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Aim: To assess the relationship between the presence of toll-like receptor 4 (TLR4) polymorphisms and bacterial infections in cirrhotic patients with ascites., Methods: We prospectively included consecutive patients with cirrhosis and ascites hospitalized during a 6-year period. Patients with human immunodeficiency virus (HIV) infection or any other immunodeficiency, patients with advanced hepatocellular carcinoma (beyond Milan's criteria) or any other condition determining poor short-term prognosis, and patients with a permanent urinary catheter were excluded. The presence of D299G and/or T399I TLR4 polymorphisms was determined by sequencing and related to the incidence and probability of bacterial infections, other complications of cirrhosis, hepatocellular carcinoma, and mortality during follow-up. A multivariate analysis to identify predictive variables of mortality in the whole series was performed., Results: We included 258 patients: 28 (10.8%) were carriers of D299G and/or T399I TLR4 polymorphisms (polymorphism group) and 230 patients were not (wild-type group). The probability of developing any bacterial infection at one-year follow-up was 78% in the polymorphism group and 69% in the wild-type group ( P = 0.54). The one-year probability of presenting infections caused by gram-negative bacilli (51% vs 44%, P = 0.68), infections caused by gram-positive cocci (49% vs 40%, P = 0.53), and spontaneous bacterial peritonitis (29% vs 34%, respectively, P = 0.99) did not differ between the two groups. The one-year probability of transplant-free survival was 55% in the polymorphism group and 66% in the wild-type group ( P = 0.15). Multivariate analysis confirmed that age, Child-Pugh score, active alcohol intake, previous hepatic encephalopathy, hepatocellular carcinoma and serum creatinine were associated with a higher risk of death during follow-up., Conclusion: Genetic polymorphisms D299G and/or T399I of TLR4 do not seem to play a relevant role in the predisposition of cirrhotic patients with ascites to bacterial infections., Competing Interests: Conflict-of-interest statement: The authors declare that there is no conflict of interest related to this study.

Monitoring the hemodynamic response of portal pressure (PP) to drug therapy accurately stratifies the risk of variceal rebleeding (VRB). We assessed whether guiding therapy with hepatic venous pressure gradient (HVPG) monitoring may improve survival by preventing VRB. Patients with cirrhosis with controlled variceal bleeding were randomized to an HVPG-guided therapy group (N = 84) or to a control group (N = 86). In both groups, HVPG and acute β-blocker response were evaluated at baseline and HVPG measurements were repeated at 2-4 weeks to determine chronic response. In the HVPG-guided group, acute responders were treated with nadolol and acute nonresponders with nadolol+nitrates. Chronic nonresponders received nadolol+prazosin and had a third HVPG study. Ligation sessions were repeated until response was achieved. The control group was treated with nadolol+nitrates+ligation. Between-group baseline characteristics were similar. During long-term follow-up (median of 24 months), mortality was lower in the HVPG-guided therapy group than in the control group (29% vs. 43%; hazard ratio [HR] = 0.59; 95% confidence interval [CI] = 0.35-0.99). Rebleeding occurred in 19% versus 31% of patients, respectively (HR = 0.53; 95% CI = 0.29-0.98), and further decompensation of cirrhosis occurred in 52% versus 72% (HR = 0.68; 95% CI = 0.46-0.99). The survival probability was higher with HVPG-guided therapy than in controls, both in acute (HR = 0.59; 95% CI = 0.32-1.08) and chronic nonresponders (HR = 0.48; 95% CI = 0.23-0.99). HVPG-guided patients had a greater reduction of HVPG and a lower final value than controls (P < 0.05)., Conclusion: HVPG monitoring, by stratifying risk and targeting therapy, improves the survival achieved with currently recommended treatment to prevent VRB using β-blockers and ligation. HVPG-guided therapy achieved a greater reduction in PP, which may have contributed to reduce the risk of rebleeding and of further decompensation of cirrhosis, thus contributing to a better survival. (Hepatology 2017;65:1693-1707)., (© 2017 by the American Association for the Study of Liver Diseases.)

Background: Hospital mortality in patients with spontaneous bacterial peritonitis (SBP) is high despite albumin treatment, particularly in those with worse liver and/or renal function., Aim: To determine the independent predictive factors of in-hospital mortality and to create and validate a predictive model of mortality in patients with SBP., Methods: We analysed all cirrhotic patients with high-risk SBP (serum urea ≥11 mmol/L and/or serum bilirubin ≥68 μmol/L) between 2001 and 2011. We developed a predictive model of in-hospital mortality and validated this in a different cohort., Results: We included 118 high-risk SBP episodes treated with antibiotics and albumin. In-hospital mortality was 33/118 (28%). The independent predictive factors of in-hospital mortality at SBP diagnosis were serum urea, blood leucocyte count, Child-Pugh score and mean arterial pressure. A predictive model including these four variables showed a discrimination accuracy (AUC) of 0.850, 95% CI 0.777-0.922. A cut-off point of 0.245 showed a sensitivity of 0.85 and specificity of 0.75. The in-hospital mortality was 28/49 (57.1%) in patients with a model value ≥0.245, and 5/69 (7.2%) in patients with a model value <0.245 (P < 0.001). The validation series included 161 patients with an in-hospital mortality of 40/161 (24.8%), 30/77 (39.0%) in patients with a model value ≥0.245, and 10/84 (11.9%) in those with a model value <0.245 (P < 0.001)., Conclusions: We developed and validated a predictive model of mortality that includes serum urea, blood leucocyte count, Child-Pugh score and mean arterial pressure in high-risk patients with spontaneous bacterial peritonitis. These findings may help to identify patients who would benefit from additional therapeutic strategies., (© 2016 John Wiley & Sons Ltd.)

The progression of cirrhosis is associated with alterations in the composition of the gut microbiome. To assess microbial translocation, we compared the serum microbial composition of patients with and without ascites and characterized the ascitic fluid microbiome using 16S rDNA high-throughput sequencing data. A complex and specific microbial community was detected in the serum and ascitic fluid of patients with cirrhosis but barely detectable in the serum of healthy controls. The serum microbiome of patients with ascites presented higher levels of lipopolysaccharide binding protein, a marker of microbial translocation, associated with higher diversity and relative abundance of Clostridiales and an unknown genus belonging to the Cyanobacteria phylum compared to patients without ascites. The composition of the fecal microbiome was also more altered in patients with than without ascites, confirming previous studies on fecal microbiome. We propose that alteration of the serum and fecal microbiome composition be considered indicators of cirrhosis progression.

Unlabelled: Nonselective β-blockers are useful to prevent bleeding in patients with cirrhosis and large varices but not to prevent the development of varices in those with compensated cirrhosis and portal hypertension (PHT). This suggests that the evolutionary stage of PHT may influence the response to β-blockers. To characterize the hemodynamic profile of each stage of PHT in compensated cirrhosis and the response to β-blockers according to stage, we performed a prospective, multicenter (tertiary care setting), cross-sectional study. Hepatic venous pressure gradient (HVPG) and systemic hemodynamic were measured in 273 patients with compensated cirrhosis before and after intravenous propranolol (0.15 mg/kg): 194 patients had an HVPG ≥10 mm Hg (clinically significant PHT [CSPH]), with either no varices (n = 80) or small varices (n = 114), and 79 had an HVPG >5 and <10 mm Hg (subclinical PHT). Patients with CSPH had higher liver stiffness (P < 0.001), worse Model for End-Stage Liver Disease score (P < 0.001), more portosystemic collaterals (P = 0.01) and splenomegaly (P = 0.01) on ultrasound, and lower platelet count (P < 0.001) than those with subclinical PHT. Patients with CSPH had lower systemic vascular resistance (1336 ± 423 versus 1469 ± 335 dyne · s · cm(-5) , P < 0.05) and higher cardiac index (3.3 ± 0.9 versus 2.8 ± 0.4 L/min/m(2) , P < 0.01). After propranolol, the HVPG decreased significantly in both groups, although the reduction was greater in those with CSPH (-16 ± 12% versus -8 ± 9%, P < 0.01). The HVPG decreased ≥10% from baseline in 69% of patients with CSPH versus 35% with subclinical PHT (P < 0.001) and decreased ≥20% in 40% versus 13%, respectively (P = 0.001)., Conclusion: Patients with subclinical PHT have less hyperdynamic circulation and significantly lower portal pressure reduction after acute β-blockade than those with CSPH, suggesting that β-blockers are more suitable to prevent decompensation of cirrhosis in patients with CSPH than in earlier stages., (© 2015 by the American Association for the Study of Liver Diseases.)

