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.

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.

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.

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.

Kristiansson, Helena MD; Nissborg, Emelie MD; Bartek, Jiri Jr MD; Andresen, Morten MD; Reinstrup, Peter MD, PhD; Romner, Bertil MD, PhD Author Information

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.

*Department of Neuroanaesthesia, Neuroscience Centre, Copenhagen University Hospital (Rigshospitalet); †Department of Neuroscience and Pharmacology, Health Faculty, University of Copenhagen; and ‡Department of Neurosurgery, Neuroscience Centre, Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark.

Background. Endothelial dysfunction might be involved in the development of cerebral vasospasm after aneurysmal subarachnoid haemorrhage (SAH).Methods. This prospective observational study of 48 SAH subjects and 23 control subjects examined associations between reactive hyperaemia index (RHI) measured by peripheral arterial tonometry and plasma concentrations of S-100B protein, nitrite/nitrate, arginine, and asymmetric dimethyl arginine (ADMA). Clinical variables were flow velocity in the middle cerebral artery (V-MCA), angiographic vasospasm, delayed neurological deficit, and 30 day survival. Five consecutive measurements were obtained at days 0-2, 3-5, 6-8, 9-11, and 12-15.Results. RHI was 1.67 (0.46) at days 0-2 after SAH but increased at days 3-15 to the same levels as in controls (P<0.05 compared with days 0-2). RHI was lower in subjects who died before day 30 (P=0.07), but no trends were observed in relation to angiographic vasospasm or delayed neurological deficit. Both arginine and ADMA increased after SAH compared with days 0-2 (P<0.05). S-100B was highest in non-survivors (P<0.01) and in subjects with neurological deficit (P<0.01). A positive correlation was found between RHI and arginine: ADMA ratio (r=0.43, P<0.005), but not with nitrite/nitrate, V-MCA, or S-100B.Conclusions. Peripheral flow-mediated vasodilation is attenuated in the first days after SAH indicating acute systemic endothelial dysfunction. Impairment of endothelial function after SAH correlates with imbalance of the arginine/ADMA pathway.

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.

INTRODUCTION:Hyperthermia is common in brain-injured patients and associated with a worse outcome. As brain rather than body temperature reduction, theoretically, is the most important in cerebral protection, there is logic in targeting cooling at the brain. Selective brain cooling can, in theory, be obtained by cooling the skull or by heat loss from the upper airways. In this preliminary safety and efficacy study, we report clinical data from brain-injured patients who because of hyperthermia were treated with intranasal cooling.METHODS:Nine intubated brain-injured patients with hyperthermia were treated using a prototype intranasal balloon system perfused with cold saline. Temperature in the cerebrum, esophagus, and bladder was monitored together with intracranial pressure.RESULTS:In only two of nine patients, normothermia was reached in the esophagus and in only four of nine patients it was reached in the bladder. When normothermia was reached, the time to normothermia was delayed. In the brain, normothermia was reached in two of five patients after approximately 72 h. Median temperature curves from the first 72 h of cooling showed that normothermia was not reached in any of the three compartments. The temperature in the brain and bladder were on average 0.6 and 0.5 °C higher than in the esophagus. ICP increased with increasing brain temperature. We found no signs of clinical important injury to the nasal mucosa from the cold saline or pressure in the balloons.CONCLUSION:In brain-injured patients with hyperthermia, cooling with a prototype intranasal balloon system was clinically inadequate as the effect was delayed and not brain selective.

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.

Nye retningslinjer for hodeskader 2342 -3 Scandinavian Neurotrauma Committee har nylig publisert oppdaterte skandinaviske retningslinjer

S100B is a calcium-binding protein most abundant in neuronal tissue. It is expressed in glia cells and Schwann cells and exerts both intra- and extracellular effects. Depending on the concentration, secreted S100B exerts either trophic or toxic effects. Its functions have been extensively studied but are still not fully understood. It can be measured in cerebrospinal fluid and blood, and increased S100B level in blood can be seen after, e.g., traumatic brain injury, certain neurodegenerative disorders and malignant melanoma. This chapter provides a short background of protein S100B, commercially available methods of analysis, and its clinical use.

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.

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. (C) 2013 Elsevier B.V. All rights reserved.

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.

