Klaus Roosen

Brain tissue oxygen guided treatment supplementing ICP/CPP therapy after traumatic brain injury

Objective: To evaluate the effects of a brain tissue oxygen (Ptio2) guided treatment in patients with traumatic brain injury. Methods: Ptio2 was monitored in 93 patients with severe traumatic brain injury. Forty patients admitted from 1993 to 1996 were treated with intracranial pressure/cerebral perfusion pressure (ICP/CPP) management alone (ICP < 20 mm Hg, CPP > 70 mm Hg). Fifty three patients admitted from 1997 to 2000 were treated using ICP/CPP management, but in this second group CPP was also increased as individually required to raise the Ptio2 above 1.33 kPa (10 mm Hg) (Ptio2 guided group). Results: Cerebral hypoxic phases with Ptio2 values below 1.33 kPa occurred significantly less often in the Ptio2 guided group. Ptio2 values were higher over the whole monitoring period. No statistical differences could be observed in outcome at six months, despite a positive trend in the Ptio2 guided group. Conclusions: Cerebral hypoxic events can be reduced significantly by increasing cerebral perfusion pressure as required. To show a clear beneficial effect of Ptio2 guided cerebral perfusion pressure management on outcome, a multicentre randomised trial needs to be undertaken.

Arachnoid cysts associated with subdural hematomas and hygromas: analysis of 16 cases, long-term follow-up, and review of the literature.

OBJECTIVE Subdural hematomas and hygromas are infrequently encountered complications of arachnoid cysts of the middle cranial fossa and are particularly rare with cysts of other regions. Reports in the literature focus on casuistic observations. Therapeutic recommendations often include fenestration or extirpation of the cyst wall, in addition to evacuation of the space-occupying lesion. This study evaluates the results of and rationale for a more conservative approach, usually without cyst removal. METHODS Sixteen cases of complicated arachnoid cysts, from a total of 658 patients with subdural hematomas or hygromas, were analyzed retrospectively together with 75 other cases reported in the literature. Additionally, 94 magnetic resonance imaging scans from 89 patients with untreated arachnoid cysts, from a total of 11,487 examinations, were reviewed for signs of hemorrhagic complications. RESULTS Arachnoid cysts of the middle cranial fossa were found in 2.43% of patients with chronic subdural hematomas or hygromas. This indicated a fivefold greater prevalence of arachnoid cysts, compared with our magnetic resonance imaging-examined patient group. Only two patients with untreated cysts showed signs of hemorrhage in magnetic resonance imaging scans. An excellent or good therapeutic result was achieved with evacuation of the subdural fluid by drainage or craniotomy in 13 cases and with conservative treatment in two cases. Only one patient underwent additional fenestration of the cyst wall. No additional symptoms from the arachnoid cysts occurred in a follow-up period of up to 14 years after therapy. CONCLUSIONS We do not generally consider it necessary to perform cyst diversion or fenestration at the time of drainage of a hematoma or hygroma in previously asymptomatic arachnoid cysts.

Effect of synthetic matrix‐metalloproteinase inhibitors on invasive capacity and proliferation of human malignant gliomas In vitro

Glioma invasion into the surrounding brain tissue is still a major obstacle for any therapeutical approach. As in other solid tumors, matrix‐metalloproteases (MMPs) have been suggested as being involved. The aim of this study was to evaluate whether the use of MMP inhibitors to target the protease‐mediated invasion process could be a feasible approach. Two human cell lines (U251 and GaMG) and surgical specimens of 6 patients with malignant gliomas were grown as monolayers and spheroid cultures respectively. MMP‐ and u‐PA‐mRNA expression was investigated by semi‐quantitative RT‐PCR. Invasion was studied in Matrigel‐coated Boyden chamber transwell assays for monolayers and in confrontation cultures of tumor spheroids with fetal rat brain aggregates in the presence of the synthetic MMP inhibitors batimastat (BB‐94) and marimastat (BB‐2516). Cytotoxicity/cytostatic effects of high concentrations of both compounds were assessed by growth curves, MTT assays and flow cytometry in human glioma cell lines. Batimastat and marimastat revealed a cytostatic effect at high concentrations (above 1 μM) without cytotoxicity. Both MMP inhibitors effectively reduced glioma invasion in Boyden‐chamber assays at low concentrations of 0.3 μM. In confrontation cultures, concentrations of 10 μM and above were necessary to reduce invasion. This effect was observable with inter‐individual heterogeneity in the patients tumor material. MMP inhibitors effectively reduce glioma invasion, although high concentrations were required in 3‐dimensional culture systems. At these concentrations, both compounds revealed a cytostatic, but no cytotoxic effect. Thus, high local concentrations of MMP inhibitors could offer a new therapeutic strategy for the treatment of gliomas. Int. J. Cancer 80:764–772, 1999.

