Preservation of the blood brain barrier and cortical neuronal tissue by liraglutide, a long acting glucagon-like-1 analogue, after experimental traumatic brain injury.

Cerebral edema is a common complication following moderate and severe traumatic brain injury (TBI), and a significant risk factor for development of neuronal death and deterioration of neurological outcome. To this date, medical approaches that effectively alleviate cerebral edema and neuronal death after TBI are not available. Glucagon-like peptide-1 (GLP-1) has anti-inflammatory properties on cerebral endothelium and exerts neuroprotective effects. Here, we investigated the effects of GLP-1 on secondary injury after moderate and severe TBI. Male Sprague Dawley rats were subjected either to TBI by Controlled Cortical Impact (CCI) or sham surgery. After surgery, vehicle or a GLP-1 analogue, Liraglutide, were administered subcutaneously twice daily for two days. Treatment with Liraglutide (200 µg/kg) significantly reduced cerebral edema in pericontusional regions and improved sensorimotor function 48 hours after CCI. The integrity of the blood-brain barrier was markedly preserved in Liraglutide treated animals, as determined by cerebral extravasation of Evans blue conjugated albumin. Furthermore, Liraglutide reduced cortical tissue loss, but did not affect tissue loss and delayed neuronal death in the thalamus on day 7 post injury. Together, our data suggest that the GLP-1 pathway might be a promising target in the therapy of cerebral edema and cortical neuronal injury after moderate and severe TBI.

Acute Traumatic Brain Injury: Mortality in the Elderly.

OBJECTIVE: Despite recent progress, prognosis for the elderly (defined as aged ≥70 years) afflicted by traumatic brain injury (TBI) is unfavorable and surgical intervention remains controversial. Research during the past decade on the mortality rates or prognostic factors for survival in the elderly is limited. METHODS: We analyzed 97 patients aged ≥70 years who were treated surgically for closed TBI at our neurosurgical unit between January 1, 2003 and December 31, 2012. In addition, we analyzed 22 patients aged ≥70 years who had sustained a closed TBI and on whom no neurosurgical intervention was performed. Outcome in both groups was measured as 30-, 90- and 180-day mortality. RESULTS: Surgically treated patients: median age, 76 years' 30-day overall mortality rate, 36%. Higher mortality was seen with lower level of consciousness, high energy trauma, one pupil fixed and dilated, and more extensive intracranial pathology. Presence of warfarin, more advanced age, or degree of midline shift were not associated with worsened outcome. Patients not treated neurosurgically: median age. 81.5 years; 30-day overall mortality rate, 23%. Mortality for patients with Glasgow coma scale (GCS) 10-15 was 6%, GCS 6-9 67%, and GCS 3-5 100%. CONCLUSIONS: Selected patients aged ≥70 years can benefit from surgical intervention for closed TBI. Level of consciousness, radiologic type of injury, mechanism of injury, and pupil abnormalities should be carefully evaluated. There also seems to exist a group of patients in whom surgical intervention offers little benefit, as mortality rate is low without surgical intervention.

Real-time changes in brain tissue oxygen during endovascular treatment of cerebral vasospasm.

The use of endovascular intervention to treat cerebral vasospasm after subarachnoid hemorrhage has increased. Although the effect on angiographic vasospasm can be easily demonstrated, the effect on cerebral blood flow and clinical outcome is still controversial. In this report, we investigate minute-by-minute changes in brain tissue oxygen during balloon angioplasty and intraarterial administration of vasodilators in three patients.Our results confirm that endovascular intervention is capable of not only resolving angiographic vasospasm, but also of normalizing values of brain tissue oxygen pressure (PtiO2) in target parenchyma. However, during the intervention, dangerously low levels of brain tissue oxygen, leading to cerebral infarction, may occur. Thus, no clinical improvement was seen in two of the patients and a dramatic worsening was observed in the third patient. Because the decrease in brain tissue oxygen was seen after administration of vasopressor agents, this may be a contributing factor.

[Guidelines for the initial management of adult patients with minimal to moderate head injury].

Mild to moderate head injuries are very common. Often diagnostics and symptomatic treatment is relatively uncomplicated and the clinical challenge is identification of patients who will later develop a potentially life-threatening complication. Based on updated knowledge, the Scandinavian Neurotrauma Committee has published new guidelines for the initial management of adult patients with minimal to moderate head injury. These categorize patients into five risk groups that should be handled by three different strategies: admission for observation, computed tomography or assessment of the biomarker S100B.

Association of the NOS3 intron-4 VNTR polymorphism with aneurysmal subarachnoid hemorrhage.