HomeStrokeVol. 44, No. 12Modifiable Risk Factors for Aneurysmal Subarachnoid Hemorrhage Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBModifiable Risk Factors for Aneurysmal Subarachnoid Hemorrhage Trine H. Andreasen, MS, Jiri BartekJr, MD, Morten Andresen, MD, Jacob B. Springborg, MD, PhD and Bertil Romner, MD, PhD Trine H. AndreasenTrine H. Andreasen From the Department of Neurosurgery, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark (T.H.A., J.B., M.A., J.B.S., B.R.); and Department of Clinical Neuroscience, Section for Neurosurgery, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden (J.B.). Search for more papers by this author , Jiri BartekJrJiri BartekJr From the Department of Neurosurgery, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark (T.H.A., J.B., M.A., J.B.S., B.R.); and Department of Clinical Neuroscience, Section for Neurosurgery, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden (J.B.). Search for more papers by this author , Morten AndresenMorten Andresen From the Department of Neurosurgery, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark (T.H.A., J.B., M.A., J.B.S., B.R.); and Department of Clinical Neuroscience, Section for Neurosurgery, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden (J.B.). Search for more papers by this author , Jacob B. SpringborgJacob B. Springborg From the Department of Neurosurgery, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark (T.H.A., J.B., M.A., J.B.S., B.R.); and Department of Clinical Neuroscience, Section for Neurosurgery, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden (J.B.). Search for more papers by this author and Bertil RomnerBertil Romner From the Department of Neurosurgery, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark (T.H.A., J.B., M.A., J.B.S., B.R.); and Department of Clinical Neuroscience, Section for Neurosurgery, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden (J.B.). Search for more papers by this author Originally published5 Nov 2013https://doi.org/10.1161/STROKEAHA.113.001575Stroke. 2013;44:3607–3612Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2013: Previous Version 1 IntroductionAneurysmal subarachnoid hemorrhage (aSAH) is bleeding into the subarachnoid space from a cerebral aneurysm, defined as a thin-walled outpouching on one of the cerebral arteries.1 SAH represents 0.8% to 15% of strokes and has a low incidence of 0.03 to 0.2 per 1000 person-years with a female preponderance.2,3 However, SAH usually occurs at a relatively young age and has a high 1-month case fatality rate (32%), leading to a high loss of potential life years.2 Subsequently, primary prevention of aSAH by identifying and addressing modifiable risk factors has been a focus of research for decades.4Although the main focus has been on identifying modifiable risk factors, less attention has been given to the underlying pathogenic mechanisms.We, therefore, conducted a literature review to identify recognized modifiable risk factors for aneurysm development and aSAH and examined the pathogenesis by which these individual risk factors are suspected to contribute to aneurysm development and rupture.MethodsWe conducted MEDLINE searches using the PubMed database for relevant articles published between 1980 and 2012 in English. We used search words such as Cerebral Arteries [Majr], Subarachnoid Hemorrhage [Majr], or Intracranial Aneurysm [Majr] combined with Medical Subject Headings (MeSH) search words for different risk factors such as Alcohol drinking, Ethanol, Estrogens, Menopause, Hypertension, Smoking, Cholesterol, Diabetes Mellitus, and Cocaine. The first search was performed in June 2012 and the last in December 2012. Articles were screened by title and abstract, and if relevant the article was reviewed in its entirety. References lists in key publications were hand-searched to reveal additional relevant studies.Initially, the focus was on epidemiological studies that helped establish the different modifiable risk factors for aSAH. Inclusion criteria comprised: (1) SAH analyzed as a separate stroke entity, although in some studies SAH was part of a hemorrhagic stroke group, and (2) diagnosis of SAH or aneurysm confirmed by CT, angiography, or at autopsy. The risk association is illustrated statistically with relative risk (RR), odds ratio (OR), and population-attributable risk.Having established the individual risk factors, each was examined with a focus on the pathogenesis of aneurysm development and rupture. This was done by PubMed searches using the same search words as above. Books on vascular pathology were consulted for information on the effects of modifiable risk factors. We focused on studies investigating cerebral aneurysms or aSAH. Furthermore, relevant articles concerning pathological effects of ≥1 risk factors on cerebral arteries in general were also selected for review. Some findings were based on