An ascitic microenvironment can condition the immune response of cells from cirrhotic patients with spontaneous bacterial peritonitis. To characterize this response, we determined the cytokine concentrations in ascitic fluid and analyzed the phenotype and function of ascitic leukocytes at diagnosis and after antibiotic-induced resolution in sterile ascites and ascitic fluid of 2 spontaneous bacterial peritonitis variants: positive and negative bacteriological culture. At diagnosis, a high concentration was found of IL-6 and IL-10 in the ascitic fluid from negative and positive bacteriological culture. The IL-6 concentration correlated with the percentage of neutrophils (R = 0.686, P < 0.001). In this context, positive and negative culture neutrophils had an impaired oxidative burst, and, after the antibiotic, the negative culture spontaneous bacterial peritonitis burst was fully recovered. Higher concentrations of IL-6 and IL-10 correlated with the presence of low granular CD 14(low) macrophages (R = -0.436, P = 0.005 and R = 0.414, P = 0.007, respectively). Positive culture spontaneous bacterial peritonitis macrophages expressed the lowest levels of CD16, CD86, CD11b and CD206, and HLA-DR, suggesting an impaired global function. Treatment increased all markers on the positive culture macrophages and CD11b and CD86 on negative culture macrophages. In negative culture spontaneous bacterial peritonitis, this increase was accompanied by phagocytic function recovery. The antibiotics then reverted the marker levels on positive and negative culture macrophages to the levels on sterile ascitis macrophages and restored ascitic negative culture cell function., (© Society for Leukocyte Biology.)

Aim: To analyze the cytokine production by peripheral blood cells from cirrhotic patients with and without TLR4 D299G and/or T399I polymorphisms., Methods: The study included nine patients with cirrhosis and TLR4 D299G and/or T399I polymorphisms, and 10 wild-type patients matched for age, sex and degree of liver failure. TLR4 polymorphisms were determined by sequence-based genotyping. Cytokine production by peripheral blood cells was assessed spontaneously and also after lipopolysaccharide (LPS) and lipoteichoic acid (LTA) stimulation., Results: Patients with TLR4 polymorphisms had a higher incidence of previous hepatic encephalopathy than wild-type patients (78% vs 20%, P = 0.02). Spontaneous production of interleukin (IL)-6 and IL-10 was lower in patients with TLR4 polymorphisms than in wild-type patients [IL-6: 888.7 (172.0-2119.3) pg/mL vs 5540.4 (1159.2-26053.9) pg/mL, P < 0.001; IL-10: 28.7 (6.5-177.1) pg/mL vs 117.8 (6.5-318.1) pg/mL, P = 0.02]. However, the production of tumor necrosis factor-α, IL-6 and IL-10 after LPS and LTA stimulation was similar in the two groups., Conclusion: TLR4 polymorphisms were associated with a distinctive pattern of cytokine production in cirrhotic patients, suggesting that they play a role in the development of cirrhosis complications.

Objectives: To determine the frequency and duration of cortical spreading depolarization (CSD) and CSD-like episodes in patients with traumatic brain injury (TBI) and malignant middle cerebral artery infarction (MMCAI) requiring craniotomy., Design: A descriptive observational study was carried out during 19 months., Setting: Neurocritical patients., Patients: Sixteen patients were included: 9 with MMCAI and 7 with moderate or severe TBI, requiring surgical treatment., Interventions: A 6-electrode subdural electrocorticographic (ECoG) strip was placed onto the perilesional cortex., Main Variables of Interest: An analysis was made of the time profile and the number and duration of CSD and CSD-like episodes recorded from the ECoGs., Results: Of the 16 patients enrolled, 9 presented episodes of CSD or CSD-like phenomena, of highly variable frequency and duration., Conclusions: Episodes of CSD and CSD-like phenomena are frequently detected in the ischemic penumbra and/or traumatic cortical regions of patients with MMCAI who require decompressive craniectomy or of patients with contusional TBI., (Copyright © 2013 Elsevier España, S.L.U. and SEMICYUC. All rights reserved.)

Background & Aims: Combined therapy with endoscopic variceal ligation (EVL) and β-blockers ± isosorbide mononitrate (ISMN) is currently recommended to prevent variceal rebleeding. However, the role of this combined therapy has been challenged by some studies. We performed a systematic review to assess the value of combined therapy with EVL and β-blockers ± ISMN as compared with each treatment alone to prevent rebleeding., Methods: Databases, references and meeting abstracts were searched to retrieve randomized trials comparing combined therapy with EVL and β-blockers ± ISMN vs either treatment alone, to prevent variceal rebleeding in cirrhosis. Random-effects model was used for meta-analysis., Results: We identified five studies comparing EVL alone or combined with drugs, including a total of 476 patients. Combination therapy reduced overall rebleeding [risk ratios (RR) = 0.44, 95% confidence interval (CI) = 0.28-0.69], and showed a trend towards lower mortality (RR = 0.58, 95% CI = 0.33-1.03), without increasing complications. We identified four trials comparing drugs alone or associated with EVL, including 409 patients. All used β-blockers plus ISMN. Variceal rebleeding decreased with combined therapy (P < 0.01) but rebleeding from oesophageal ulcers increased (P = 0.01). Overall, there was a trend towards lower rebleeding (RR = 0.76, 95% CI = 0.58-1.00) without effect on mortality (RR = 1.24, 95% CI = 0.90-1.70)., Conclusions: The addition of drug therapy to EVL improves the efficacy of EVL alone. However, the addition of EVL to β-blockers and ISMN achieves a non-significant decrease of rebleeding with no effect on mortality. Although combination therapy with EVL plus β-blockers ± ISMN is adequate to prevent rebleeding, β-blockers + ISMN alone may be a valid alternative., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Chiari type I malformation (CM-I) is characterised by caudal ectopia of the cerebellar tonsils through the foramen magnum. This is associated with brain stem, high spinal cord, and cranial nerve compression phenomena. The most frequent symptoms are occipital headaches and dizziness. Less well-known symptoms are sleep disorders and nocturnal respiratory abnormalities., Sources: MEDLINE and information from patients evaluated at the Neurosurgery and Clinical Neurophysiology Departments at Hospital Universitario Vall d'Hebron., Development: Review article based on data obtained from MEDLINE articles since 1966, using combinations of the following keywords: «Chiari malformation» or «Arnold-Chiari malformation» and «sleep apnea» or «sleep disorders»., Conclusions: CM-I patients show a higher prevalence of sleep disorders than that observed in the general population. Some studies report a 50% prevalence of sleep apnea-hypopnea syndrome (SAHS), probably associated with sudden death in some cases. These results support analysing sleep respiratory parameters in theses patients. Identifying SAHS symptoms may help optimise treatment, thereby improving quality of life and prognosis., (Copyright © 2010 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.)