Acoustic neuroma surgery as an interdisciplinary approach: a neurosurgical series of 508 patients

OBJECTIVES To evaluate an interdisciplinary concept (neurosurgery/ear, nose, and throat (ENT)) of treating acoustic neuromas with extrameatal extension via the retromastoidal approach. To analyse whether monitoring both facial nerve EMG and BAEP improved the functional outcome in acoustic neuroma surgery. METHODS In a series of 508 patients consecutively operated on over a period of 7 years, functional outcome of the facial nerve was evaluated according to the House/Brackmann scale and hearing preservation was classified using the Gardner/Robertson system. RESULTS Facial monitoring (396 of 508 operations) and continuous BAEP recording (229 of 399 cases with preserved hearing preoperatively) were performed routinely. With intraoperative monitoring, the rate of excellent/good facial nerve function (House/Brackmann I-II) was 88.7%. Good functional hearing (Gardner/Robertson 1–3) was preserved in 39.8%. CONCLUSION Acoustic neuroma surgery via a retrosigmoidal approach is a safe and effective treatment for tumours with extrameatal extension. Functional results can be substantially improved by intraoperative monitoring. The interdisciplinary concept of surgery performed by ENT and neurosurgeons was particularly convincing as each pathoanatomical phase of the operation is performed by a surgeon best acquainted with the regional specialties.

Prophylactic intravenous magnesium sulfate for treatment of aneurysmal subarachnoid hemorrhage: A randomized, placebo-controlled, clinical study

Objective:To examine whether the maintenance of elevated magnesium serum concentrations by intravenous administration of magnesium sulfate can reduce the occurrence of cerebral ischemic events after aneurysmal subarachnoid hemorrhage. Design:Prospective, randomized, placebo-controlled study. Setting:Neurosurgical intensive care unit of a University hospital. Interventions:One hundred ten patients were randomized to receive intravenous magnesium sulfate or to serve as controls. Magnesium treatment was started with a bolus of 16 mmol, followed by continuous infusion of 8 mmol/hr. Serum concentrations were measured every 8 hrs, and infusion rates were adjusted to maintain target levels of 2.0–2.5 mmol/L. Intravenous administration was continued for 10 days or until signs of vasospasm had resolved. Thereafter, magnesium was administered orally and tapered over 12 days. Measurements and Main Results:Delayed ischemic infarction (primary end point) was assessed by analyzing serial computed tomography scans. Transcranial Doppler sonography and digital subtraction angiography were used to detect vasospasm. Delayed ischemic neurologic deficit was determined by continuous detailed neurologic examinations; clinical outcome after 6 months was assessed using the Glasgow outcome scale. Good outcome was defined as Glasgow outcome scale score 4 and 5. The incidence of delayed ischemic infarction was significantly lower in magnesium-treated patients (22% vs. 51%; p = .002); 34 of 54 magnesium patients and 27 of 53 control patients reached good outcome (p = .209). Delayed ischemic neurologic deficit was nonsignificantly reduced (9 of 54 vs. 15 of 53 patients; p = .149) and transcranial Doppler-detected/angiographic vasospasm was significantly reduced in the magnesium group (36 of 54 vs. 45 of 53 patients; p = .028). Fewer patients with signs of vasospasm had delayed cerebral infarction. Conclusion:These data indicate that high-dose intravenous magnesium can reduce cerebral ischemic events after aneurysmal subarachnoid hemorrhage by attenuating vasospasm and increasing the ischemic tolerance during critical hypoperfusion.