experimental data or observed general effects on the cardiovascular system.To provide the reader with a more structured overview of the topic, the following section gives a description of the more general mechanisms of action related to aneurysm formation and rupture and subsequently a review of the current body of evidence concerning each known modifiable risk factor.Results and DiscussionModifiable risk factors predispose to aSAH by different mechanisms of action. The mechanisms could be classified as vessel wall injury, loss of ability to repair vessel wall injury, hemodynamic stress, and synergistic effects. The mechanisms are summarized in Figure 1 (vessel wall injury) and Figure 2 (hemodynamic stress) along with the risk factors associated with each mechanism.Download figureDownload PowerPointFigure 1. Mechanisms leading to vessel wall damage that contributes to aneurysm formation with the associated modifiable risk factors for each mechanism.Download figureDownload PowerPointFigure 2. Mechanisms inducing hemodynamic stress that contributes to aneurysm formation with the associated modifiable risk factors for each mechanism.Wall InjuryThe vessel wall of cerebral arteries is made up of tunica intima, media, and adventitia, with endothelium lining the tunica intima.1 The tunica media consists of smooth muscle cells and extracellular matrix containing collagen, elastin, and glycosaminoglycanes, whereas the adventitia consists of loose connective tissue, nerve fibers, and vasa vasorum. An internal elastic lamina separates the tunica intima and media. Cerebral arterial vessels lack the external elastic lamina.1It is proposed that aneurysm formation is initiated by endothelial damage, followed by vessel wall inflammation, and finally completed by a defect in the inflammatory zone causing an outpouching.5Vessel wall injury has been associated with toxins and an increased amount of proteases (eg, elastase) in blood, causing wall injury by degrading the extracellular matrix of the vessel wall.1,6 This increased degradation can also be achieved by the inhibition of enzymes with an inhibiting effect on the proteases. Singh et al6 proposed α1-antitrypsin deficiency and an imbalance between protease and protease inhibitor to be contributing causes for aneurysm formation, as have been corroborated by other studies.7,8 α1-Antitrypsin is a protease inhibitor that has a significant inhibitory effect on elastase, a proteolytic enzyme. The role of α1-antitrypsin is to maintain the integrity of connective tissue by keeping the balance with proteolytic enzymes.8 A lower affinity of α1-antitrypsin for elastase causes an increased proteolytic activity and consequently high levels of elastase in blood.Vessel wall inflammation is mediated by several pathways associated with carbon monoxide and the proinflammatory cytokine tumor necrosis factor-α (TNF-α). Increased levels of carbon monoxide reduce the oxygen content of blood, thus causing hypoxemia-induced inflammation in the vessel wall.9 TNF-α damages the endothelium, the smooth muscle cells, as well as the internal elastic membrane, which are all important structural components of the vessel wall. This is done by activating inflammation in the vessel wall with resulting migration of inflammatory cells such as monocytes.10 TNF-α has also been found to inhibit cell proliferation as well as endothelial repair.11 Furthermore, TNF-α is known to activate matrix metalloproteinases, which degrade structural components of the vessel wall, such as elastin and collagen.10Because of vessel wall injury combined with vessel wall inflammation, the vessel wall undergoes morphological changes, including endothelial cell swelling, subendothelial accumulation of fibrin, and cellular infiltration. The result is intimal thickening, which is thought to reduce the flow of nutrients to the intima as well as to the inner tunica media.12 Reduced nutrients then lead to deterioration of the internal elastic lamina and the extracellular matrix, which normally provide the elasticity and dynamic strength of the vessel wall, further potentiating the possibility of aneurysm development.13Loss of Ability to Repair Vessel Wall InjuryImpaired ability to repair vessel wall injury is thought to be a contributing factor in aneurysm formation, mainly because of impaired expression of proteins important for flow modulation and impaired collagen formation.14Collagen, elastin, and the elastin-to-collagen ratio along with the tunica media determine the mechanical properties of the vessel. The oscillations that stimulate the smooth muscle cells to produce collagen and elastin can be attenuated by intimal thickening.12 This could affect the metabolism of the connective tissue and leave the vessel wall less resistant to increased hemodynamic stress.Hemodynamic StressHemodynamic stress is caused by elevated blood pressure, uncompensated blood flow, as well as