Background & Aims: Terlipressin and albumin is the standard of care for classical type-1 hepatorenal syndrome (HRS) not associated with active infections. However, there is no information on efficacy and safety of this treatment in patients with type-1 HRS associated with sepsis. Study aim was to investigate the effects of early treatment with terlipressin and albumin on circulatory and kidney function in patients with type-1 HRS and sepsis and assess factors predictive of response to therapy., Methods: Prospective study in 18 consecutive patients with type-1 HRS associated with sepsis., Results: Treatment was associated with marked improvement in arterial pressure and suppression of the high levels of plasma renin activity and norepinephrine. Response to therapy (serum creatinine <1.5mg/dl) was achieved in 12/18 patients (67%) and was associated with improved 3-month survival compared to patients without response. Non-responders had significantly lower baseline heart rate, poor liver function tests, slightly higher serum creatinine, and higher Child-Pugh and MELD scores compared to responders. Interestingly, non-responders had higher values of CLIF-SOFA score compared to responders (14±3 vs. 8±1, respectively p<0.001), indicating greater severity of acute-on-chronic liver failure (ACLF). A CLIF-SOFA score ⩾11 had 92% sensitivity and 100% specificity in predicting no response to therapy. No significant differences were observed between responders and non-responders in baseline urinary kidney biomarkers. Treatment was safe and no patient required withdrawal of terlipressin., Conclusions: Early treatment with terlipressin and albumin in patients with type-1 HRS associated with sepsis is effective and safe. Patients with associated severe ACLF are unlikely to respond to treatment., (Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Introduction: Laparoscopic Heller myotomy has become the gold standard procedure for patients with achalasia. This study evaluates the clinical status, quality of life, and functional outcomes after laparoscopic Heller myotomy., Material and Methods: We analyzed patients who underwent laparoscopic Heller myotomy with an associated anti-reflux procedure from October 1998 to December 2010. Before surgery, we administered a clinical questionnaire and as of 2002, we also evaluated quality of life using a specific questionnaire (GIQLI). In 2011, we performed a follow up for all available patients. We administered the same clinical questionnaire and quality of life test as before surgery and performed manometry and 24-hour pH monitoring. According to the length of follow up, patients were divided into 3 groups. Group 1 with a follow-up between 6 and 47 months; group 2 follow-up between 48 and 119 months, and group 3 with a follow-up of more than 120 months). Moreover, 27 patients had already been evaluated with this same protocol in 2003. Pre- and postoperative data were compared for the 3 groups and for patients who completed follow up in 2003 and 2011., Results: Ninety-five patients underwent laparoscopic Heller myotomy. Seventy-six (80%) were available for follow-up. Mean follow-up was 56 months (range 6-143). Global improvement in dysphagia was 89%. Total DeMeester score decreased in the 3 groups. GIQLI scores improved after surgery, reaching normal values. Manometric determinations showed normal LES pressures after myotomy in the 3 groups. Ten percent of overall 24-hour pH monitoring was abnormal. The group of patients followed up in 2003 and in 2011 showed no impairment in the variables studied in the long term., Conclusions: Long-term follow up of the laparoscopic approach to achalasia showed good results concerning clinical status and quality of life, with normal sphincteric pressures and a low incidence of gastroesophageal reflux., (Copyright © 2013 AEC. Published by Elsevier Espana. All rights reserved.)

Background: The hemoglobin threshold for transfusion of red cells in patients with acute gastrointestinal bleeding is controversial. We compared the efficacy and safety of a restrictive transfusion strategy with those of a liberal transfusion strategy., Methods: We enrolled 921 patients with severe acute upper gastrointestinal bleeding and randomly assigned 461 of them to a restrictive strategy (transfusion when the hemoglobin level fell below 7 g per deciliter) and 460 to a liberal strategy (transfusion when the hemoglobin fell below 9 g per deciliter). Randomization was stratified according to the presence or absence of liver cirrhosis., Results: A total of 225 patients assigned to the restrictive strategy (51%), as compared with 61 assigned to the liberal strategy (14%), did not receive transfusions (P<0.001) [corrected].The probability of survival at 6 weeks was higher in the restrictive-strategy group than in the liberal-strategy group (95% vs. 91%; hazard ratio for death with restrictive strategy, 0.55; 95% confidence interval [CI], 0.33 to 0.92; P=0.02). Further bleeding occurred in 10% of the patients in the restrictive-strategy group as compared with 16% of the patients in the liberal-strategy group (P=0.01), and adverse events occurred in 40% as compared with 48% (P=0.02). The probability of survival was slightly higher with the restrictive strategy than with the liberal strategy in the subgroup of patients who had bleeding associated with a peptic ulcer (hazard ratio, 0.70; 95% CI, 0.26 to 1.25) and was significantly higher in the subgroup of patients with cirrhosis and Child-Pugh class A or B disease (hazard ratio, 0.30; 95% CI, 0.11 to 0.85), but not in those with cirrhosis and Child-Pugh class C disease (hazard ratio, 1.04; 95% CI, 0.45 to 2.37). Within the first 5 days, the portal-pressure gradient increased significantly in patients assigned to the liberal strategy (P=0.03) but not in those assigned to the restrictive strategy., Conclusions: As compared with a liberal transfusion strategy, a restrictive strategy significantly improved outcomes in patients with acute upper gastrointestinal bleeding. (Funded by Fundació Investigació Sant Pau; ClinicalTrials.gov number, NCT00414713.).

Introduction: Pupil assessment is a fundamental part of the neurological examination. Size and reactivity to light of each pupil should be recorded periodically since changes in these parameters may represent the only detectable sign of neurological deterioration in some patients. However, there is great intraobserver and interobserver variability in pupil examination due to the influence of many factors, such as the difference in ambient lighting, the visual acuity and experience of the examiner, the intensity of the luminous stimulus, and the method used to direct this stimulus. In recent years, digital cameras have incorporated infrared devices allowing the development of user-friendly portable devices that permit repeated, non-invasive examinations of pupil size and its reactivity to light with an objective, accessible and inexpensive method., Development: The purpose of this review is to describe the fundamentals of infrared pupillometry and discuss potential applications in the monitoring of neurocritical patients. We also present some recommendations in the routine assessment of pupils in neurocritical patients., Conclusions: The possibility of evaluating the changes in pupil reactivity in an early, objective and almost continuous way provides a new non-invasive monitoring method. This method could improve the predictive factor of neurological deterioration and the bedside monitoring of the neurological state of the patient, avoiding unnecessary examinations and enabling early therapeutic intervention., (Copyright © 2010 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.)

Unlabelled: Falls are frequent among patients with debilitating disorders and can have a serious effect on health status. Mild cognitive disturbances associated with cirrhosis may increase the risk for falls. Identifying subjects at risk may allow the implementation of preventive measures. Our aim was to assess the predictive value of the Psychometric Hepatic Encephalopathy Score (PHES) in identifying patients likely to sustain falls. One hundred and twenty-two outpatients with cirrhosis were assessed using the PHES and were followed at specified intervals. One third of them exhibited cognitive dysfunction (CD) according to the PHES (<-4). Seventeen of the forty-two patients (40.4%) with CD had at least one fall during follow-up. In comparison, only 5 of 80 (6.2%) without CD had falls (P < 0.001). Fractures occurred in 4 patients (9.5%) with CD, but in no patients without CD (P = 0.01). Patients with CD needed more healthcare (23.8% versus 2.5%; P < 0.001), more emergency room care (14.2% versus 2.5%; P = 0.02), and more hospitalization (9.5% versus 0%; P = 0.01) as a result of falls than patients without CD. Patients taking psychoactive treatment (n = 21) had a higher frequency of falls, and this was related to an abnormal PHES. In patients without psychoactive treatment (n = 101), the incidence of falls was 32.4% in patients with CD versus 7.5% in those without CD (P = 0.003). In the multivariate analysis, CD was the only independent predictive factor of falls (odds ratio, 10.2; 95% confidence interval, 3.4-30.4; P < 0.001). The 1-year probability of falling was 52.3% in patients with CD and 6.5% in those without (P < 0.001)., Conclusion: An abnormal PHES identifies patients with cirrhosis who are at risk for falls. This psychometric test may be useful to promote awareness of falls and identify patients who may benefit from preventive strategies., (Copyright © 2012 American Association for the Study of Liver Diseases.)