OBJECT: The nitric oxide system has been linked to the pathogenesis of aneurysmal subarachnoid hemorrhage (SAH). The authors performed a case-control study to investigate the association between SAH and common genetic variants within the endothelial nitric oxide synthase gene (NOS3). METHODS: Three hundred thirty-three Caucasian SAH patients and 498 controls were genotyped for the -922A > G (rs 1800779), -786T > C (rs2070744), and 894G > T (rs1799983) single nucleotide polymorphisms and the intron-4 27-bp variable number of tandem repeats polymorphism (27-bp-VNTR). RESULTS: The b/b (5 repeats) genotype of the 27-bp-VNTR was overrepresented in cases (77%) versus controls (69%) (p = 0.02). In male patients the b/b genotype was found in 85% compared with 67% in male controls, whereas in women, the frequencies were 73% and 72%, respectively. This corresponds to an odds ratio of 2.8 (95% CI 1.5-5.6, p = 0.0005) for SAH in men with the b/b genotype versus men with a/b or a/a. In women, no such association was found (OR 1.1, 95% CI 0.7-1.6, p = 0.76). Stepwise logistic regression including arterial hypertension, smoking, sex, and age with interactions yielded similar effect estimates of the 27-bp-VNTR. Haplotype analysis revealed that no single haplotype containing the b-allele was responsible for the observed genotype effect. CONCLUSIONS: The authors' results suggest that the NOS3 27-bp-VNTR b/b genotype independent of other risk factors act in concert with male sex to substantially increase risk of SAH. This effect is not mediated by any single NOS3 haplotype.

Therapeutic Hypothermia in Children and Adults with Severe Traumatic Brain Injury.

Great expectations have been raised about neuroprotection of therapeutic hypothermia in patients with traumatic brain injury (TBI) by analogy with its effects after heart arrest, neonatal asphyxia, and drowning in cold water. The aim of this study is to review our present knowledge of the effect of therapeutic hypothermia on outcome in children and adults with severe TBI. A literature search for relevant articles in English published from year 2000 up to December 2013 found 19 studies. No signs of improvement in outcome from hypothermia were seen in the five pediatric studies. Varied results were reported in 14 studies on adult patients, 2 of which reported a tendency of higher mortality and worse neurological outcome, 4 reported lower mortality, and 9 reported favorable neurological outcome with hypothermia. The quality of several trials was low. The best-performed randomized studies showed no improvement in outcome by hypothermia-some even indicated worse outcome. TBI patients may suffer from hypothermia-induced pulmonary and coagulation side effects, from side effects of vasopressors when re-establishing the hypothermia-induced lowered blood pressure, and from a rebound increase in intracranial pressure (ICP) during and after rewarming. The difference between body temperature and temperature set by the biological thermostat may cause stress-induced worsening of the circulation and oxygenation in injured areas of the brain. These mechanisms may counteract neuroprotective effects of therapeutic hypothermia. We conclude that we still lack scientific support as a first-tier therapy for the use of therapeutic hypothermia in TBI patients for both adults and children, but it may still be an option as a second-tier therapy for refractory intracranial hypertension.

Cerebral blood flow and transcranial doppler sonography measurements of CO2-reactivity in acute traumatic brain injured patients.

BACKGROUND: Cerebral blood flow (CBF) measurements are helpful in managing patients with traumatic brain injury (TBI), and testing the cerebrovascular reactivity to CO(2) provides information about injury severity and outcome. The complexity and potential hazard of performing CBF measurements limits routine clinical use. An alternative approach is to measure the CBF velocity using bedside, non-invasive, and transcranial Doppler (TCD) sonography. This study was performed to investigate if TCD is a useful alternative to CBF in patients with severe TBI. METHOD: CBF and TCD flow velocity measurements and cerebrovascular reactivity to hypocapnia were simultaneously evaluated in 27 patients with acute TBI. Measurements were performed preoperatively during controlled normocapnia and hypocapnia in patients scheduled for hematoma evacuation under general anesthesia. MAIN FINDING AND CONCLUSION: Although the lack of statistical correlation between the calculated reactivity indices, there was a significant decrease in TCD-mean flow velocity and a decrease in CBF with hypocapnia. CBF and TCD do not seem to be directly interchangeable in determining CO(2)-reactivity in TBI, despite both methods demonstrating deviation in the same direction during hypocapnia. TCD and CBF measurements both provide useful information on cerebrovascular events which, although not interchangeable, may complement each other in clinical scenarios.