increased blood viscosity.Elevated blood pressure is an important contributor to hemodynamic stress and has its effect on aneurysm formation and rupture, suggested Vlak et al.15 who established several trigger factors (eg, vigorous physical exercise) for aneurysm rupture, all causing a sudden rise in blood pressure.Another cause of elevated blood pressure is oxidative stress, which increases levels of the potent vasoconstrictor endothelin in a dose-dependent manner.11The vasculature is nourished by the vasa vasorum, the presence of which was confirmed in 1996 in a study identifying vascular channels in the outer tunica media and adventitia.16 It is thought that elevated blood pressure could result in increased vascular resistance of the vasa vasorum, and that the tension could compress the vasa vasorum, causing an occlusion and subsequent ischemia and necrosis of the tunica media. This leaves the vessel thinned and bulging in response to increased intra-arterial pressure.12Uncompensated blood flow is mainly the consequence of disturbances in the cerebral autoregulation, resulting in an increased risk of aneurysm formation and rupture, because of the vasculature not being able to compensate or adapt to elevated blood pressure.17 A disturbance of the cerebral autoregulation has been described in relation to alcohol intoxication, with regulation of cortical neurons and lower medullary centers being depressed at high alcohol levels.1 This can lead to respiratory acidosis and build-up of carbon dioxide, that is, hypercapnia. A study by Blaha et al18 examined the effects of ethanol and hypercapnia on cerebral autoregulation. The study found no significant effect on dynamic cerebral autoregulation by ethanol alone, but revealed that hypercapnia can cause an impairment of cerebral autoregulation, possibly resulting in uncompensated blood flow because of carbon dioxide being a potent vasodilator, increasing cerebral blood flow.19Finally, an increased blood viscosity, caused by increased fibrinogen and hematocrit levels in blood, has also been shown to exert increased hemodynamic stress on the vessel wall, contributing to possible aneurysm formation.6,11Synergistic EffectsThe combined pathological effect of hemodynamic stress and an injured vessel wall potentiates the risk of aneurysm formation by further increasing the level of shearing injuries.As an example, Singh et al6 suggested that hemodynamic stress, also referred to as wall shear stress, on the vessel wall increases the production of NO by inducing the enzyme iNOS (inducible nitric oxide synthase), which is responsible for the synthesis of NO. Because NO is a vasodilator responsible for adjusting the vascular tone and, therefore, blood flow, this change in endothelial production may result in loss of vascular homeostasis, which may again have a damaging effect on the vessel wall.6 Increased NO production can also lead to production of the cytotoxic peroxynitrite, which is the product of NO reacting with superoxide,11 potentially further damaging the vessel wall. In general, production of reactive oxygen species leads to accumulation of superoxide and subsequent induction of apoptosis.20Another example is wall shear stress stimulating endothelial cells to produce matrix metalloproteinase-13, leading to degeneration of the internal elastic lamina, which is part of the vessel wall.6 The smooth muscle cells of the tunica media of the vessel wall are also damaged by wall shear stress because of increased transmural flow gradients, further contributing to vessel injury.6 In general, an increase in shearing injuries, that is, endothelial damage, degeneration of the internal elastic lamina, and thinning of the media smooth muscle cells, are all early signs of aneurysm formation.12Individual Risk FactorsTable 1 shows the statistics for different modifiable risk factors with RR and OR, whereas Table 2 shows the population-attributable risk.Table 1. Relative Risk (RR) and Odds Ratio (OR) of Aneurysmal Subarachnoid Hemorrhage (ASAH) Associated With Modifiable Risk FactorsRisk FactorRR (95% CI)OR (95% CI)SmokingTeunissen et al21: 1.9 (1.5–2.3); Ruigrok et al22: 1.9 (1.5–2.3); Juvela et al23: 2.1 (1.2–3.6)*; Feigin et al4: 2.2 (1.3–3.6); Feigin et al24: 2.4 (1.8–3.4); Bonita et al25: 3.3 (2.0–5.3)*; Bonita et al25: 5.4 (3.0–9.7)†; Sandvei et al26: 6.1 (3.6–10.4); Juvela et al23: 7.3 (3.8–14.3)†Feigin et al4: 3.1 (2.7–3.5); Ohkuma et al27: 3.12 (2.05–4.77); Teunissen et al21: 3.5 (2.9–4.3)HypertensionFeigin et al24: 2.0 (1.5–2.7); Feigin et al4: 2.5 (2.0–3.1); Teunissen et al21: 2.8 (2.1–3.6); Ruigrok et al22: 2.8 (2.1–3.6); Sandvei et al26: 3.3 (1.7–6.3); Bonita et al25: 3.4 (2.3–5.7)Ohkuma et al27: 2.29 (1.66–3.16); Isaksen et al28: 2.46 (1.52–3.97); Feigin et al4: 2.6 (2.0–3.1); Teunissen et al21: 2.9 (2.4–3.7)Heavy alcohol consumption (>150 g/wk)Feigin et al4: 2.1 (1.5–2.8); Teunissen et al21: 4.7 (2.1–10.5)Feigin et al4: 1.5 (1.3–1.8); Teunissen et al21: 1.5 (1.3–1.8)Estrogen preparationsn/aLongstreth et al29: 0.47 (0.26–0.86)‡; Feigin et al4: 0.6 (0.4–0.8)‡; Mhurchu et al30: 0.64 (0.41–0.98)‡Cocainen/aLongstreth et al31: 12.2 (1.4–103.7)§Hypercholesterolemian/aOhkuma et al27: 0.41 (0.24–0.71); Feigin et al4: 0.6 (0.4–0.9)Diabetes mellitusFeigin et al4: 0.3 (0–2.2)Feigin et al4: 0.7 (0.5–0.8)n/a indicates not available.