A. D. Mendelow

Prognostic implications of p53 protein, epidermal growth factor receptor, and Ki-67 labelling in brain tumours.

The expression of p53 protein, epidermal growth factor receptor (EGFR), and Ki-67 nuclear antigen was examined by immunohistochemistry in biopsies of 16 types of human brain tumours, including 43 astrocytomas. P53 protein, almost certainly its mutant form, was expressed in seven of the 16, and EGFR in 11 of the 16 types of tumours. In astrocytomas both the proportion of tumours which expressed p53 or EGFR increased with grade of malignancy as did the mean Ki-67 labelling index (LI): p53-0% in grade 1, 17% in grade 2, 38% in grade 3, 65% in grade 4; EGFR-0% in grade 1, 33% in grade 2, 85% in grade 3, 95% in grade 4; mean Ki-67 L1-1.1% in grades 1 and 2, 8.3% in grade 3, and 13.4% in grade 4. Astrocytomas which expressed p53 or EGFR had a significantly higher Ki-67 LI at P less than 0.05 (11.8% and 10.7%, resp.) than those that did not (6.2% or 4.1%, resp.). Patients with astrocytomas expressing p53 or EGFR had a significantly reduced survival (P = 0.035 and P = 0.007, resp.): only 11% of the p53 + ve and 13% of the EGFR + ve patients were alive at 100 weeks following diagnosis compared to 36% of p53-ve or 60% of EGFR-ve patients. Patients with Ki-67 LI greater than 5% had a reduced survival (P less than 0.0001)--none survived beyond 86 weeks following diagnosis, whilst 63% of patients with less than 5% positive cells were still alive at 100 weeks. The univariate analysis showed that in astrocytomas expression of p53 mutants, EGFR protein, and Ki-67 greater than 5% are associated with malignant progression and poor prognosis. The multivariate analysis revealed that only tumour grade and Ki-67LI were independent prognostic factors for survival.

Surgery in Intracerebral Hemorrhage: The Uncertainty Continues

Background and Purpose Primary intracerebral hemorrhage (ICH) accounts for 10% to 20% of stroke but carries the highest rates of mortality and morbidity of all stroke subtypes. Current treatment, however, is varied and haphazard. The most recent Cochrane systematic review refers to 4 prospective, randomized controlled trials. We present a further meta-analysis to include 3 new trials. In addition, we review the trials of Chen et al and McKissock et al and discuss aspects of their quality that, we believe, prevent their inclusion in modern day meta-analysis. Methods Literature databases and articles were searched from 1966 to October 1999. Using the end points of death and dependency, the results of the 7 identified randomized trials were expressed as odds ratios. All available data were then analyzed with meta-analysis techniques. Analysis of relevant subsets of trials was also carried out. Results Meta-analysis of all 7 trials shows a trend toward a higher chance of death and dependency after surgery (OR 1.20; 95% CI 0.83 to 1.74). Meta-analysis was also carried out after exclusion of the Chen and McKissock trials for reasons discussed in the text. This meta-analysis suggests a benefit from surgery, with a reduction in the chances of death and dependency after surgical treatment by a factor of 0.63 (OR 0.63; 95% CI 0.35 to 1.14). Conclusions When meta-analysis is restricted to modern-day, post-CT, well-constructed, balanced trials, a trend for surgery to reduce the chances of death and dependency is found. Perhaps, then, in the modern era of CT, good neuroanesthesia, intensive care, and the operating microscope, surgery has a role in the treatment of supratentorial intracerebral hemorrhage. The results of a large, multicenter, randomized controlled trial are urgently needed, and the ongoing International Surgical Trial of Intracerebral Hemorrhage should fulfill this objective.

Intraventricular hemorrhage and hydrocephalus after spontaneous intracerebral hemorrhage: results from the STICH trial.

INTRODUCTION Intraventricular hemorrhage (IVH), either independent of or as an extension of intracranial bleed, is thought to carry a grave prognosis. Although the effect of IVH on outcome in patients with subarachnoid hemorrhage has been extensively reviewed in the literature, reports of spontaneous intracerebral hemorrhage (ICH) in similar situations have been infrequent. The association of hydrocephalus in such situations and its influence on outcome is also uncertain. PATIENTS AND METHODS As a sub-analysis of data obtained through the international Surgical Trial in Intracerebral Hemorrhage (STICH), the impact of IVH, with or without the presence of hydrocephalus, on outcome in patients with spontaneous ICH was analyzed. CT scans of randomized patients were examined for IVH and/or hydrocephalus. Other characteristics of hematoma were evaluated to see if they influenced outcome, as defined by the STICH protocol. RESULTS Favorable outcomes were more frequent when IVH was absent (31.4% vs. 15.1%; p < 0.00001). The presence of hydrocephalus lowered the likelihood of favorable outcome still further to 11.5% (p = 0.031). In patients with IVH, early surgical intervention had a more favorable outcome (17.8%) compared to initial conservative management (12.4%) (p = 0.141). CONCLUSION The presence of IVH and hydrocephalus are independent predictors of poor outcome in spontaneous ICH. Early surgery is of some benefit in those with IVH.

