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Aneurysmal 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.4 Although 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. We 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 …

Background— Asymmetrical dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthases, predicts mortality in cardiovascular disease and has been linked to cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH). In this prospective study, we assessed whether circulating ADMA, arginine:ADMA ratio, and nitrite/nitrate levels were associated with survival and cerebral vasospasm in SAH patients. Methods— One hundred and eleven patients were observed day 1 to 15 after SAH, with serial measurements of transcranial Doppler flow velocities (V MCA ) and plasma biomarkers. Clinical status was assessed by the World Federation of Neurosurgical Societies grading scale. Results— Overall 30-day mortality was 18%, but differed between patients grouped by low, midrange, and high arginine:ADMA ratio in the first week after SAH. Mortality rates were 14/37, 1/37, and 5/37 in the 3 groups, respectively ( P -logrank=0.0003). Cox regression showed that low versus midrange or high arginine:ADMA was associated with a hazard ratio of 4.1 independent of World Federation of Neurosurgical Societies grade (95% confidence interval, 1.5–10.9; P =0.006). ADMA or arginine:ADMA had no association to V MCA , but there was an inverse relationship between V MCA and nitrite/nitrate levels ( P NOS3 894G/G genotype was associated with 15% lower V MCA ( P =0.01). ATbG- NOS3 haplotype homozygosity was associated with up to 64% higher nitrite/nitrate levels ( P =0.003). Conclusions— This study suggests that plasma arginine:ADMA ratios predict mortality after SAH. Both clinical and physiological measures of changes in cerebral hemodynamics are coupled to the nitric oxide system.

OBJECTIVE To investigate relations between predictors and outcomes, and especially to identify predictors influencing the time trend in recovery after mild traumatic brain injury. METHODS We included 59 patients with mild head injury in a prospective study. They underwent comprehensive assessment with neurological and neuroradiological examinations, serum S-100B analysis, and apolipoprotein E (APOE) genotyping. Neuropsychological testing was performed before and 6 months after discharge. Linear mixed models were used to assess associations between baseline predictors and neurocognitive performance and its change. RESULTS A Glasgow Coma Scale score of less than 15, traumatic brain injury demonstrated with computed tomography, magnetic resonance imaging, and serum S-100B greater than 0.14 microg/L predicted impaired cognitive performance both at baseline and after 6 months; APOE genotype did not. There was significant improvement of performance after 6 months. APOE-epsilon4 genotype was the only independent factor significantly predicting less improvement. CONCLUSION The presence of the APOE-epsilon4 allele predicts less recovery of cognitive function after mild head injury.

Background and Purpose— Cerebral artery aneurysms rupture when wall tension exceeds the strength of the wall tissue. At present, risk-assessment of unruptured aneurysms does not include evaluation of the lesions shape, yet clinical experience suggests that this is of importance. We aimed to develop a computational model for simulation of fluid-structure interaction in cerebral aneurysms based on patient specific lesion geometry, with special emphasis on wall tension. Methods— An advanced isogeometric fluid-structure analysis model incorporating flexible aneurysm wall based on patient specific computed tomography angiogram images was developed. Variables used in the simulation model were retrieved from a literature review. Results— The simulation results exposed areas of high wall tension and wall displacement located where aneurysms usually rupture. Conclusion— We suggest that analyzing wall tension and wall displacement in cerebral aneurysms by numeric simulation could be developed into a novel method for individualized prediction of rupture risk.

Background and Purpose— Wall shear stress (WSS) and pressure are important factors in the development of cerebral aneurysms. We aimed to develop a computational fluid dynamics simulator for flow in the complete circle of Willis to study the impact of variations in vessel radii and bifurcation angles on WSS and pressure on vessel walls. Methods— Blood flow was modeled with Navier-Stokes equations as an incompressible newtonian fluid within rigid vessel walls. A model of the circle of Willis geometry was approximated as a network of tubes around cubic curves. Pulsatile inlet flow rates and constant outlet pressure were used as boundary conditions. Results— The simulations confirmed that differences in vessel radii and asymmetric branch angles influence WSS magnitude and spatial distribution. High WSS occurred at locations where aneurysms are frequent and in anatomic variants known to be associated with an increased risk for aneurysm development. Conclusions— Computational fluid dynamics analysis can be applied to the complete circle of Willis and should be used to study the pathophysiology of this complex vascular structure, including risk factors for aneurysm development. Further development of the method should include simulations with flexible vessel walls.