Background & Aims: Intravenous administration of albumin decreases the incidence of renal failure and mortality among patients with spontaneous bacterial peritonitis (SBP). However, it is unclear whether it should be given to all patients with SBP; we evaluated its efficacy., Methods: We analyzed data from all episodes of SBP (n = 216) during a 7-year period that occurred in a nonselected series of 167 patients with cirrhosis. Low-risk episodes (urea <11 mmol/L and bilirubin <68 μmol/L) were not treated with albumin, whereas high-risk episodes (urea >11 mmol/L and/or bilirubin >68 μmol/L) were or were not given albumin at the discretion of the attending physician., Results: Sixty-four episodes of SBP (29.6%) were low risk and not treated with albumin, whereas 152 (70.4%) were high risk; 73 of these (48%) were treated with albumin and 79 (52%) were not. Renal failure before SBP resolution was less frequent after low-risk episodes than high-risk episodes (4.7% versus 25.6%; P = .001), in-hospital mortality was lower (3.1% versus 38.2%; P < .001), and the 3-month probability of survival was higher (93% versus 53%; P < .001). In an analysis of only the high-risk group, patients who received albumin had lower in-hospital mortality than those not treated with albumin (28.8% versus 46.8%; P = .02) and a greater 3-month probability of survival (62% versus 45%; P = .01)., Conclusions: Albumin therapy increases survival of patients who have high-risk episodes of SBP, although it does not seem to be necessary for patients with low risk of death., (Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objectives: In compensated cirrhosis, a threshold value of hepatic venous pressure gradient (HVPG) ≥10 mm Hg is required for the development of decompensation. However, whether the treatment of portal hypertension (PHT) can prevent the transition into development of ascites once this level has been reached is unclear. Our aim was to assess the relationship between changes in HVPG induced by β-blockers and development of ascites in compensated cirrhosis with severe PHT., Methods: Eighty-three patients without any previous decompensation of cirrhosis, with large esophageal varices and HVPG ≥12 mm Hg were included. After baseline hemodynamic measurements nadolol was administered and a second hemodynamic study was repeated 1-3 months later., Results: During 53±30 months of follow-up, decompensation occurred in 52 patients (62%) and in 81% of them ascites was the first manifestation. Using receiver operating characteristic curve analysis a decrease in HVPG ≥10% was the best cutoff to predict ascites. As compared with nonresponders, patients with an HVPG decrease ≥10% had a lower probability of developing ascites (19% vs. 57% at 3 years, P<0.001), refractory ascites (P=0.007), and hepatorenal syndrome (P=0.027). By Cox regression analysis hemodynamic nonresponse was the best predictor of ascites. By stepwise logistic regression, development of ascites was independently associated with nonresponse, whereas refractory ascites, hepatorenal syndrome, and spontaneous bacterial peritonitis were not., Conclusions: In patients with compensated cirrhosis and large varices treated with β-blockers, an HVPG decrease ≥10% significantly reduces the risk of developing ascitic decompensation and other related complications such as refractory ascites or hepatorenal syndrome.

Prognostic markers of compensated cirrhosis should mainly investigate factors involved with progression to decompensation because death in cirrhosis is related with decompensation. Portal hypertension plays a crucial role in the pathophysiology of most complications of cirrhosis. Accordingly, HVPG monitoring has strong prognostic value. An HVPG ≥ 10 mmHg determines a significantly higher risk of developing decompensation. Esophageal varices also can develop when the HVPG is ≥ 10 mmHg, although an HVPG ≥ 12 mmHg is required for variceal bleeding to occur. Monitoring the changes induced by the treatment of portal hypertension on HVPG, provides strong prognostic information. In compensated cirrhosis hemodynamic response is appropriate when the HVPG decreased to < 10 mmHg or by > 10% from baseline, because the incidence of complications such as bleeding or ascites significantly decrease when these targets are achieved. Whether serum markers, such as the FibroTest, they, may be valuable to predict decompensation should be established. Transient Elastography is a promising technique that has shown an excellent accuracy to detect severe portal hypertension. However, whether it can adequately determine clinically significant portal hypertension, and risk of developing varices and decompensation, should be established. Magnetic Resonance Elastography is also promising.

Unlabelled: Lactate and the lactate-pyruvate index (LPI) are two hypoxia markers widely used to detect brain tissue hypoxia in patients with acute traumatic brain injury. These two markers have a more complex behavior than expected as they can be abnormally high in circumstances with no detectable brain hypoxia. This condition must be considered in the differential diagnosis because it also reflects an alteration of brain energy metabolism., Objectives: 1. To describe cerebral energy metabolism characteristics observed in the acute phase of traumatic brain injury (TBI) based on two traditional indicators of anaerobic metabolism: lactate and LPI, 2. To determine the concordance between these two biomarkers in order to classify the incidence of anaerobic metabolism and 3. To classify the different types of metabolic abnormalities found in patients with moderate and severe TBI using both lactate and LPI., Materials and Methods: Twenty-one patients were randomly selected from a cohort of moderate or severe TBI patients admitted to the neurotraumatology intensive care unit. All of them who underwent both cerebral microdialysis and brain tissue oxygen monitoring (PtiO(2)). We analyzed the levels of lactate and the LPI for every microvial within the first 96 hours after head trauma. These data were correlated with PtiO(2) values., Results: Lactate levels and the LPI were respectively increased during 49.5% and 38.4% of the monitoring time. The incidence and behavior of high levels of both markers were extremely heterogeneous. The concordance between these two biomarkers to determine episodes of dysfunctional metabolism was very weak (Kappa Index=0.29; IC 95%: 0.24-0.34). Based on the levels of lactate and the LPI, we defined four metabolic patterns: I: L>2.5 mmol/L and LPR>25; II: L>2.5 mmol/L and LPR< or = 25; III: L< or = 2.5 mmol/L and LPR< or = 25; IV: L< or = 2.5 mmol/L and LPR>25). In more than 80% of cases in which lactate or LPI were increased, PtiO(2) values were within the normal range (PtiO(2)> 15 mmHg)., Conclusions: Increased lactate and LPI were frequent findings after acute TBI and in most cases they were not related to episodes of brain tissue hypoxia. Furthermore, the concordance between both biomarkers to classify metabolic dysfunction was weak. LPI and lactate should not be used indistinctly in everyday clinical practice because of the weak correlation between these two markers, the difficulty in their interpretation and the heterogeneous and complex nature of the pathophysiology. Other differential diagnoses apart from tissue hypoxia should always be considered when high lactate and/or LPI are detected in the acute injured brain.

Introduction: Matrix metalloproteinases (MMP) are a family of proteolytic enzymes that degrade the extracellular matrix and are found in a large amount of human tissues. Their main functions are to maintain the integrity of the extracellular matrix, to modulate the interaction of the cells during development, to contribute to tissue remodeling, to directly participate in angiogenesis and to facilitate cellular migration. Due to the importance of its maintaining extracellular matrix function, MMP expression is tightly regulated at transcriptional level, through proform activation and with the binding to tissular inhibitors. Despite this complex regulation system, MMP regulation can be altered, producing an overexpression of these proteolytic proteins that alter the tissular structure, possibly destroying the tissue, as observed in some neurologic pathologies such as multiple sclerosis, aneurism formation and cerebral ischemia. The role that MMP have in traumatic brain lesions is almost unknown and is derived mainly from in vivo and in vitro experimental studies, and only from three papers performed in humans. There are some experimental studies that relate the brain alterations produced after traumatic brain injury with an increase in the concentration of various MMP., Aim: To review the role of these proteases in human brain lesions, emphasizing on the function of these proteases in traumatic brain injury lesions and their possible therapeutic target., Development: A bibliographic search was performed on Medline database., Conclusions: Some MMP could be related to blood-brain barrier alteration and postraumatic edema formation, turning them into promising therapeutic targets.

Objective: To determine the response to cognitive event-related potentials (P300) in patients with normal-pressure hydrocephalus (NPH) and their relationship with clinical and cognitive status before and after shunt surgery., Methods: We performed a prospective study in a series of 26 patients with NPH who underwent clinical and cognitive assessment before surgery and 6 months afterwards. Visual P300 potentials obtained before and after treatment were also compared with those obtained in 18 healthy volunteers., Results: Before shunting, the P300 wave was detected in 11 (42.3%) NPH patients, compared with the 18 (100%) volunteers. Six months after shunting, the P300 wave was found in 20 (76.9%) NPH patients. P300 latency was significantly longer in NPH patients than in the control group before surgery, but not at 6 months after surgery. No significant differences in neuropsychological studies or in the level of dependence for daily life activities were found between the subgroups of NPH patients with and without pre-surgical P300 waves, or between changes in P300 parameters and clinical and cognitive changes., Conclusions: The P300 wave was delayed or undetectable in a substantial percentage of patients with NPH before surgery. These alterations can be reversed by shunting. P300 analysis and neuropsychological tests could be complementary measures to evaluate functional status in patients with NPH.