Decompressive Craniectomy in Patients with Uncontrollable Intracranial Hypertension

There has been controversial discussion about the benefits of decompressive craniectomy in patients with critically raised intracranial pressure (ICP) after severe head injury. The aim of this retrospective study was to analyze the results of secondary decompressive craniectomy in patients with uncontrollable raised ICP after maximum aggressive medical treatment. The data of 28 patients (mean age 22 years, range 8-44 years) with severe head injury and posttraumatic cerebral edema were analyzed retrospectively. Surgery was not indicated in patients with vast primary lesions, hypoxia, ischemic infarction, brainstem injuries and central herniation. The outcome was classified according to the Glascow Outcome Scale (GOS) after one year. The decompressive crainectomy was performed an average of 68 hours after trauma, and ICP (< 25 mm Hg) decreased always while cerebral perfusion pressure (CPP > 75 mm Hg) improved as well as cerebral blood flow and microcirculation to normal values. 15 patients (56%) had a good outcome after one year (GOS 4 + 5). 5 patients (18%) were severely disabled, 4 patients (14%) remained in vegetative state and 3 patients (11%) died. Decompressive craniectomy should be kept in mind as the last therapeutic step, especially in young patients with head injury and raised ICP, which is not controllable with conservative methods.

Brain tissue pO2 in relation to cerebral perfusion pressure, TCD findings and TCD-CO2-reactivity after severe head injury

SummaryAs a reliable continuous monitoring of cerebral blood flow and/or cerebral oxygen metabolism is necessary to prevent secondary ischaemic events after severe head injury (SHI) the authors introduced brain tissue pO2 (ptiO2) monitoring and compared this new parameter with TCD-findings, cerebral perfusion pressure (CPP) and CO2-reactivity over time on 17 patients with a SHI. PtiO2 reflects the balance between the oxygen offered by the cerebral blood flow and the oxygen consumption by the brain tissue. According to TCD-CO2reactivity PtiO2-CO2-reactivity was introduced.After initally (day 0) low mean values (ptiO2 7.7 +/−2.6 mmHg, TCD 60.5 +/−32.0 cm/sec and CPP 64.5 +/−16.0 mmHg/, ptiO2 increased together with an increase in blood flow velocity of the middle cerebral artery and CPP. The relative hyperaemic phase on days 3 and 4 was followed by a decrease of all three parameters. Although TCD-CO2-reactivity was except for day 0 (1.4+/−1.5%), sufficient. ptiO2-CO2-reactivity sometimes showed so-called paradox reactions from day 0 till day 3, meaning an increase of ptiO2 on hyperventilation. Thereafter ptiO2-CO2-reactivity increased, increasing the risk of inducing ischaemia by hyperventilation.The authors concluded that ptiO2-monitoring might become an important tool in our treatment regime for patients requiring haemodynamic monitoring.

Studies of Tissue PO2 in Normal and Pathological Human Brain Cortex

Brain cortex PO2 was measured after craniotomy and opening of the dura mater in 26 patients. We determined the brain tissue PO2 under standard narcotic conditions and after changing arterial PO2 and PCO2. Patients were divided into two groups (normal and pathological), depending on the aspect of their cortex on Ct/MRI and intraoperative appearance of the cortex. No statistical significantly difference was seen between tissue PO2 of the normal and the pathological group. A significant difference was seen only between the normal group and a subgroup with brain swelling (p = 0.0344). In the normal group no correlation was seen between tissue PO2 and arterial PO2 (r = 0.1541, p = 0.3076), whereas in the pathological group and especially in the oedema subgroup there was a highly significant correlation between tissue PO2 and PaO2 (r = 0.754, p = 0.0015 and r = 0.888, p = 0.0007). Breathing 100% oxygen changed tissue PO2 to 137.8 or 352 mmHg in the normal or the pathological group, respectively. Again, there was no correlation between tissue PO2 and PaO2 in the normal group (r = 0.1071, p = 0.392), whereas this correlation was significant in the pathological and the oedema subgroup (r = 0.6291, p = 0.0473 and r = 0.8385, p = 0.0185). This is evidence for regulatory mechanisms of tissue PO2. During hyperventilation no significant difference in tissue PO2 between the normal and the pathological group was seen. Low tissue PO2 values, however, indicate a risk for inducing ischemia.