Triphenyltetrazolium chloride (TTC) as a marker for ischaemic changes in rat brain following permanent middle cerebral artery occlusion

Triphenyltetrazolium chloride (TTC) was used to delineate ischaemic lesions in the rat brain at various times following middle cerebral artery occlusion. A comparison was made of TTC staining by immersion and perfusion techniques and conventional light microscopy. The lesions were quantified by measuring the ischaemic area at the sections corresponding to 7 mm in front of the AO line (atlas of Konig and Klippel). In animals examined 24 h after middle cerebral artery occlusion (MCAO), the area of infarction was 17.4 ± 1.3 mm2 on the TTC perfused slices and 17.6 ± 1.6 mm2 on the TTC immersed slices (mean ± SEM). By contrast, there was a marked difference between the two TTC methods when tissues were examined at shorter intervals after artery occlusion. In the TTC–perfused animals, there was no significant difference between the mean areas of infarction measured at 5–20 min, 3–4 h, or 24 h post occlusion. Immersion in TTC, however, failed to reveal any consistent ischaemic damage when applied at the earlier post–occlusion times. Conventional histopathology demonstrated minimal lesions at 5–20 min but at 4 h or more the lesions were not significantly different from those demonstrated by TTC perfusion. TTC immersion staining can, thus, only be used as a reliable marker of cerebral ischaemia damage with post–occlusion survival periods of 24 h. TTC perfusion staining gives results not significantly different from histopathology at 4 h or more post–occlusion but at earlier intervals than 24 h it differs significantly from TTC immersion staining. Thus at times of less than 24 h it may reflect mainly changes in stain perfusion, rather than ischaemic damage.

Endovascular stenting of the transverse sinus in a patient presenting with benign intracranial hypertension

The authors present a 37-year-old lady with symptoms and signs suggestive of benign intracranial hypertension (BIH). Routine CT and MRI scans were normal. Further investigations were performed with magnetic resonance venography (MRV) and cerebral venography. These revealed obstruction of the right transverse sinus with high pressure (40 mmHg) proximal to the obstruction and low pressure (15 mmHg) distally. She was treated by transvenous stent deployment with resolution of her symptoms and the bilateral papilloedema. Evaluation of the cerebral venous system with MRV and or with formal cerebral venography should be included in routine investigations of patients with suspected BIH.

Serum concentration of adhesion molecules in patients with delayed ischaemic neurological deficit after aneurysmal subarachnoid haemorrhage: the immunoglobulin and selectin superfamilies

OBJECTIVES Adhesion molecules are involved in the pathogenesis of cerebral ischaemia and may play a part in the pathophysiology of delayed ischaemic neurological deficit (DIND) after aneurysmal subarachnoid haemorrhage. It was hypothesised that after aneurysmal subarachnoid haemorrhage, adhesion molecules may play a part in the pathophysiology of DIND as reflected by significantly altered serum concentrations in patients with and without DIND. METHODS In a prospective study, mean serum concentrations of ICAM-1, VCAM-1, PECAM, and E, P, and L-selectin were compared between patients without (n=23) and with (n=13) DIND in patients with World Federation of Neurological Surgeons (WFNS) grades 1 or 2 subarachnoid haemorrhage. Serum was sampled from patients within 2 days of haemorrhage and on alternate days until discharge. Concentrations of adhesion molecules were measured by standard procedures using commercially available enzyme linked immunoabsorbent assays. RESULTS There were non-significant differences in serum concentrations of ICAM-1 (290.8 ng/ml v 238.4 ng/ml, p=0.0525), VCAM-1 (553.2 ng/ml v 425.8 ng/ml, p=0.053), and PECAM (22.0 ng/ml v 21.0 ng/ml, p=0.56) between patients without and with DIND respectively. The E-selectin concentration between the two patient groups (44.0 ng/mlv 37.4 ng/ml, p=0.33) was similar. The P-selectin concentration, however, was significantly higher in patients with DIND compared with those patients without DIND (149.5 ng/mlv 112.9 ng/ml, p=0.039). By contrast, serum L-selectin concentrations were significantly lower in patients with DIND (633.8 ng/ml v 897.9 ng/ml, p=0.013). CONCLUSIONS Of all the adhesion molecules examined in this study, P and L-selectin are involved in the pathophysiology of DIND after aneurysmal subarachnoid haemorrhage.