Cerebral microdialysis is a tool that provides very relevant information in the metabolic monitoring of brain injured patients. It is a particularly effective technique for the detection and analysis of small molecules, given that the pores of the dialysis membrane act as a barrier to restrict the transport of larger species, such as proteins and other macromolecules. The recent availability of microdialysis catheters with membrane pores of larger size, termed "high resolution" catheters, would widen the spectrum of molecules detectable in the dialisate. However, there are technical complications related to the use of these catheters for such purposes, and therefore, this potential capacity for the recovery of proteins needs to be validated, in order to begin its application as a tool in studies of proteomics associated with brain injuries. The following review depicts the basic principles of microdialysis, and describes some of the issues involved in the recovery of molecules in the dialisate, including the physical properties of the dialysis membrane and of the molecules of interest.

Summary: Alexander disease (AD) is a rare neurodegenerative disorder characterized by megalencephaly, leukoencephalopathy, and Rosenthal fibers within astrocytes. This report describes the case of a female patient with sonography-detected ventriculomegaly at 32 weeks' gestation and distinctive MR imaging features at 33 and 36 weeks' gestation, at birth, and at 2 months of age, which led to the suggested diagnosis of Alexander disease. Molecular analysis confirmed a missense mutation in the GFAP gene. The literature contains little information on the fetal MR imaging findings that may allow prenatal diagnosis of AD.

Normal pressure hydrocephalus (NPH) is characterized by gait disturbance, urinary incontinence and dementia, and is associated with variable ventricular enlargement. The most accepted treatment of NPH is the placement of a cerebrospinal fluid shunt. Owing to the characteristics of the patients and the invasive nature of the surgical treatment, it is fundamental to detect those patients who could obtain a greater benefit from the treatment. Neuropsychological assessment of these patients could significantly contribute to a better diagnosis of NPH, determining a cognitive deterioration profile for these patients, allowing the assessment of treatment efficacy and helping to detect other additional causes of dementia. The aim of this study is to describe the cognitive deterioration profile of NPH patients and to present the clinical, functional and neuropsychological assessment protocol used in our hospital.

Malignant middle cerebral artery infarction (MMCAI) refers to an infarction type normally accompanied by massive cerebral edema, and associated with a high mortality rate under conventional therapeutic measures. Both moderate hypothermia and decompressive hemicraniectomy have been shown to significantly improve survival rate, although controversy still persists regarding the criteria for the selection of patients that could benefit from this type of treatment, and whether application of these measures is justified given the residual sequelae. In our centre, both measures are being applied simultaneously for the first time in humans. The present work is a literature review on the results of moderate hypothermia application and decompressive surgical techniques in patients suffering from MMCAI. We also introduce our management scheme for handling these patients in our centre, and propose a final result evaluation protocol that is easily applied in a clinical setting. This protocol includes an evaluation of patients with ischemic lesions specific for the right or left hemisphere, and allows for the description of specific neuropsychological sequelae and their repercussions on patients' quality of life.

Traumatic brain injury (TBI) frequently results in cerebrovascular lesions that may increase secondary damage and cause neuropsychological impairment. Previous studies suggest an association among the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE), cardiovascular disease, and cognitive performance. Clinical and experimental studies have demonstrated the beneficial effects of ACE inhibitor treatment on vascular injury, hypertension, brain ischemia, and cognitive functioning. In a sample of 73 moderate and severe TBI patients, the authors assessed whether cognitive sequelae differed in relation to the ACE I/D polymorphism. D allele carrier patients performed worse than those with I/I polymorphism on tests involving attention and processing speed. Findings suggest that the physiopathological changes associated with TBI may have greater consequences in ACE D allele carriers.

The long term outcome of head-injured patients depends not only on the primary brain lesions but also to a large extent on the secondary lesions. The diagnosis of many secondary lesions, and specially that of brain ischemia, is based on simultaneous monitoring of several intracranial and systemic variables. Continuous intracranial pressure (ICP) monitoring is currently considered indispensable in the management of all patients with a severe head injury and intracranial lesions. However, the information provided by this technique is insufficient to diagnose some of the complex physiopathological processes that characterize traumatic brain lesions. Consequently, the use of methods to estimate cerebral blood flow such as transcranial Doppler and jugular oximetry to complement ICP monitoring is becoming increasingly widespread. Nevertheless, determining the effect of tissue lesions and therapeutic measures on cerebral metabolism currently requires direct access to the brain parenchyma at the bedside. In this review we focus on three methods of regional cerebral monitoring: oxygen tissue pressure (PtiO(2)) monitoring, microdialysis and near-infrared spectroscopy. The bases of each method and reference values for the variables analyzed will be discussed. We also make a series of recommendations on how results should be interpreted in light of current knowledge.

Because of the importance of hypoxic/ischemic phenomena in head-injured patients, brain monitoring in these patients should be complemented by systems providing information on cerebral blood flow and metabolism. Indirect estimations of cerebral blood flow have been obtained from blood extracted from the jugular bulb, as a special bedside application of the Fick's principle to the brain. In the last few years, the use of jugular oximetry techniques has become routine in centers treating head-injured and other neurocritical patients such as those presenting subarachnoid hemorrhage or malignant middle cerebral artery infarction. The experience acquired in the use of these techniques, as well as the introduction of new neuromonitoring systems, have deepened our understanding of the information gained and have enabled more precise definition of their indications and limitations. This review describes the basic concepts underlying the use of jugular oximetry techniques in the neurocritical patient. We also explain the reasons why several variables derived from jugular blood such as arterio-jugular differences of lactate (AVDL) or the lactate-oxygen index (LOI) do not provide accurate information on brain metabolism.

Introduction: The surgical treatment of focal intradural lesions is still a matter of considerable debate. This is especially important in the decision to evacuate brain contusions. We present the results of a prospective observational study in which the main goal was to analyze intracenter variability in the indication for surgery in focal posttraumatic intradural lesions in a department of Neurosurgery of a University Hospital with a specialized neurotrauma unit., Clinical Material and Methods: Between May 1 and December 31, 2001, 32 patients with a closed traumatic brain injury and an intradural posttraumatic focal lesion were included. The patients studied were a subgroup included in the European multicenter observational study of the management of intradural lesions conducted under the aegis of the European Brain Injury Consortium (EBIC)., Results: Intradural lesions > 25 cc were immediately evacuated. Nine out of thirteen patients with lesions < 25 cc also underwent surgery due to intracranial hypertension or neuroworsening. In all patients in whom lesions were surgically evacuated, the postoperative CT-scan showed neuroradiological improvement of the signs of mass effect or midline shift., Conclusions: In our center, we found no evidence of significant variability in the indications for surgery in intradural lesions of more than 25 cc. However, significant differences were detected among neurosurgeons in the surgical indications for lesions below 25 cc. The small sample analyzed precludes generalization of these conclusions. The definitive results of the EBIC study will provide the neurosurgical community with a better understanding of variability in the management of these lesions.

Unlabelled: Because of the centralization of neurosurgical services, many head-injured patients who are initially evaluated in district general hospitals need to be transferred to a high technology centre for neurosurgical assessment. However, after assessment, many of these patients are sent back to the original hospital. Establishing a teleradiological system between the two hospitals would eliminate these unnecessary transfers., Objectives: 1) to describe our initial experience and the results of a pilot study of the teleradiological link between a district general hospital and a tertiary hospital for neurosurgical assessment of head-injured patients, 2) to describe the infrastructure and the technological support required for this project, 3) to analyse the effects of the teleradiological link in both centers (referring and receiving), 4) to evaluate the effectiveness of the system in avoiding unnecessary transfers, and 5) to assess its effectiveness in improving the speed and the quality of transfers in head-injured patients., Material and Methods: In January 1998, the Neurotraumatology Unit of Vall d'Hebron University Hospital established a teleradiological link with the General Hospital of Vic for the neurosurgical evaluation of headinjured patients. The General Hospital of Vic sent the patients' clinical information by fax. CT scan images were digitalized, compressed and prepared for transmission with the StatView program, and were then transmitted by modem to the receiving center. The duty neurosurgeon viewed the images on a PC screen using MutiView software. After evaluating this clinical and radiological information the neurosurgeon sent a report back to the referring center recommending transfer or management (admission, observation, etc.)., Results: We analyse the results of our experience 5 years after the implantation of the teleradiological link., Conclusions: The use of teleradiology in the daily management of head-injured patients provides clear benefits and leads to a more rational use of resources, thus significantly reduces costs. The effectiveness of the system in reducing the interval between the injury and treatment in severe cases depends more on the infrastructure of the health system in each geographical area than on sophisticated telemedicine systems. These methods should be accompanied by other measures designed to hasten the transfer of selected patients.