Microglial/macrophage expression of interleukin 10 in human glioblastomas

Interleukin 10 (IL‐10) expression has been found to be correlated with the extent of malignancy in gliomas. In vitro, IL‐10 increases proliferation and migratory capacity in human glioma cell lines. In this study, we localized the site of IL‐10 synthesis in gliomas to cells of microglial origin. Biopsy specimens from 11 patients with malignant glioma were processed on native tissues and at early cell culture passages (0–4). IL‐10 mRNA was analyzed by RT‐PCR and in situ hybridization. Protein was quantitatively assessed by ELISA in cell culture supernatants, and cells expressing IL‐10 were determined by a combination of immunohistochemistry for CD68 (specific for microglia/macrophage lineage) and IL‐10 in situ hybridization. IL‐10 mRNA decreased from passage 0 to 4 in all samples and was undetectable beyond passage 5. Such downregulation of mRNA leads to a steep decrease of IL‐10 protein in culture supernatants (below detection level, 0.05 ng/ml, beyond passage 1). The combination of in situ hybridization for IL‐10 and CD68 immunostaining revealed that only cells of the microglia/macrophage lineage produced IL‐10 mRNA. Our results identify microglia/macrophage cells as the major source of IL‐10 expression in gliomas which decreases markedly during early passages of primary cultures of human gliomas due to a progressive reduction of microglia/macrophages present. Int. J. Cancer 82:12–16, 1999.

Correlation of Intra-Operative Ultrasound with Histopathologic Findings After Tumour Resection in Supratentorial Gliomas A Method to Improve Gross Total Tumour Resection

SummaryThe aim of this study was to evaluate whether intra-operative ultrasound (=IOUS) is a suitable tool to detect residual tumour tissue after gross total resection in supratentorial gliomas.During a period of 18 months 45 patients with supratentorial gliomas (38 high-grade and 9 low-grade, according to the WHO-grading system [42]) were operated on. A series of 78 biopsies was taken from the resection cavity under continuous sonographic control at the end of surgery. Gross total tumour resection was intended in 34 patients (=76%). The biopsy specimens were matched with the sonographic features at each biopsy site. The sonographic appearance of the resection margins were classified into 2 groups: (1) Irregular hyperechoic areas extending from the cavity into the iso-echogenic brain tissue and (2) a dense small (≤3 mm in diameter) rather regular hyperechoic rim surrounding the resection cavity.47 out of 53 biopsies taken from hyperechoic areas (group 1) (36 high-grade/11 low-grade) revealed solid tumour tissue (=89%). 34 (=72%) of these 47 areas were microscopically assessed as inconspicuous by the surgeon. 6 samples (4 high-grade/2 low-grade) contained tumour infiltration zone. 25 biopsies (23 high-grade/2 low-grade) taken from the hyperechoic rim [group 2] were diagnosed as follows: Normal brain tissue in 11, tumour infiltration zone in 8 and solid tumour tissue in 6 cases.Of 34 cases with “gross total removal” according to the surgeons assessement 25 showed sonographic signs of residual tumour tissue, which was confirmed histologically as solid tumour tissue in 22 of these cases.It is concluded, that IOUS following resection of supratentorial gliomas can detect residual tumour tissue with high specificity and thus improve gross total resection. However, a thin hyperechoic rim surrounding the resection cavity (less than 3 mm in diameter) is a non-specific finding, which can mask thin residual tumour layers and therefore needs further evaluation of its nature.