*For ≤20 cigarettes/d.†For >20 cigarettes/d.‡For hormone replacement therapy.§For stimulant drugs in the week preceding SAH.Table 2. Population-Attributable Risk and Dose–Response Relationship for Aneurysmal Subarachnoid Hemorrhage and Their Associated Modifiable Risk FactorsRisk FactorPopulation-Attributable RiskDose–Response RelationshipSmoking20% to 40%22,24,25Yes23,25,31Hypertension17% to 28%22,24,25n/aHeavy alcohol consumption11% (100–299 g/wk); 21% (≥300 g/wk)22Yes22,23Estrogen preparationsn/aYes29,32Cocainen/an/aHypercholesterolemian/an/aDiabetes mellitusn/an/an/a indicates not available.SmokingCigarette smoking is a significant risk factor for the development of aSAH.23,25,31 Longstreth et al31 demonstrated a dose–response relationship between numbers of cigarettes smoked and increased risk for aSAH by an OR of 11.1 (95% CI, 5.0–24.9) for heavy smokers (>20 cigarettes per day), OR of 4.1 (95% CI, 2.3–7.3) for current smokers (≤20 cigarettes per day), and an OR of 1.8 (95% CI, 1.0–3.2) for former smokers. The risk of developing aSAH associated with smoking seems to be highest in the initial 3 hours after smoking.31 Also, a higher RR in women than in men has been established.25The formation of carbon monoxide and release of cigarette toxins into the blood stream link smoking with aneurysm formation and rupture.9,33 Smoking also promotes increased blood levels of proteases such as elastase. Inhalation of smoke from cigarettes irritates the lung tissue and causes an inflammatory reaction with migration of neutrophil granulocytes to the site of inflammation, causing release of elastase.1Inhibition of α1-antitrypsin could increase elastase activity. Gaetani et al7 showed that cigarette smoking reduces the inhibitory effectiveness of α1-antitrypsin on proteases such as elastase. Furthermore, oxidative stress by smoking was found to inactivate the methionine site in the inhibitory active site of α1-antitrypsin, causing a lower affinity of α1-antitrypsin toelastase.Smoking also elevates levels of fibrinogen in blood, causing increased blood viscosity and thus hemodynamic stress.11 Additionally, blood pressure has been shown to be elevated transiently 2 to 3 hours after smoking,23 with nicotine stimulating the release of catecholamines and thus increasing hemodynamic stress.9 This transient elevation of blood pressure has been associated with aneurysm rupture.27Finally, smoking has been associated with antiestrogenic properties, diminishing the beneficial effects of estrogens,10 which we will discuss later in this article.HypertensionHypertension has been associated with an increased risk of aSAH in several studies (Table 1) with a reported RR as high as 3.4 (95% CI, 2.3–5.7).25Inci et al12 have proposed 3 mechanisms by which hypertension predisposes to aneurysm formation:Endothelial damageOcclusion of the vasa vasorumDisturbance in the synthesis of elastin and collagen by smooth muscle cellsHypertension may also damage the vessel wall by affecting endothelial production of several mediators, such as matrix metalloproteinase-13 and NO.6 Additionally, mechanical damage may be inflicted by increasing hemodynamic stress on the vessel wall of cerebral arteries.6,27Alcohol ConsumptionAn increased risk of aSAH has been shown with a weekly consumption of >150 g of alcohol (Table 1). The risk of aSAH grows with increasing amounts of alcohol, as illustrated by a dose–response relationship in Table 3. Conversely, a protective effect of light drinking has also been established.21Table 3. Relative Risk (RR) for Aneurysmal Subarachnoid Hemorrhage (aSAH) in Relation to Alcohol Consumed Within 24 Hours Preceding aSAHAmount of Alcohol Consumed <24 h Preceding aSAHRREffectLight drinking1–40 g0.3 (95% CI, 0.1–0.8)Reduced risk of aSAHModerate drinking41–120 g2.5 (95% CI, 1.1–5.5)Increased risk of aSAHHeavy drinking>120 g4.5 (95% CI, 1.5–12.9)Increased risk of aSAHThe results depict male population only. In women, RR was higher in all categories of drinking, but light drinking was still associated with a reduced risk for aSAH. Data are from Juvela et al.23Heavy alcohol consumption is thought to damage the endothelium11 by inducing oxidative stress10,11 and has also been associated with induction of TNF-α as well as increased NO production.11 Also, a breakdown product of alcohol, acetaldehyde, has been shown to cause cell damage through the generation of reactive oxygen species.20Heavy alcohol consumption has been associated with elevated blood