Objective: The aim of this study was to characterize regional cerebral blood flow in patients with Adult Hydrocephalus Syndrome (AHS) and to evaluate the changes in brain perfusion after surgical derivation treatment., Patients and Methods: 20 patients with AHS (age: 72 +/- 14, 12 men) were studied before and six months after surgery. All patients underwent a brain perfusion SPECT (99mTc-HMPAO) prior to surgery and at 6 months post-surgery. Semi-quantitative analysis was done for brain uptake: 0=Normal, 1=Mild, 2=Moderate, 3= Severe, 4=No uptake. The severity of ventricular dilatation was assessed by classifying the intensity and extension of subcortical defects: 0=Normal, 1=Mild, 2=Moderate, 3=Severe. The scores of the pre- and post-surgical studies were compared using the Student-t test., Results: A global reduction of brain uptake was observed (mean score 12.85), mainly in frontal, parietal and temporal lobes, with a significant improvement in post surgical studies (mean score 6, p<0,001). After surgery, 16 (80%) of the 20 patients improved brain uptake. In relationship to subcortical uptake, 5 patients showed mild defects, 9 moderate defects and 6 patients presented severe uptake reduction. In post-surgical studies 15 (75%) patients improved almost one degree in the subcortical score and 65% of the patients showed a normal or mild subcortical uptake reduction., Conclusions: Brain perfusion SPECT is useful in patients with AHS, detecting brain perfusion defects and evaluating cerebral blood flow improvement after shunt operation.

The management of severe head injuries in general and that of high intracranial pressure (ICP) in particular are among the most challenging tasks in neurocritical care. One of the difficulties still faced by clinicians is that of reducing variability among centers when implementing management protocols. The purpose of this paper is to propose a standardized protocol for the management of high ICP after severe head injury, consistent with recently published clinical practice guidelines and other clinical evidence such as that provided by the systematic reviews of the Cochrane Collaboration. Despite significant advances in neuromonitoring, deeper insight into the physiopathology of severe brain trauma and the many therapeutic options available, standardized protocols are still lacking. Recently published guidelines provide sketchy recommendations without details on how and when to apply different therapies. Consequently, great variability exists in daily clinical practice even though different centers apply the same evidence-based recommendations. In this paper we suggest a structured protocol in which each step is justified and integrated into an overall strategy for the management of severe head injuries. The most recent data from both the preliminary and definitive results of randomized clinical trials as well as from other sources are discussed. The main goal of this article is to provide neurotraumatology intensive care units with a unified protocol that can be easily modified as new evidence becomes available. This will reduce variation among centers when applying the same therapeutic measures. This goal will facilitate comparisons in outcomes among different centers and will also enable the implementation of more consistent clinical practice in centers involved in multicenter clinical trials.

Objectives: The aims of the study were 1) to assess the degree of agreement between CSF flow dynamics determined by MR and ICP monitoring in the diagnosis of NPH, and 2) to determine the sensitivity and specificity of CSF flow dynamics studied by MR in predicting improvement after shunting., Patients and Methods: A prospective study was carried out in 35 consecutive patients with suspected NPH. CSF velocity (Phase Contrast) through the aqueduct was determined in sagittal plane. Patients were classified as "normal" or hyperdynamic in comparison with a control group of 27 healthy volunteers. Continuous extradural ICP monitoring was performed for at least 72 hours and patients were classified as having active, compensated, or ex-vacuo hydrocephalus. Patients with active or compensated hydrocephalus were shunted., Results: The degree of agreement between MR dynamics and ICP monitoring was 82%. Sensitivity of CSF velocity was 90% and specificity was 50%., Conclusions: The degree of agreement between ICP monitoring and CSF velocity is high. High CSF velocity through the aqueduct is a good predictor of improvement after surgery. However, patients with normal velocity in MR required additional tests before a diagnosis of NPH is ruled out.

Objective: To determine ICP changes in patients with Chiari type I malformation after posterior fossa reconstruction (PFR)., Patients and Methods: We continuously monitored ICP before and after PFR in 12 patients with Chiari I malformation and with an Evans' Index below or equal to 0.33. Mean ICP (epidural sensor) and percentage of B waves were calculated 24 hours before surgery and during the first 7 days after surgery., Results: Mean ICP and percentage of B waves significantly increased after surgery despite a significant increase in the volume of the posterior fossa. The main finding revealed by control CT scans was compression of the quadrigeminal cistern with a reduction in size of the fourth ventricle. In six patients, a small transitory increase in supratentorial ventricular size was found., Conclusions: A transitory increase in ICP is common after PFR. This increase could be explained by an initial reperfusion phenomena in the cerebellum that provokes a transitory deterioration in CSF dynamics. The effacement of the quadrigeminal cistern and the reduction in size of the fourth ventricle suggests this hypothesis.

Hydrocephalus is an increase in cerebrospinal fluid volume that can be caused by a variety of etiologies. The most common connatal and acquired causes of hydrocephalus are spina bifida, aqueduct stenosis, and preterm low birthweight infants with ventricular hemorrhage. In general, the literature suggests mild neuropsychological deficits associated with hydrocephalus, which are predominant in visuospatial and motor functions, and other nonlanguage skills. Although the precise nature of the neuropsychological deficits in hydrocephalus are not completely known, several factors such as etiology, raised intracranial pressure, ventricular size, and changes in gray and white matter tissue composition as well as shunt treatment complications have been shown to influence cognition. In fact, the presence of complications and other brain abnormalities in addition to hydrocephalus such as infections, trauma, intraventricular hemorrhage, low birthweight, and asphyxia are important determinants of the ultimate cognitive status, placing the child at a high risk of cognitive impairment.

Normal pressure hydrocephalus, or adult chronic hydrocephalus, is a relatively unknown entity. Classically, this disease is characterized by progressive dementia, gait disturbance, and urinary incontinence. Despite an increase in the prevalence of this type of dementia due to longer life expectancy, its diagnosis and treatment remain controversial. Recent studies have reported that the percentage of patients who show clinical improvement after shunting is still low and that the complication rate is excessively high. However, our experience and that of other authors indicates that the percentage of improvement after shunting can be greater than 80% and the complication rate can be low if a strict diagnostic protocol is applied and if the most appropriate valve is selected, based on the hydrodynamic characteristics of the shunt. The aim of this review is to provide an update of the clinical features, diagnosis and treatment of adult chronic hydrocephalus. We also discuss the diagnostic and treatment protocols applied in our centre in patients with suspected adult chronic hydrocephalus.

Traumatic brain injury is a major health problem in all developed countries. The main aim of this review is to provide a short update on the most recent advances in our knowledge of the brains response to mechanical injuries, focusing on metabolic, cellular, subcellular, and molecular events that take place in severe head injuries. Knowledge of these events is essential for a better understanding of new pharmacological avenues and non-pharmacological strategies, such as moderate hypothermia, which are being developed to improve the outcome of this silent epidemic. We will focus on several topics that we consider to be the most significant: diffuse axonal injury, ischemia and the cascades it generates, metabolic derangements, excitotoxicity, oxidative stress, and other phenomena that have been included in the term tertiary injuries. Recent evidence has clearly demonstrated that traumatic brain lesions are highly dynamic and that the different lesions observed after closed head injury are not single events but processes set in motion by the mechanical impact. These processes are not finished until an unpredictable time after injury. We will discuss recent evidence showing that in diffuse axonal injury, primary immediate damage can coexist with axons that, although initially intact, may be evolving towards secondary disconnection. The concept of ischemic penumbra and the more recent concept of traumatic penumbra are discussed, together with recent experimental and clinical data that shed light on the non-ischemic forms of brain hypoxia. The role of excitotoxicity in mechanically-induced cell death and the molecular events that excessive release of glutamate induce, including apoptosis and delayed inflammatory processes, are reviewed. Finally, new knowledge on how central nervous system cells regulate their volume, the new family of channel water molecules known as aquaporins and their possible role in the physiopathology of the swollen brain are discussed. Basic and clinical investigations are still needed to translate the huge amount of pathophysiological knowledge acquired in the last decade into effective treatments for these patients.