Objective: Pain measurement is a necessity in pain treatment but can be difficult in young children. The aim of this study was to evaluate the validity and reliability of the Behavioural Observational Pain Scale (BOPS) as a postoperative pain measurement scale for children aged 1-7 yrs. The scale assesses three elements of pain behaviors: facial expression, verbalization, and body position. Design: A prospective study. Setting. A day surgery care unit for children and a neurosurgical postoperative care unit. Patients: Seventy-six children aged 1-7 yrs (4.5 +/- 1.8) undergoing elective surgical procedures were observed. Interventions. None. Measurements and Main Results. The study was divided into interrater reliability, concurrent validity, and construct validity. The interrater reliabilities of the observers were very good with a high agreement between the different nurses' BOPS scores. Each item of the BOPS scale ranged from kappa(w) 0.86 to 0.95. In the concurrent validity, BOPS and Children's Hospital of Eastern Ontario Pain Scale scores had a positive correlation indicating that both tools described similar behaviors (r(s) =.871, p

Coagulopathy is a contributor to and predictor of death in bleeding patients. Acidosis is known to be a predictor of worse outcome in trauma patients and to be a coexisting factor in coagulopathic patients, but it has not been studied if it is a causal factor in the development of coagulopathy.We have adjusted the pH level in blood samples from healthy volunteers to different levels between 7.4 and 6.8 by the use of hydrochloric acid. Thereafter we have studied the coagulation at the different pH levels by the use of thromboelastography.We found a strong correlation between pH levels and impairment of the coagulation, where the clot strength is increased much slower at pH levels below 7.4 even though the initiation of the clotting seems to be normal. The clot formation time was increased by 168% at pH 6.8 as compared with pH 7.4 (p0.00001, r = 0.89) whereas the clotting time was left unaffected.Acidosis causes a strong impairment of the coagulation as measured with thromboelastography. The impairment found when lowering pH from 7.4 to 7.15 was almost identical to the impairment seen in another study by Kettner et al. when the temperature was lowered from 36 degrees C to 32 degrees C.

Progressive intracerebral contusions are a major problem in the management of patients with severe traumatic brain injury that is also linked to worse outcome. Microdialysis studies have revealed that lactate levels are very high inside contusions, corresponding to significant acidosis. The current study was performed in an effort to investigate whether the lactate accumulation inside cerebral contusions may be a contributing factor to the prolonged bleeding inside contusions. We have investigated the effects of lactic acidosis on the coagulation system with rotational thromboelastometry. It was a laboratory study involving 6 healthy volunteers. Blood was drawn and the pH was adjusted by addition of lactic acid in vitro. The pH levels studied were 7.4, 7.2, 7.0, and 6.8. The pH was also readjusted to 7.4 by addition the buffer THAM to blood initially adjusted to a pH of 6.8 to study the reversibility of potential adverse effects induced by the lactic acidosis. We found the coagulation to be significantly impaired by lactic acidosis (P = 0.000l). The impairment found was reversible after correction of the acidosis by a buffer. In conclusion, we found that lactic acidosis impaired the coagulation system. The impairment caused by lactic acidosis may be one factor causing the progressive hemorrhage in posttraumatic cerebral contusions, known to have high levels of lactate and correspondingly low pH. It may also be important to consider in bleeding trauma patients.