pressure22,23 and increased hematocrit, plasma osmolarity, and fibrinogen levels in blood.11,19 Together, these are synonymous with increased hemodynamic stress.6 Subsequent alcohol withdrawal, however, is associated with increased levels of catecholamines, causing elevated blood pressure.23On the contrary, light to moderate alcohol consumption has been inversely associated with the risk of aSAH, suggesting a protective effect, in some studies. Alcohol shows an effect on lipid profiles, with moderate amounts of alcohol reported to increase serum levels of high-density lipoprotein cholesterol, and heavy consumption reported to lower the serum levels of high-density lipoprotein cholesterol.1,17 The protective effect of light to moderate drinking could be associated with higher high-density lipoprotein serum levels, acting as an effective antioxidant.11 Similarly, moderate drinking has been associated with decreased TNF-α activity and antioxidant effect.11 Overall, these effects are beneficial to the vessels by acting against vessel inflammation.Oral Contraceptive Pills and Hormone Replacement TherapyEstrogens are used in oral contraceptive pills and hormone replacement therapy for postmenopausal women.1 A meta-analysis on the use of oral contraceptives and the risk of subarachnoid hemorrhage found a trend toward greater risk when using high-estrogen preparations compared with low-estrogen preparations, although the difference was not statistically significant.32 Because estrogen has been shown to promote hypertension,1 older oral contraceptive compounds, with larger amounts of estrogens, may have led to elevated blood pressure and increased risk of aSAH.29,32 The mechanism by which estrogens elevate blood pressure is unknown, but it is speculated that estrogens induce retention of sodium and plasma, increasing blood volume and affecting the actions of renin, angiotensin, and aldosterone.9Despite the fact that estrogens promote hypertension, a beneficial effect has been established for the use of estrogen compounds. Estrogen hormone replacement therapy has shown a risk-reducing effect in regard to aSAH,4,29,30 as well as a risk-reducing effect for premenopausal women in regard to aSAH.30 Estrogens have been shown to have protective effects by having a direct effect on blood vessel integrity. Using transcranial Doppler technique imaging, the effect of estrogens on cerebral blood vessels was investigated,34 revealing a decrease in pulsatory index in postmenopausal women receiving hormone replacement therapy. This indicates decreased vessel resistance, suggesting an increased elasticity of blood vessels and thus lower risk of aneurysm formation.29,32,34 Similarly, it has been shown that estrogen deficiency leads to reduced amounts of collagen and elastin in skin,29 which might also be true for collagen and elastin of vessel wall.Estrogens promote increased endothelial NO production and collagen strengthening, contributing to the integrity of vessel wall.35 This may indicate a beneficial effect of NO in low amounts. Furthermore, estrogens have been associated with lowered TNF-α activity, thus protecting against vascular inflammation.10Both alcohol and smoking are associated with antiestrogenic effects, inhibiting the beneficial effects of estrogens in regard to collagen strengthening and lowering TNF-α levels.Other Risk FactorsStimulant drugs such as cocaine have been associated with an increased risk of aSAH (Table 1). Cocaine inhibits the reuptake of norepinephrine at the presynaptic neuron, resulting in elevated blood pressure.36 Cocaine also induces vasospasms by promoting intracellular calcium release from the sarcoplasmatic reticulum in cerebral vascular smooth muscle cells17,36 and disturbs cerebral autoregulation, with the vasculature being unable to compensate for high blood flow at high blood pressures as a consequence, that is, an uncompensated blood flow.17Hypercholesterolemia is inversely associated with the risk of aSAH,4,27 although not all studies have found such an association.21 It has also been shown that low serum cholesterol increases the risk of hemorrhagic strokes.37 The risk-reducing effect of hypercholesterolemia could partly be explained because of the fact that lipids are required by most cells for the maintenance of plasma membranes.9 Also, smooth muscle cell necrosis has been shown to be inhibited by a high cholesterol diet in experiment with rats,38 thus protecting blood vessel integrity.Diabetes mellitus seems to be associated with a reduced risk of SAH.4 However, insulin resistance (type 2 diabetes mellitus) has been shown to be associated with endothelial dysfunction, inflammation, and oxidative stress.11 Nevertheless, the reduced risk was only statistically significant in case–control studies in a review, leading the authors of the review to conclude that these findings may have been biased and explain the results