represents a compendium of recent studies suggesting that modification of post-traumatic neurochemical and cellular events with targeted pharmacotherapy can promote functional recovery following traumatic injury to the central nervous system.
Implant infection and obstruction are major complications for ventriculoperitoneal shunts in pati... more Implant infection and obstruction are major complications for ventriculoperitoneal shunts in patients with post-haemorrhagic hydrocephalus. In an effort to (1) reduce the incidence of these complications, (2) reduce the rate of shunt failure and (3) shorten the duration of neurosurgical hospitalisation, we have implemented valveless ventriculoperitoneal shunts at our department for adult patients with post-haemorrhagic hydrocephalus and haemorrhagic cerebrospinal fluid at the time of shunt insertion. All adult patients (>18 years old) treated for post-haemorrhagic hydrocephalus with ventriculoperitoneal shunting at our institution from 1 January 2008 to 31 December 2014 were included in this retrospective population-based consecutive cohort study. Data were collected by retrospectively reviewing medical records. We compared two different shunt modalities (valveless vs valve-regulated), analysing frequencies of complications, shunt survival and duration of neurosurgical hospitalis...
... T. Gudrunardottir .A. Sehested .K. Schmiegelow (*) Department of Pediatrics, University Hospi... more ... T. Gudrunardottir .A. Sehested .K. Schmiegelow (*) Department of Pediatrics, University Hospital Rigshospitalet, Copenhagen, Denmark e-mail: kschmiegelow@rh.dk ... methods of monitoring the acute and late sequelae of posterior fossa surgery, that is now recognized to ...
American journal of physiology. Regulatory, integrative and comparative physiology, Jan 14, 2015
We evaluated postural effects on intracranial pressure (ICP) and cerebral perfusion pressure (CPP... more We evaluated postural effects on intracranial pressure (ICP) and cerebral perfusion pressure (CPP: mean arterial pressure (MAP) - ICP) in neurosurgical patients undergoing 24-hour ICP monitoring as part of their diagnostic workup. We identified 9 patients (5 women, age 44±20 yrs.; mean±SD) who were "as normal as possible" i.e. without indication for neurosurgical intervention (e.g. focal lesions, global edema, abnormalities in ICP-profile or cerebrospinal fluid dynamics). ICP (tip-transducer probe, Raumedic) in the brain parenchyma (N=7) or in the lateral ventricles (N=2) and cardiovascular variables (Nexfin) were determined from 20° head-down tilt to standing up. Compared to the supine position, ICP increased during 10° and 20° of head-down tilt (from 9.4±3.8 to 14.3±4.7 and 19±4.7 mmHg, P<0.001). Conversely, 10° and 20° head-up tilt reduced ICP to 4.8±3.6 and 1.3±3.6 mmHg and ICP reached -2.4±4.2 mmHg when standing up (P<0.05). Concordant changes in MAP maintained ...
For decades, the preferred and almost sole method for measurement of gene expression has been RT-... more For decades, the preferred and almost sole method for measurement of gene expression has been RT-qPCR. The method is robust, inexpensive, and well-studied; however, PCR is also quite laborious and vulnerable to contamination. As part of an investigation of VEGF-A gene expression in meningiomas, an alternative and less laborious method for gene expression analysis based on branched DNA hybridization and chemiluminescence (Lumistar) was tested. Albeit the two methods differ, in principle, cellular mRNA-concentration is measured with both. Because they both determine gene expression via the measurement of mRNA-concentration, they were expected to be comparable. The aim of the present study was to compare Lumistar to the traditional RT-qPCR approach in a routine laboratory setting, where there is emphasis on rapid analysis response. Meningioma (n = 10) and control brain tissue (n = 5) samples were collected and VEGF-A and GAPDH mRNA were quantified using both RT-qPCR and Lumistar. Furth...
Journal of neurosurgical anesthesiology, Jan 4, 2015
Delayed cerebral ischemia (DCI) is a serious and frequent complication following subarachnoid hem... more Delayed cerebral ischemia (DCI) is a serious and frequent complication following subarachnoid hemorrhage. Treatments with convincing effect are lacking and the pathophysiology behind DCI remains poorly understood. Neuropeptide Y (NPY) is a potent endogenous vasoconstrictor and a role of NPY in the development of DCI has been proposed. This study investigated the relationship between plasma-NPY and cerebral blood flow (CBF), cerebral vasospasm, DCI, and clinical outcome. In 90 patients with subarachnoid hemorrhage, NPY was measured in peripheral blood days 2 to 11. Any occurrence of DCI was recorded and CBF was quantified day 3 and day 8 using computed tomography (CT) perfusion. CT angiography was performed day 8. Clinical outcome was assessed after 3 months. No correlation was found between plasma-NPY and CBF or angiographic vasospasm. The correlation between reduced plasma-NPY and DCI reached borderline statistical significance (P=0.05). Increased levels of NPY measured on days 2 t...
Delayed ischemic neurological deficits (DINDs) are a major contributing factor for poor outcome i... more Delayed ischemic neurological deficits (DINDs) are a major contributing factor for poor outcome in patients with subarachnoid hemorrhage. In this trial, we investigated the therapeutic potential of prostacyclin, an endogen substance with known effect on vascular tone and blood flow regulation, on factors related to DIND. This trial is a single-center, randomized, blinded, clinical, pilot trial with 3 arms. Ninety patients were randomized to continuous infusion of prostacyclin 1 ng/kg per minute, prostacyclin 2 ng/kg per minute, or placebo. The intervention was initiated day 5 after subarachnoid hemorrhage and discontinued day 10. Primary outcome was the difference in change from baseline in global cerebral blood flow. Secondary outcome measures were occurrence of DIND, angiographic vasospasm, and clinical outcome at 3 months. No statistically significant difference in change of global cerebral blood flow was found between the intervention groups. The observed incidence of DIND and a...
One of the main causes of mortality and morbidity following subarachnoid hemorrhage (SAH) is the ... more One of the main causes of mortality and morbidity following subarachnoid hemorrhage (SAH) is the development of cerebral vasospasm, a frequent complication arising in the weeks after the initial bleeding. Despite extensive research, no effective treatment of vasospasm exists to date. Prostacyclin is a potent vasodilator and inhibitor of platelet aggregation. In vitro models have shown a relaxing effect of prostacyclin after induced contraction in cerebral arteries, and a recent pilot trial showed a positive effect on cerebral vasospasm in a clinical setting. No randomized clinical trials have investigated the possible pharmacodynamic effects of prostacyclin on the human brain following SAH. This trial is a single centre, randomized, placebo-controlled, parallel group, double blinded, clinical pilot trial. A total of 90 patients with SAH will be randomized to one of three intervention arms: epoprostenol at 1 ng/kg/min, epoprostenol at 2 ng/kg/min, or placebo in addition to the standa...
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