[Scandinavian guidelines for the acute management of adult patients with minimal, mild, or moderate head injuries]. / Skandinaviske retningslinjer for akutt håndtering av voksne pasienter med minimal, lett eller moderat hodeskade.

BACKGROUND In 2000, the Scandinavian Neurotrauma Committee (SNC) published evidence-based guidelines for the management of minimal, mild or moderate head injuries. Since then, considerable new evidence has emerged on the clinical use of these guidelines and on the radiation risks associated with computer tomographic (CT) examinations. The SNC has recently published updated Scandinavian guidelines. Here we present the Norwegian version of the updated guidelines with emphasis on the professional recommendations and the reasons the new guidelines were necessary, plus comments from the Norwegian authors.MATERIALS AND METHODS A task force appointed by the SNC compiled recommendations based on a systematic, evidence-based review. These recommendations were revised through consensus in the SNC and through consultation with relevant clinical experts.RESULTS A blood test of the brain injury biomarker S100B is for the first time recommended as an initial diagnostic measure for mild head injury patients with low risk. Of these patients, CT examination is only recommended for those who show a pathologically elevated S100B. CT examination is still the recommended routine for moderate head injury patients and for mild head injury patients with medium to high risk. An updated information sheet on head injuries has also been compiled for patients and their relatives.CONCLUSION The SNC recommends the implementation of these guidelines in Norway.

Accuracy of physical examination for chronic lumbar radiculopathy.

BACKGROUND: Clinical examination of patients with chronic lumbar radiculopathy aims to clarify whether there is nerve root impingement. The aims of this study were to investigate the association between findings at clinical examination and nerve root impingement, to evaluate the accuracy of clinical index tests in a specialised care setting, and to see whether imaging clarifies the cause of chronic radicular pain. METHODS: A total of 116 patients referred with symptoms of lumbar radiculopathy lasting more than 12 weeks and at least one positive index test were included. The tests were the straight leg raising test, and tests for motor muscle strength, dermatome sensory loss, and reflex impairment. Magnetic resonance imaging (n = 109) or computer tomography (n = 7) were imaging reference standards. Images were analysed at the level of single nerve root(s), and nerve root impingement was classified as present or absent. Sensitivities, specificities, and positive and negative likelihood ratios (LR) for detection of nerve root impingement were calculated for each individual index test. An overall clinical evaluation, concluding on the level and side of the radiculopathy, was performed. RESULTS: The prevalence of disc herniation was 77.8%. The diagnostic accuracy of individual index tests was low with no tests reaching positive LR >4.0 or negative LR <0.4. The overall clinical evaluation was slightly more accurate, with a positive LR of 6.28 (95% CI 1.06-37.21) for L4, 1.74 (95% CI 1.04-2.93) for L5, and 1.29 (95% CI 0.97-1.72) for S1 nerve root impingement. An overall clinical evaluation, concluding on the level and side of the radiculopathy was also performed, and receiver operating characteristic (ROC) analysis with area under the curve (AUC) calculation for diagnostic accuracy of this evaluation was performed. CONCLUSIONS: The accuracy of individual clinical index tests used to predict imaging findings of nerve root impingement in patients with chronic lumbar radiculopathy is low when applied in specialised care, but clinicians' overall evaluation improves diagnostic accuracy slightly. The tests are not very helpful in clarifying the cause of radicular pain, and are therefore inaccurate for guidance in the diagnostic workup of the patients. The study population was highly selected and therefore the results from this study should not be generalised to unselected patient populations in primary care nor to even more selected surgical populations.

Can S100B Predict Cerebral Vasospasms in Patients Suffering from Subarachnoid Hemorrhage?

BACKGROUND: Protein S100B has proven to be a useful biomarker for cerebral damages. Increased levels of serum and cerebrospinal fluid (CSF) S100B have been shown in patients suffering subarachnoid hemorrhage (SAH), severe head injury and stroke. In patients with SAH, the course of S100B levels has been correlated with neurological deficits and outcome. Cerebral vasospasm is a major contributor to morbidity and mortality. The primary aim of this study was to investigate the potential of S100B protein as a predictor of cerebral vasospasm in patients with severe SAH. MATERIALS AND METHODS: Patients with SAH, Fisher grade 3 and 4, were included in the study. Five samples of CSF and serum S100B were collected from each patient. The first sample (baseline sample) was drawn within the first 3 days following ictus and the following four samples, once a day on days 5-8, with day of ictus defined as day 1. Clinical suspicion of cerebral vasospasm confirmed by computed tomography angiography was used to diagnose cerebral vasospasm. RESULTS: A total of 18 patients were included. Five patients (28%) developed cerebral vasospasm, two (11%) developed ventriculitis. There were no significant differences between S100B for those with and without vasospasm. Serum S100B levels in patients with vasospasm were slightly lower within the first 5 days following ictus, compared to patients without vasospasm. Two out of five patients had elevated and increasing serum S100B prior to vasospasm. Only one showed a peak level of S100B 1 day before vasospasm could be diagnosed. Due to the low number of patients in the study, statistical significance could not be reached. CONCLUSION: Neither serum nor CSF S100B can be used as predictor of cerebral vasospasm in patients suffering from SAH.