The cause and incidence of secondary insults in severely head-injured adults and children

The cause and incidence of reductions in cerebral perfusion pressure, and rises in intracranial pressure have been examined in a series of patients with severe head injury defined as an initial Glasgow Coma Sum of less than or equal to 8. Two-hundred-and-seven adults (aged over 16 years) and 84 children admitted to Newcastle General Hospital, who had intracranial pressure monitoring as part of their routine management, were studied. Intracranial pressure (ICP), arterial pressure and cerebral perfusion pressure (CPP) were sampled and recorded every 2 min. Patients‘ CT findings were classified into distinct groups using the method described by Marshall. Secondary insults were defined using the Edinburgh University Secondary Insult Grades (EUSIG) and the incidence and cause (raised ICP, reduced CPP or combination of the two) was established. Outcome was assessed at 6 months using the Glasgow Outcome Scale. In the majority of adults with head injury it is the combination of reduced arterial pressure and raised ICP that contributes to the reduction in cerebral perfusion pressure. This was not the case for Diffuse Injury Type I. In children similar characteristics were found across each of the CT classifications. The vast majority of falls in CPP down to 60 mmHg were caused by reduced arterial pressure. Reductions below 50 mmHg were almost always due to a combination of both reduced arterial pressure and raised ICP.The results in adults were similar, but not identical, to those of the paediatric cases. Diffuse Injury Type I stood out from all the other categories as the only one where reductions in perfusion pressure were almost exclusively due to reductions in arterial pressure and not to increases in ICP.The management of these patients should ensure the adequacy of perfusion pressure by maintaining arterial pressure at a satisfactory level. These results suggest that vigilant monitoring of both intracranial pressure and arterial pressure is required to lower the incidence of secondary insults.

Intracranial pressure within a developing intracerebral haemorrhage

We report the time course of intracranial pressure within a developing intracerebral haemorrhage. Simultaneous readings of intracranial pressure were obtained from a contralateral parenchymal monitor and ventricular fluid pressure monitor. This recording demonstrates the existence of large pressure gradients in patients with expanding mass lesions.We report the time course of intracranial pressure within a developing intracerebral haemorrhage. Simultaneous readings of intracranial pressure were obtained from a contralateral parenchymal monitor and ventricular fluid pressure monitor. This recording demonstrates the existence of large pressure gradients in patients with expanding mass lesions.

Trends over time in the management of subarachnoid haemorrhage in Newcastle: review of 1609 patients

This article reviews trends in the management of subarachnoid haemorrhage (SAH) at the Regional Neurosurgery Unit in Newcastle over 9 years. This is a comprehensive analysis of prospectively collected data on patients with SAH. We review the changes in clinical therapy and outcome with regards to conservative (non-surgical), surgical and endovascular therapy. Since 1990, the demographic and management/outcome details of patients with SAH have been recorded systematically. This study involves patients admitted over the 9 years, from January 1990 to December 1998. The data were computerized using Microsoft Access (Microsoft Inc. USA), and analysed using SPSS statistical package. A total of 1609 had aneurysmal SAH confirmed with CT, lumbar puncture and/or angiography. Sixty-seven per cent (1073 patients) were female with a female to male ratio of 2:1. This ratio was maintained from 1990 to date. The mean age has slowly increased from 49 years in 1990 to 55 years of age in 1998, (range 18‘91). Overall, 53.9% (from 66.3% in 1990 to 35.3% in 1998) were surgically treated, 8.1% had embolization (range 0.6‘18.4%) and 38% (range 28.2‘46.4%) were managed without surgical intervention for the aneurysm. The proportion of patients undergoing surgery has decreased since 1994 with improvements in endovascular therapy, participation in the ISAT trial and increased admission of poor grade patients (WFNS grades 4 and 5, from 17% in 1990 to 31% in 1998). The mortality rate has doubled over the years under review (18‘32%). The percentage of severely disabled patients has remained constant at about 7% with none in a vegetative state. Only 54% had a favourable outcome in 1998 compared with 78% in 1990. Total morbidity and mortality has increased particularly during the last 3 years. This has been associated with double the number of admissions in grade 5. Favourable outcome occurred in 90% of good grade patients (WFNS 1 and 2) with 6.2% mortality in surgical candidates and 5.5% in patients treated endovascularly. The mortality for poor grade (WFNS 4 and 5) patients was 64%.

The effect of immunosuppression on the development of cerebral oedema in an experimental model of intracerebral haemorrhage: whole body and regional irradiation.

The oedema which forms around an intracerebral haemorrhage has a complex aetiology. The immune response may have a role in its formation. There is clinical and experimental evidence that circulating leucocytes and platelets may mediate oedema formation. Global depletion of circulating leucocytes and platelets by whole body irradiation in a rodent model of intracerebral haemorrhage was found to confer protection against both ischaemia and oedema formation. This was not a direct effect of irradiation of the brain. The possible mechanisms for this protection are discussed.