by considering an increased mortality caused by diseases other than SAH, or that these patients had access to better medical treatment or different and healthier lifestyles.Synergistic EffectA synergistic effect of smoking and hypertension in regard to increased risk of aSAH has been shown in both sexes,25,39,40 whereas the risk of cerebral hemorrhage (including aSAH) due to alcohol consumption has been shown to be increased in individuals with hypertension.41This suggests that the harmful effects of one modifiable risk factor can amplify the effects of another, increasing the overall risk of aSAH.Difference Between SexesAlcohol, smoking, and hypertension have been found to have a more hazardous effect on women than on men,4,27,42 explaining the increased incidence of SAH in women.43The fact that women, compared with men, often experience earlier hazardous effects of heavy alcohol consumption could be attributed to the fact that women have lower total body water mass, lower activity of alcohol dehydrogenase, and that alcohol has been associated with inhibiting the otherwise beneficial effects of estrogen on endothelial cells.11A second reason could be differences in the force of hemodynamics on the vessels. Lindekleiv et al44 showed that women have smaller blood vessel diameters compared with men, and that this contributes to a higher hemodynamic force acting on female cerebral vessel bifurcations.In addition, fluctuations in estrogen levels are also thought to play an important role, because the highest number of aSAH in women are observed in perimenstrual and postmenopausal period.29ConclusionsCigarette smoking, hypertension, heavy alcohol consumption, cocaine abuse, estrogen compounds, hypercholesterolemia, and diabetes mellitus are associated with aneurysm formation and rupture by mechanisms involved in vessel wall injury, inhibition of wall injury repair, and increased hemodynamic stress. The synergistic effect of these mechanisms would result in a higher degree of shearing injuries, increasing the risk of aneurysm formation and rupture.The different modifiable risk factors, once identified, may be avoided so as to reduce the risk of aSAH. Knowledge about the pathogenesis behind aneurysm build-up and rupture gives a better understanding of why exposure to the risk factors should be reduced. Because none of the risk factors have been fully explored, acquisition of more data is warranted.DisclosuresNone.FootnotesBertil Romner, MD, PhD, is deceased.Correspondence to Jiri Bartek Jr, MD, Department of Clinical Neuroscience, Section for Neurosurgery, Karolinska University Hospital and Karolinska Institute, Karolinskavägen, 171 76 Stockholm, Sweden. E-mail [email protected]References1. Kumar V, Abbas AK, Fausto N, Mitchell RN, eds. Robbins Basic Pathology, 8th ed. Philadelphia, PA: Saunders Elsevier; 2007:287–294, 340–347, 354–355, 867.Google Scholar2. Feigin VL, Lawes CM, Bennett DA, Anderson CS. Stroke epidemiology: a review of population-based studies of incidence, prevalence, and case-fatality in the late 20th century.Lancet Neurol. 2003; 2:43–53.CrossrefMedlineGoogle Scholar3. Bederson JB, Awad IA, Wiebers DO, Piepgras D, Haley EC, Brott T, et al. Recommendations for the management of patients with unruptured intracranial aneurysms: a statement for healthcare professionals from the Stroke Council of the American Heart Association.Stroke. 2000; 31:2742–2750.LinkGoogle Scholar4. Feigin VL, Rinkel GJ, Lawes CM, Algra A, Bennett DA, van Gijn J, et al. Risk factors for subarachnoid hemorrhage: an updated systematic review of epidemiological studies.Stroke. 2005; 36:2773–2780.LinkGoogle Scholar5. Jamous MA, Nagahiro S, Kitazato KT, Tamura T, Aziz HA, Shono M, et al. Endothelial injury and inflammatory response induced by hemodynamic changes preceding intracranial aneurysm formation: experimental study in rats.J Neurosurg. 2007; 107:405–411.CrossrefMedlineGoogle Scholar6. Singh PK, Marzo A, Howard B, Rufenacht DA, Bijlenga P, Frangi AF, et al. Effects of smoking and hypertension on wall shear stress and oscillatory shear index at the site of intracranial aneurysm formation.Clin Neurol Neurosurg. 2010; 112:306–313.CrossrefMedlineGoogle Scholar7. Gaetani P, Tartara F, Tancioni F, Klersy C, Forlino A, Baena RR. Activity of alpha 1-antitrypsin and cigarette smoking in subarachnoid haemorrhage from ruptured aneurysm.J Neurol Sci. 1996; 141:33–38.CrossrefMedlineGoogle Scholar8. Schievink WI, Prakash UB, Piepgras DG, Mokri B. Alpha 1-antitrypsin deficiency in intracranial aneurysms and cervical artery dissection.Lancet. 1994; 343:452–453.CrossrefMedlineGoogle Scholar9. McCance KL, Huether SE, eds. Pathophysiology: The Biologic Basis for Disease in Adults and Children, 5th ed. St. Louis, MO: Elsevier Mosby;2005:1090, 1102.Google Scholar10. Jayaraman T, Paget A, Shin YS, Li X, Mayer J, Chaudhry H, et al. TNF-alpha-mediated inflammation in cerebral