OBJECTIVE: To assess the clinical value of serial single photon-emission computed tomographic (SPECT) measurements after aneurysmal subarachnoid hemorrhage (SAH). METHODS: Thirty-two patients were studied prospectively during the first 26 days after SAH with repeated SPECT measurements, clinical examinations, and transcranial Doppler recordings. Time trends were analyzed with a general linear model. A final SPECT measurement was performed after 1 year. RESULTS: A mean of 2.6 (range, 1–5) SPECT measurements revealed a significant (P = 0.001) quadratic curve consistent with initial hypoperfusion and then with hyperperfusion during the acute stage. SPECT findings were significantly associated with transcranial Doppler recordings (P = 0.016) and clinical assessments (P = 0.008). Patients fulfilling clinical and transcranial Doppler criteria for vasospasm demonstrated a more pronounced relative hypoperfusion-hyperperfusion time course. A multivariate logistic regression analysis identified SPECT measurements obtained during Days 7 to 14 after the SAH as the only independent predictor (β = 0.042, P = 0.02) for impaired perfusion after 1 year. CONCLUSION: Serial SPECT measurements after aneurysmal SAH demonstrate that regional changes in cerebral perfusion follow a nonlinear time trend, and repeated measurements are necessary. This observation, as well as the low feasibility of SPECT, restricts the clinical value of such measurements.

OBJECTIVE: To investigate the role of prophylactic hyperdynamic postoperative fluid therapy in preventing delayed ischemic neurological deficits attributable to cerebral vasospasm. METHODS: We designed a prospected, randomized, controlled study and included 32 patients with subarachnoid hemorrhage. Sixteen patients received hypervolemic hypertensive hemodilution fluid therapy; the other 16 patients received normovolemic fluid therapy. All patients were monitored for at least 12 days, with clinical assessments, transcranial Doppler recordings, single-photon emission computed tomographic (SPECT) scanning, and routine computed tomographic scanning. For fluid balance monitoring, a number of blood samples were obtained on a daily basis and continuous central venous pressure and mean arterial blood pressure measurements were performed for both groups. All patients received intravenous nimodipine infusions between Day 1 and Day 12. End points of this study were clinical outcomes, clinically evident and transcranial Doppler sonographyevident vasospasm, SPECT findings, complications, and costs. Clinical examinations (using the Glasgow Outcome Scale) performed 1 year after discharge, together with neuropsychological assessments and SPECT scanning, were the basis for the evaluation of clinical outcomes. RESULTS: No differences were observed between the two groups with respect to cerebral vasospasm (as observed clinically or on transcranial Doppler recordings). When regional cerebral blood flow was evaluated by means of SPECT analysis performed on Day 12 after subarachnoid hemorrhage, no differences were revealed. One-year clinical follow-up assessments (with the Glasgow Outcome Scale), including SPECT findings and neuropsychological function results, did not demonstrate any significant group differences. Costs were higher and complications were more frequent for the hyperdynamic therapy group. CONCLUSION: Neither early nor late outcome measures revealed any significant differences between the two subarachnoid hemorrhage treatment models. (Neurosurgery 49:593–606, 2001)

Background: The Scandinavian Neurotrauma Committee was initiated by the Scandinavian Neurosurgical Society to develop evidence-based guidelines for improved care of neurotrauma patients. Methods: A MEDLINE search identified 475 papers dealing with the management of minimal, mild, and moderate head injuries. Forty-two studies presenting class II evidence on the initial management of such injuries were reviewed and management guidelines were developed. Results: Implementation of the Head Injury Severity Scale is advocated. Patients with minimal injuries (no loss of consciousness, Glasgow Coma Scale score of 15) can be safely discharged. Routine early computed tomographic scan is recommended in cases with mild injuries (history of loss of consciousness, Glasgow Coma Scale score = 14-15) and patients with normal scans may be discharged. Computed tomographic scan and admission is mandatory in moderate injuries (Glasgow Coma Scale score = 13). All patients harboring additional risk factors should be scanned and admitted. A flow-chart for clinical decision making and a Head Injury Instruction card is introduced. Conclusions: The Scandinavian Neurotrauma Committee suggests guidelines that should be safe and cost-effective for the initial management of minimal, mild, and moderate head injuries.

