Spreading depolarisations and outcome after traumatic brain injury: a prospective observational study.

BACKGROUND: Pathological waves of spreading mass neuronal depolarisation arise repeatedly in injured, but potentially salvageable, grey matter in 50-60% of patients after traumatic brain injury (TBI). We aimed to ascertain whether spreading depolarisations are independently associated with unfavourable neurological outcome. METHODS: We did a prospective, observational, multicentre study at seven neurological centres. We enrolled 109 adults who needed neurosurgery for acute TBI. Spreading depolarisations were monitored by electrocorticography during intensive care and were classified as cortical spreading depression (CSD) if they took place in spontaneously active cortex or as isoelectric spreading depolarisation (ISD) if they took place in isoelectric cortex. Investigators who treated patients and assessed outcome were masked to electrocorticographic results. Scores on the extended Glasgow outcome scale at 6 months were fitted to a multivariate model by ordinal regression. Prognostic score (based on variables at admission, as validated by the IMPACT studies) and spreading depolarisation category (none, CSD only, or at least one ISD) were assessed as outcome predictors. FINDINGS: Six individuals were excluded because of poor-quality electrocorticography. A total of 1328 spreading depolarisations arose in 58 (56%) patients. In 38 participants, all spreading depolarisations were classified as CSD; 20 patients had at least one ISD. By multivariate analysis, both prognostic score (p=0·0009) and spreading depolarisation category (p=0·0008) were significant predictors of neurological outcome. CSD and ISD were associated with an increased risk of unfavourable outcome (common odds ratios 1·56 [95% CI 0·72-3·37] and 7·58 [2·64-21·8], respectively). Addition of depolarisation category to the regression model increased the proportion of variance in outcome that could be attributed to predictors from 9% to 22%, compared with the prognostic score alone. INTERPRETATION: Spreading depolarisations were associated with unfavourable outcome, after controlling for conventional prognostic variables. The possibility that spreading depolarisations have adverse effects on the traumatically injured brain, and therefore might be a target in the treatment of TBI, deserves further research. FUNDING: US Army CDMRP PH/TBI research programme.

Neuropathological findings in disabled survivors of a head injury.

We investigated how the occurrence and severity of the main neuropathological types of traumatic brain injury (TBI) influenced the severity of disability after a head injury. Eighty-five victims, each of whom had lived at least a month after a head injury but then died, were studied. Judged by the Glasgow Outcome Scale (GOS), before death 35 were vegetative, 30 were severely and 20 were moderately disabled. Neuropathological assessment showed that 71 (84%) victims had sustained cerebral contusions, 49 (58%) had diffuse axonal injury (DAI), 57 (67%), had ischemic brain damage (IBD), 58 (68%) had symmetrical ventricular enlargement, and in 47 (55%) intracranial pressure (ICP) had been increased. Thirty-five (41%) had undergone evacuation of an intracranial hematoma. Brainstem damage was seen in only 11 (13%). Analysis (χ(2) test for trends) of the relationship between these features and outcome showed that findings of DAI, raised ICP, thalamic damage, or ventricular enlargement (all p<0.005), and IBD (p=0.04) were associated with an increasingly worse outcome. Conversely, moderate or severe contusions (p=0.001) were increasingly associated with better outcomes, and evacuation of a hematoma was associated (p=0.001) with outcomes likely to be better than vegetative. We conclude that diffuse or multifocal neuropathological patterns of TBI from primary axonal injury or secondary ischemic damage are most likely to be associated with the most severely impaired outcomes after a head injury.

Critical lower-limb ischemia: the diagnostic performance of dual-phase injection MR angiography (including high-resolution distal imaging) compared with digital subtraction angiography.

PURPOSE: To prospectively compare contrast-enhanced (CE) magnetic resonance (MR) angiography against digital subtraction angiography (DSA) in patients with critical lower-limb ischemia. MATERIALS AND METHODS: Thirty patients with critical lower limb ischemia underwent both CE MR angiography and DSA. CE MR angiography commenced with a dedicated high-resolution study of the below-knee arteries followed by a three-station bolus-chase examination. Two blinded observers recorded the severity of the most significant stenosis within each arterial segment. Interobserver agreement was calculated and, with DSA as the reference standard, the sensitivity and specificity of CE MR angiography for the detection of significant stenosis (>or=50% luminal narrowing) or occlusion was calculated. RESULTS: All 390 arterial segments were scored by both observers. Sensitivity was higher in the distal segments (92%-96%) compared with the proximal segments (69%-79%). Specificity was similar in distal (90%-91%) and more proximal segments (86%-96%). Overall, interobserver agreement was excellent (kappa = 0.95 for CE MR angiography and DSA) and was superior within the distal segments. Twenty-eight segments that were considered occluded on DSA were shown to be patent on CE MR angiography and 16 segments that were considered occluded on CE MR angiography were shown to be patent on DSA. CONCLUSIONS: In patients with critical lower-limb ischemia, CE MR angiography with high-resolution distal imaging is highly accurate for assessment of the below-knee arteries. Both DSA and CE MR angiography may identify patent vessels that are considered occluded based on the other modality.

Uterine-artery embolization versus surgery for symptomatic uterine fibroids.