HomeStrokeVol. 44, No. 8Response to Letter Regarding Article, "Low Plasma Arginine:Asymmetric Dimethyl Arginine Ratios Predict Mortality After Intracranial Aneurysm Rupture" Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBResponse to Letter Regarding Article, "Low Plasma Arginine:Asymmetric Dimethyl Arginine Ratios Predict Mortality After Intracranial Aneurysm Rupture" Jonatan Myrup Staalsø, MD Bertil Romner, DMSc Niels Vidiendal Olsen, DMSc Jonatan Myrup StaalsøJonatan Myrup Staalsø Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark Bertil RomnerBertil Romner Department of Neurosurgery, Copenhagen University Hospital, The Neuroscience Centre, Copenhagen, Denmark Niels Vidiendal OlsenNiels Vidiendal Olsen Department of Neuroanaesthesia, Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark Originally published25 Jun 2013https://doi.org/10.1161/STROKEAHA.113.001915Stroke. 2013;44:e93Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2013: Previous Version 1 Response:We thank Dr Tsuda for his interest. Asymmetrical dimethylarginine (ADMA) and l-arginine are compounds with significant and well-known biological effects.1 Symmetrical dimethylarginine (SDMA), on the other hand, has long been regarded as a biologically inactive molecule, and as such has been under investigation as a putative marker of renal dysfunction.1 In vitro evidence provides some support for a mechanism by which SDMA through inhibition of transmembrane l-arginine transport theoretically could exert a rate-limiting effect on nitric oxide biosynthesis.2 However, recent experiments showed that chronic SDMA infusion in mice did not change glomerular filtration rate, systolic blood pressure, or ejection fraction, nor did it exert any effect on kidney histopathology or eNOS expression.3 It is likely that the correlations between SDMA and outcome in ischemic stroke4 occur not as a causative relationship but because of correlation between SDMA and other markers (such as ADMA) influenced by kidney function and cellular protein turnover.Our primary objective was to investigate ADMA and l-arginine in relation to mortality and vasospasm after SAH, and therefore we did not analyze SDMA initially.5 However, prompted by the request of Dr Tsuda, we have made a brief analysis of the SDMA measurements, which we have as a biproduct of the high-performance liquid chromatography method. The within-subject linear correlation of ADMA and SDMA was 0.54 (P<10–9). The log-rank test of SDMA tertiles versus survival was P=0.43, but followed a similar trend as reported for the arginine:ADMA ratio with 5 events in the group of low SDMA, 6 in the group of midrange SDMA, and 9 in the group of high SDMA.In conclusion, our data seem to follow the same trend as in the previously published data on ischemic stroke.4Jonatan Myrup Staalsø, MDDepartment of Neuroscience and PharmacologyUniversity of CopenhagenCopenhagen, DenmarkBertil Romner, DMScDepartment of NeurosurgeryCopenhagen University HospitalThe Neuroscience CentreCopenhagen, DenmarkNiels Vidiendal Olsen, DMScDepartment of NeuroanaesthesiaCopenhagen University Hospital (Rigshospitalet)Copenhagen, DenmarkDisclosuresNone.FootnotesStroke welcomes Letters to the Editor and will publish them, if suitable, as space permits. Letters must reference a Stroke published-ahead-of-print article or an article printed within the past 3 weeks. The maximum length is 750 words including no more than 5 references and 3 authors. Please submit letters typed double-spaced. Letters may be shortened or edited. Include a completed copyright transfer agreement form (available online at http://stroke.ahajournals.org and http://submit-stroke.ahajournals.org). References 1. Teerlink T, Luo Z, Palm F, Wilcox CS. Cellular ADMA: regulation and action.Pharmacol Res. 2009; 60:448–460.CrossrefMedlineGoogle Scholar2. Closs EI, Basha FZ, Habermeier A, Förstermann U. Interference of L-arginine analogues with L-arginine transport mediated by the y+ carrier hCAT-2B.Nitric Oxide. 1997; 1:65–73.CrossrefMedlineGoogle Scholar3. Veldink H, Faulhaber-Walter R, Park JK, Martens-Lobenhoffer J, Bode-Böger S, Schuett H, et al. Effects of chronic SDMA infusion on glomerular filtration rate, blood pressure, myocardial function and renal histology in C57BL6/J mice.Nephrol Dial Transplant. January 4, 2013. doi:10.1093/ndt/gfs554.CrossrefMedlineGoogle Scholar4. Worthmann H, Chen S, Martens-Lobenhoffer J, Li N, Deb M, Tryc AB, et al. High plasma dimethylarginine levels are associated with adverse clinical outcome after stroke.J Atheroscler Thromb. 2011; 18:753–761.CrossrefMedlineGoogle Scholar5. Staalsø JM, Bergström A, Edsen T, Weikop P, Romner B, Olsen NV. Low plasma arginine:asymmetric dimethyl arginine ratios predict mortality after intracranial aneurysm rupture.Stroke. 2013; 44:1273–1281.LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails August 2013Vol 44, Issue 8 Advertisement Article InformationMetrics © 2013 American Heart Association, Inc.https://doi.org/10.1161/STROKEAHA.113.001915PMID: 23800555 Originally publishedJune 25, 2013 PDF download Advertisement SubjectsCerebrovascular Disease/Stroke