Objective The present study was conducted to validate S-100 protein as a marker of brain damage after minor head injury. Methods We studied 50 patients with minor head injuries and Glasgow Coma Scale scores of 13 to 15 in whom computed tomographic scans of the brain revealed no abnormalities. Serum levels of S-100 protein were measured at admittance and hourly thereafter until 12 hours after injury. Magnetic resonance imaging and baseline neuropsychological examinations were performed within 48 hours, and neuropsychological follow-up was conducted at 3 months postinjury. Results Fourteen patients (28%) had detectable serum levels of S-100 protein (mean peak value, 0.4 microg/L [standard deviation, +/- 0.3]). The S-100 protein levels were highest immediately after the trauma, and they declined each hour thereafter. At 6 hours postinjury, the serum level was below the detection limit (0.2 microg/L) in five (36%) of the patients with initially detectable levels. Magnetic resonance imaging revealed brain contusions in five patients, four of whom demonstrated detectable levels of S-100 protein in serum. The proportion of patients with detectable serum levels was significantly higher when magnetic resonance imaging revealed a brain contusion. In patients with detectable serum levels, we observed a trend toward impaired neuropsychological functioning on measures of attention, memory, and information processing speed. Conclusion Determination of S-100 protein levels in serum provides a valid measure of the presence and severity of traumatic brain damage if performed within the first hours after minor head injury.

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 …

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 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 P P r =0.43, P 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.

OBJECTIVE: We sought to assess the value of adjusting shunt valve opening pressure, complications, and outcomes with the use of an adjustable shunt valve in the treatment of patients with normal-pressure hydrocephalus (NPH). METHODS: In a single-center retrospective study, 231 adjustable valves (range, 30-200 mm H2O) were the first shunt implantations in 147 patients with idiopathic NPH (INPH) and 71 patients with secondary NPH (SNPH). The effect of adjustment on gait disturbance, cognitive impairment, urinary incontinence and other symptoms were evaluated, and an improvement index was created. RESULTS: In the INPH group, 138 adjustments were performed in 49.0% of the patients (average, 0.94 adjustments/patient). For the SNPH group, 49 adjustments were performed in 32.4% of the patients (average, 0.69 adjustments/patient). The reasons for adjustment were overdrainage in 48 patients (25.7%), underdrainage in 98 patients (52.4%), subdural hematoma in 37 patients (19.8%), and other reasons in 2 patients (2.1%). Clinical status improved after 56 (49.1%) of all 114 adjustments, whereas 23 (42.6%) of 54 minor (< or = 20 mm H2O) and 33 (66.0%) of 50 larger adjustments improved the patient's clinical status. The correlation of the improvement index with the size of the individual adjustments was not significant. Complications occurred in 43 (19.7%) of 218 patients, valve malfunction occurred in 3 patients (1.3%), infection occurred in 14 patients (6.4%), and nontraumatic subdural effusion occurred in 15 patients (6.9%; 8 were treated by adjustment alone). The 5-year shunt survival rate was 80.2%. Outcomes were excellent or good in 71 (78.9%) of 90 patients with INPH and in 30 (69.8%) of 43 patients with SNPH. CONCLUSION: Noninvasive, particularly consecutive, minor or single larger adjustments to the valve opening pressure can further improve outcome in patients with NPH who undergo shunting. (Less)

Objective Spontaneous intracranial hypotension is a potentially severe condition characterized by a distinct clinical picture caused by low cerebrospinal fluid pressure. Although coma has been reported previously as a presentation of this condition, this is the first report in which misdiagnosis of this condition and unwarranted surgery led to coma. Clinical presentation A 62-year-old man presented with a history of headache, and cranial magnetic resonance imaging showed bilateral chronic subdural hematomas. After evacuation of the hematoma, the patient's condition deteriorated into a state of profound depression of consciousness. Repeated cranial computed tomographic scans showed intracranial air, and intracranial pressure monitoring showed negative recording. Spinal magnetic resonance imaging demonstrated epidural cerebrospinal fluid leaks at the middle and lower thoracic levels. Intervention Epidural blood patch resulted in almost immediate improvement in the patient's condition, and he was fully awake 24 hours later. Conclusion This case report expands the presently known clinical spectrum of this uncommon and generally benign illness.