BACKGROUND: The efficacy and safety of uterine-artery embolization, as compared with standard surgical methods, for the treatment of symptomatic uterine fibroids remain uncertain. METHODS: We conducted a randomized trial comparing uterine-artery embolization and surgery in women with symptomatic uterine fibroids. The primary outcome was quality of life at 1 year of follow-up, as measured by the Medical Outcomes Study 36-Item Short-Form General Health Survey (SF-36). RESULTS: Patients were randomly assigned in a 2:1 ratio to undergo either uterine-artery embolization or surgery, with 106 patients undergoing embolization and 51 undergoing surgery (43 hysterectomies and 8 myomectomies). There were no significant differences between groups in any of the eight components of the SF-36 scores at 1 year. The embolization group had a shorter median duration of hospitalization than the surgical group (1 day vs. 5 days, P<0.001) and a shorter time before returning to work (P<0.001). At 1 year, symptom scores were better in the surgical group (P=0.03). During the first year of follow-up, there were 13 major adverse events in the embolization group (12%) and 10 in the surgical group (20%) (P=0.22), mostly related to the intervention. Ten patients in the embolization group (9%) required repeated embolization or hysterectomy for inadequate symptom control. After the first year of follow-up, 14 women in the embolization group (13%) required hospitalization, 3 of them for major adverse events and 11 for reintervention for treatment failure. CONCLUSIONS: In women with symptomatic fibroids, the faster recovery after embolization must be weighed against the need for further treatment in a minority of patients. (ISRCTN.org number, ISRCTN23023665 [controlled-trials.com].)

Endoscopy has minimal impact on mortality from upper gastrointestinal cancer in patients older than 55 years with uncomplicated dyspepsia.

INTRODUCTION: The objective of the study was to determine the effectiveness of endoscopy to detect curable upper gastrointestinal malignancy in patients older than 55 years presenting with uncomplicated dyspepsia. METHODS: A cohort study was performed in North Glasgow Health Trust. One hundred and thirty-one patients older than 55 years of age, diagnosed to have upper gastrointestinal cancer within the North Glasgow Trust between January 1995 and December 1997, identified by the West of Scotland Cancer Registry were included. The main outcome measures were the proportion of upper gastrointestinal cancers that present in patients older than 55 years with uncomplicated dyspepsia, and the proportion of patients that presented with uncomplicated dyspepsia who have curable upper gastrointestinal cancer. RESULTS: Of the 131 cancer cases identified, only 30 (23%) had dyspepsia (complicated or uncomplicated) as their predominant symptom and only eight (6%) patients presented with uncomplicated dyspepsia. Of those eight patients presenting with uncomplicated dyspepsia and found to have upper gastrointestinal cancer, six were found to have lymph node metastases and/or extensive metastases at the time of diagnosis. Each of these six patients died from their cancer within 39 months of diagnosis. Of the two patients presenting with uncomplicated dyspepsia without evidence of lymph node spread, one died 55 days after diagnosis. Only one patient presenting with uncomplicated dyspepsia and found to have cancer remains alive at 5-year follow-up. CONCLUSIONS: Of the 131 patients diagnosed with upper gastrointestinal cancer, only eight presented with uncomplicated dyspepsia and only one of these was cured. Consequently a policy of endoscoping patients older than 55 years with uncomplicated dyspepsia will reduce death from upper gastrointestinal cancers by less than 1% in our population.

A putative placebo comparison of the SCOPE and LIFE trials.

The Losartan Intervention For Endpoint reduction in hypertension (LIFE) trial and the Study on Cognition and Prognosis in the Elderly (SCOPE) superficially produced comparable outcomes, with effects on stroke greater than those anticipated from blood pressure (BP) lowering alone. This, however, ignores important features of both studies. It ignores firstly the disparate comparator agents - atenolol in LIFE and predominantly hydrochlorthiazide in SCOPE, secondly the small, but potentially important BP differential between the treatment arms in SCOPE and finally the small, statistically non-significant increase in coronary heart disease (CHD) in both trials. This analysis compares the major cardiovascular outcomes in these trials with reference to placebo. Two alternative reference populations were employed to calculate the imputed placebo, firstly the MRC Trial in Elderly Hypertensives and secondly a meta-analysis of trials in the elderly, which included comparisons between diuretic- and b-blocker-based regimens. Overall, the choice of 'comparator placebo' did not substantially influence the derived results. Accounting for BP differences and based on the meta-analysis, both trials demonstrated statistically significant reductions in fatal/non-fatal stroke compared with placebo - relative risks (95% confidence intervals [CI]) of 0.53 (0.39, 0.73) and 0.56 (0.41, 0.76) for SCOPE and LIFE, respectively. For fatal/non-fatal MI, there were greater discrepancies between the studies, but with neither achieving statistical significance compared with placebo - relative risks of 0.85 (0.59, 1.24) and 1.08 (0.80, 1.46) for SCOPE and LIFE, respectively. This analysis clearly demonstrates that both candesartan in SCOPE and losartan in LIFE are associated with reductions in stroke events compared with placebo, greater than that observed in the well-established meta-analysis of placebo-controlled hypertensive trials. However, the CIs are such that it is not possible to suggest definitively that this is a benefit beyond BP reduction alone. Neither trial is sufficiently 'powered' to demonstrate a benefit in CHD outcomes, but with SCOPE there was a trend towards benefit with a point estimate compatible with the major meta-analysis.

Involvement of apolipoprotein E in glioblastoma: immunohistochemistry and clinical outcome.

We hypothesised that apolipoprotein E (apoE) influences brain tumours by delivery of lipids to tumour cells and by analogy with other brain insults. APOE gene analysis was performed for 126 glioblastomas, the commonest primary brain tumour. Neither APOE epsilon2 nor epsilon4 alleles were significantly associated with differences in post-operative survival. However, there was apoE immunoreactivity of tumour cells, macrophages in areas of necrosis and astrocytes nearby. The immunohistochemistry findings support the hypothesis that apoE is involved in the delivery of lipids to tumour cells and in the recycling of lipids by macrophages in necrotic areas, raising the possibility that apoE-mediated lipid transport may represent a new therapeutic target in brain tumours.