The Traumatic Coma Data Bank (TCDB) classification of CT (computed tomography) scan has been related to the general outcome and intracranial pressure evolution. Our aim was to analyse the relationship of this classification with neuropsychological outcome and late indices of ventricular dilatation. Fifty-seven patients with a moderate or severe head injury (mean admission Glasgow Coma Scale Score, 7.7) were studied from 122 consecutive cases. There were 49 males and 8 females (mean age, 27.7 years). Subjects were classified into TCDB categories on the basis of their most serious acute CT scan finding. From the last control CT scan image, performed at a mean of 6.12 months postinjury, several measures of ventricular dilatation were calculated. Neuropsychological assessment at 6-month included tests of verbal and visual memory, visuoconstructive functions, fine motor speed, and frontal lobe functions. Patients with diffuse injury type I showed better neuropsychological outcome than patients with more severe diffuse injuries and those with mass lesions. Within the diffuse injury groups, the degree of diffuse damage was related to measures of verbal memory and attention and cognitive flexibility. Ventricular enlargement was more evident in patients with mass lesions and it decreased in the remaining groups as the severity of diffuse injury diminished. These results show that there is a relationship between acute intracranial lesion diagnosis according to TCDB classification and neuropsychological results and ventricular dilatation indices at 6 months postinjury.

The study of cerebrospinal fluid (CSF) dynamics is central to the diagnosis of adult chronic hydrocephalus (ACH). At present, many neurology and neurosurgery departments use one or more tests to guide diagnosis of this syndrome and to predict patient response to shunting. In specialised centres, the study of CSF dynamics is combined with continuous intracranial pressure (ICP) monitoring. Determination of several variables of CSF dynamics and definitions of qualitative and quantitative characteristics of ICP can be used to establish whether the hydrocephalus is active, compensated or arrested. CSF dynamics and ICP monitoring can also be used to check the correct functioning of the shunt and can be of use in the clinical management of patients with pseudotumor cerebri. Moreover, ICP monitoring is used to guide the treatment of several acute neurological processes. The aim of this review is to describe the fundamentals of CSF dynamics studies and the bases of continuous ICP monitoring. The advantages and disadvantages of several hydrodynamic tests that can be performed by lumbar puncture, as well as the normal and abnormal characteristics of an ICP recording, are discussed.

Objectives: Recent data indicate that alterations in brain neuropeptides may play a pathogenic role in dementia. Neuropeptide Y (NPY), somastostatin (SOM), and corticotropin releasing factor (CRF) are neuropeptides involved in cognitive performance. Decreased SOM and NPY concentrations have been found in patients with normal pressure hydrocephalus and are probably the result of neuronal dysfunction, which could potentially be restored by shunting. The effects of shunt surgery on preoperative SOM, NPY, and CRF concentrations were studied. Any improvements in neuropeptide concentrations that could lead to clinically significant neuropsychological and functional changes were also investigated., Methods: A prospective study was performed in 14 patients with normal pressure hydrocephalus syndrome with a duration of symptoms between 3 months and 12 years. Diagnosis was based on intracranial pressure (ICP) monitoring and CSF dynamics. Concentrations of SOM, NPY, and CRF in lumbar CSF were determined before shunting and again 6-9 months after surgery. A battery of neuropsychological tests and several rating functional scales were also given to patients before and after shunting., Results: After shunting, SOM and CRF concentrations were significantly increased in all patients. Concentrations of NPY were increased in 12 of the 14 patients studied. The clinical condition of 13 of the 14 patients was significantly improved 6 months after surgery. This improvement was more pronounced in gait disturbances and sphincter dysfunction than in cognitive impairment. No significant differences in any of the neuropsychological tests were seen for the group of patients as a whole despite the increased neuropeptide concentrations., Conclusions: Shunting can restore SOM, NPY, and CRF concentrations even in patients with longstanding normal pressure hydrocephalus. However, despite the biochemical and clinical improvement in some areas such as ambulation and daily life activities, cognitive performance did not significantly improve. The role of neuropeptides in the diagnosis and treatment of patients with normal pressure hydrocephalus syndrome is discussed.

Traumatic brain injury initiates several metabolic processes that can increase the primary injury. It is well established that in severe head injuries, posttraumatic secondary insults, such as brain hypoxia, hypotension or anemia, exacerbate neuronal injury and lead to a poorer outcome. Experimental and clinical evidence suggests that moderate hypothermia (32-34 degrees C), may limit some of these deleterious secondary metabolic responses. Recent laboratory studies and prospective controlled clinical trials of induced moderate hypothermia for relatively short periods (24-48 h) in patients with severe head injury, have demonstrated good intracranial pressure control and better outcome when compared with patients maintained in normothermia and given conventional treatment. Despite its proven clinical role in neuroprotection, hypothermia research has been inconstantly followed for various reasons. In this paper we review the mechanisms of neuroprotection in hypothermia, the different preclinical and clinical studies that favor its use as a neuroprotector in severe head injury or in patients in whom high intracranial pressure is refractory to first tier measures. The evidence that favors hypothermia is discussed. We also discuss the negative results of the still unpublished multicentre trial on prophylactic moderate hypothermia developed in the USA. The main problem with moderate hypothermia is the lack of a systematic methodology to induce and maintain it. Also, optimal duration of its use and the methodology and timing for rewarming have not been determined. Consequently, the results of different trials are difficult to analyze and compare. However, most evidence suggests that hypothermia provides remarkable protection against the adverse effects of neuronal damage that is exacerbated by secondary injury. Further prospective controlled trials with clearly defined methodology are needed before this method is implemented in daily clinical practice. The most important task for the years to come may be to focus on refining this procedure, defining the optimal time of cooling and rewarming and to optimize the methods of rapidly inducing and maintaining low temperature. It is also essential to define the most appropriate method and velocity of the rewarming phase, in which many successfully controlled patients deteriorate and die.

The aim of the present study was to investigate the acute effects of 7.2% hypertonic saline (HS) on intracranial pressure (ICP), cerebral and systemic hemodynamics, serum sodium, and osmolality in 14 patients with moderate and severe traumatic brain injury (Glasgow Coma Scale < or =13) and raised ICP (>15 mm Hg) within the first 72 h postinjury. After CO2 reactivity and autoregulation were tested, each patient received a 15-min infusion of 7.2% HS (1,232 mEq/L, volume 1.5 mL/kg). ICP, serial hemodynamics, cerebral blood flow (CBF) estimated from cerebral arteriovenous oxygen content difference (AVDO2), and laboratory variables, including serum osmolality, electrolytes, urea, and creatinine were collected before infusion (T0) and at 5, 30, 60, and 120 min after (T5, T30, T60, T120). Urine output was measured 2 h before infusion and at T120. While CO2 reactivity was preserved in all patients, autoregulation was preserved in only four. ICP decreased to about 30% of base line (p = 0.0001) during the whole study period. During the first hour after infusion, cerebral perfusion pressure (p< or =0.04) and cardiac index (CI; p< or =0.01) increased, while systemic vascular resistance index fell (p< or =0.05). Heart rate increased (p< or =0.04) during the first 30 min. Pulmonary artery occlusion pressure (PAOP) increased (p = 0.004) at T5. There were no significant changes in mean arterial blood pressure (MABP), urine output, and estimated CBF. A significant positive correlation (r = 0.75; p = 0.02) between ICP and serum osmolality was found at T5. The administration of 7.2% HS in patients with traumatic brain injury significantly reduces ICP without significant changes in relative global CBF (expressed as 1/AVDO2), increases CI and transiently increases PAOP, without changing MABP and urine output. The correlation between changes in osmolality and ICP supports the hypothesis that HSS may in part decrease ICP by means of an osmotic mechanism.