Accuracy of tunnelated vs. bolt-connected external ventricular drains.

BACKGROUND: Ventriculostomy is one of the most common neurosurgical procedures and an important tool in the treatment and monitoring of elevated intracranial pressure. Low accuracy has frequently been reported in the literature with risk of drain misplacement over 20% and with a need for reinsertion in up to 40%. As an alternative to the tunnelated EVD technique we often use a bolt-connected EVD. The aim of the present study was to investigate whether the use of bolt-connected EVDs would lead to higher accuracy, fewer passes and reoperations due to poor placement compared to tunnelated EVDs. PATIENTS AND METHODS: We retrospectively identified all patients who received an EVD from January 1st 2008 to December 31st 2010. Postoperative images were evaluated for anatomical placement of the EVD-tip, distance from tip to optimal placement and were categorized as optimal, suboptimal and undesired. Patient files were evaluated for EVD technique, number of passes and postoperative complications and handling. RESULTS: 147 patients with 154 separate EVDs met the inclusion criteria. We found a statistical significant higher accuracy in the bolt-group compared to the tunnelated-group (p=0.023). Eleven patients were reoperated following ventriculostomy and we found a statistical significant 11.9% reduction in reoperations due to poor placement in the bolt-group (p=0.006). CONCLUSIONS: We have showed in this study that by using a bolt-connected EVD and maintaining the freehanded technique we can significantly increase precision and decrease the number of reoperations due to poor placement.

Measuring elevated intracranial pressure through noninvasive methods: a review of the literature.

Elevated intracranial pressure (ICP) is an important cause of secondary brain injury, and a measurement of ICP is often of crucial value in neurosurgical and neurological patients. The gold standard for ICP monitoring is through an intraventricular catheter, but this invasive technique is associated with certain risks. Intraparenchymal ICP monitoring methods are considered to be a safer alternative but can, in certain conditions, be imprecise due to zero drift and still require an invasive procedure. An accurate noninvasive method to measure elevated ICP would therefore be desirable. This article is a review of the current literature on noninvasive methods for measuring and evaluating elevated ICP. The main focus is on studies that compare noninvasively measured ICP with invasively measured ICP. The aim is to provide an overview of the current state of the most common noninvasive techniques available. Several methods for noninvasive measuring of elevated ICP have been proposed: radiologic methods including computed tomography and magnetic resonance imaging, transcranial Doppler, electroencephalography power spectrum analysis, and the audiological and ophthalmological techniques. The noninvasive methods have many advantages, but remain less accurate compared with the invasive techniques. None of the noninvasive techniques available today are suitable for continuous monitoring, and they cannot be used as a substitute for invasive monitoring. They can, however, provide a reliable measurement of the ICP and be useful as screening methods in select patients, especially when invasive monitoring is contraindicated or unavailable.

Post-ischemic continuous infusion of erythropoeitin enhances recovery of lost memory function after global cerebral ischemia in the rat.

BACKGROUND: Erythropoietin (EPO) and its covalently modified analogs are neuroprotective in various models of brain damage and disease. We investigated the effect on brain damage and memory performance, of a continuous 3-day intravenous infusion of EPO, starting 20 min after a transient 10 minute period of global cerebral ischemia in the rat. RESULTS: We found no effect on selective neuronal damage in the CA1 region of the hippocampus, neocortical damage and damage to the striatum assessed at 7 days after ischemia. Also, no differences were observed in sensori-motor scores between EPO treated and saline treated ischemic animals. In contrast, memory performance was significantly improved in the EPO treated group. Saline treated injured animals (n = 7) failed in a test assessing recovery of spatial memory (6/6 and 5/6), while EPO treated animals had few and none failures (0/7 and 1/7). CONCLUSION: We conclude that although post-ischemic treatment with EPO is not neuroprotective in a model of cardiac arrest brain ischemia, its markedly positive effect on brain plasticity and recovery of memory function warrants consideration as treatment of cardiac arrest patients.