The adequate management of cerebral perfusion pressure (CPP) continues to be a controversial issue in head-injured patients. The purpose of our study was to test two hypotheses. The first was that in patients with a CPP below 70 mm Hg, oxygen delivery is compromised and that therefore signs of tissue hypoxia would be reflected in low PtiO2 measurements. The second hypothesis was that manipulating mean arterial blood pressure to increase CPP improves oxygen delivery, particularly in patients with a CPP below 70 mm Hg. Twenty-five moderately or severely head-injured patients were included in the study. In all of them PtiO2 was monitored in the non-injured hemisphere using the Licox system (GMS, Kiel-Mielkendorf, Germany). Arterial hypertension was induced with phenylephrine 29 times. To quantify the effect of increasing mean arterial blood pressure (MABP) on oxygen delivery to the brain, the PtiO2-BP index was calculated (PtiO2-BP index = delta PtiO2/delta MABP). In 16 tests (55%) baseline CPP was above or equal to 70 mm Hg and in the remaining 13 (45%) it was below 70 mm Hg. Mean increase in MABP after phenylephrine was 23.7 +/- 10.2 mm Hg. Mean PtiO2 was 29.5 +/- 14.7 mm Hg in patients with a basal CPP of below 70 mm Hg and 28.9 +/- 10.6 mm Hg in patients in the high CPP group. These differences being not statistically significant. The PtiO2-BP index was 0.29 +/- 0.23 in patients with a basal CPP of below 70 mm Hg and in patients with a CPP of above 70 mm Hg this index was 0.16 +/- 0.11 Hg. These differences were not statistically significant (Student's t-test, P = 0.09). In our study a low PtiO2 was not observed in patients with marginally low CPPs (48-70 mm Hg) and readings below 15 mm Hg were observed in cases with both normal or supranormal CPPs. We conclude that episodes of low PtiO2 could not be predicted on the basis of CPP alone. On the other hand, raising CPP did not increase oxygen availability in the majority of cases, even if the CPP was markedly improved.

False autoregulation has been described as an alteration of autoregulation in which the apparent maintenance of a constant cerebral blood flow (CBF) when increasing cerebral perfusion pressure (CPP) is due to an increase in brain tissue pressure. The objective of our study was to investigate how often false autoregulation occurred in patients with a severe head injury. In forty-six patients with a moderate or severe head injury autoregulation was studied using arteriojugular differences of oxygen (AVDO2) to estimate changes in CBF after inducing arterial hypertension with phenylephrine. Changes in mean arterial blood pressure (MABP), intracranial pressure (ICP), cerebral perfusion pressure (CPP) and AVDO2 were calculated before and after inducing hypertension. Ninety-five episodes of provoked hypertension were studied in 46 patients. In 28 tests (29.5%) a constant or even reduced CBF was detected simultaneously with a median increase in parenchymal ICP of 8.5 mm Hg (false autoregulation). In this group the median of the induced increase in MABP was 20.6 mm Hg with a median increase in CPP of 11.5 mm Hg. From our data we can conclude that false autoregulation is frequently found in patients after a severe head injury. Increasing MABP to obtain a better CPP in these patients is not beneficial because CBF is not modified or may even be reduced.

Spontaneous ventriculostomy is a rare condition that occurs with the spontaneous rupture of a ventricle, resulting in a communication between the ventricular system and the subarachnoid space. Three cases of spontaneous ventriculostomy through the floor of the third ventricle that occurred in cases of chronic obstructive hydrocephalus are presented. The communication was identified via flow-sensitive phase-contrast cine MR imaging. Spontaneous ventriculostomy is probably a result of a rupture of the normally thin membrane that forms the floor of the third ventricle and, with long-standing obstructive hydrocephalus, creates an internal drainage pathway that spontaneously compensates for the hydrocephalus.

Object: It is generally accepted that the intracranial compartment behaves as a unicameral space in which intracranial pressure (ICP) is uniformly distributed. However, this concept has been challenged many times. Although there is general agreement on the existence of craniospinal and suprainfratentorial gradients, the existence of interhemispheric gradients is still a matter of debate. The object of this study was to reexamine the issue of interhemispheric supratentorial ICP gradients in patients with head injuries and the clinical significance of these gradients in their management., Methods: The authors present the results of a prospective study conducted in 50 head-injured patients to determine the clinical significance of supratentorial ICP gradients. In each case a concurrent bilateral frontal intraparenchymatous device was implanted within the 6-hour window after computerized tomography (CT) scanning. According to CT criteria, each patient was categorized into one of three different groups: 1) diffuse lesions, in which no unilaterally measured volumes greater than 25 ml were present and the midline shift was 3 mm or less; 2) Focal A, in which added hemispheric volumes were greater than 25 ml and midline shift was 3 mm or less; and 3) Focal B, in which all patients with a midline shift greater than 3 mm were included. From the results of the entire group the authors were able to distinguish four different patterns of supratentorial ICP. In Pattern I, the intracranial compartment behaved as a true unicameral space with similar mean ICPs and pulse amplitudes in both hemispheres; in Pattern II, different mean ICPs and amplitudes were observed although ICP increases or decreases were congruent; and in Pattern III, patients with different mean ICPs, different ICP amplitudes, and no congruent increases or decreases of ICP were included. All (15 cases) but one patient with a diffuse lesion presented with ICP Pattern I. Fifteen patients with focal lesions showed a Type II pattern, whereas only one patient presented with a Type III pattern. In 10 patients, of whom all but one presented with a focal lesion, transient gradients that disappeared in less than 4 hours were also observed., Conclusions: In many patients with focal lesions, clinically important interhemispheric ICP gradients exist. In this subset, transient gradients that disappear with time are frequently observed and may indicate an increase in the size of the lesion. The clinical relevance of such gradients is discussed and guidelines for adequately monitoring ICP are suggested to optimize head injury management and to avoid suboptimal or even harmful care in patients with mass lesions.

Chiari type I malformation and so-called Chiari-I/syringomyelia complex continue to inspire controversy. Disagreement on these malformations concern both etiopathogenesis and treatment. Our still poor understanding of the natural course of the disease, the lack of consensus regarding therapeutic indications and even disagreement on appropriate surgery all contribute to cause disagreement. Significant progress has been made in our understanding of contributing etiopathogenetic factors in recent years. The most widely accepted hypothesis is that anomalous embryonic development characterized by paraxial mesodermal insufficiency would put volumetric constraints on postnatal development of the posterior fossa. We review historical and current controversies regarding Chiari type I malformation and classic theories on causative and contributing factors. We also discuss the latest surgical treatments that have been suggested, as well as associated anomalies--mainly syringomyelia, hydrocephalus and malformed cranial-cervical articulation. Finally, we propose a protocol useful for the diagnosis and treatment of Chiari type I malformation associated with dilation of the ventricular system.

The present study was undertaken to elucidate the status of autoregulation and CO2-reactivity soon after injury in patients with a post-traumatic diffuse bilateral brain swelling. A prospective study was carried out in 31 consecutively admitted patients with a severe head injury and a Diffuse Brain Injury type III, following the definition stated by the Traumatic Coma Data Bank classification. To evaluate CO2-reactivity, AVDO2 was measured before and after ventilator manipulations. Assuming a constant CMRO2 during the test, changes in 1/AVDO2 reflect changes in CBF. Patients with changes in estimated CBF below or equal to 1% were included in the impaired/abolished CO2-reactivity group. To test autoregulation, hypertension was induced using phenylephrine. Arterial and jugular blood samples were taken to calculate AVDO2 before and after a steady state of MABP was obtained. Cerebrovascular response to CO2 was globally preserved in all but two cases (6.5%). In contrast, autoregulation was globally preserved in 10 (32.3%) and impaired/abolished in 21 cases (67.7%). Our data do not support the premise that increasing cerebral perfusion pressure by inducing arterial hypertension is beneficial in those patients with a diffuse brain swelling in whom autoregulation is impaired or abolished. Clinical implications for treatment are discussed.