CT perfusion predicts secondary cerebral infarction after aneurysmal subarachnoid hemorrhage.

OBJECTIVE: To prospectively assess the diagnostic accuracy of CT perfusion (CTP) and transcranial Doppler sonography (TCD) for the prediction of secondary cerebral infarction (SCI) after aneurysmal subarachnoid hemorrhage (SAH). METHODS: During 2 weeks after SAH, 38 consecutive patients completed an average of 3.5 CT/CTP and 10.7 TCD examinations at regular intervals as required by the study protocol. SCI was defined as delayed infarction on native CT between 3 and 14 days after SAH and developed in n = 14 patients (n = 24 without SCI). Analysis was based on examination dates before SCI. Common measures of diagnostic accuracy were calculated for qualitative CTP (visual color-map ratings from two blinded observers) and TCD assessments (mean flow velocity >120 cm/s in anterior, middle, and posterior cerebral artery territories). Quantitative measures, which for CTP were obtained from cortical a priori regions of interest corresponding to the vascular territories, were analyzed by binary logistic regression. RESULTS: Time of prediction for SCI by CTP was at a median of 3 days (range 2 to 5 days) before manifestation of complete infarction on native CT. Visual assessment of time-to-peak (TTP) color maps performed best for the prediction of SCI with 0.93 sensitivity (95% CI: 0.7 to 1.0) and 0.67 specificity (95% CI: 0.53 to 0.7). On quantitative analysis, the odds ratio (OR) for 1 second of side-to-side delay in TTP was 1.4 (p = 0.01, Wald chi(2) = 8.57, CI: 1.07 to 1.82). Daily TCD measures were not significantly related to SCI at any time before complete infarction on native CT. CONCLUSIONS: Time to peak as indicated by CT perfusion is a sensitive and early predictor of secondary cerebral infarction.

Influence of cerebral oxygenation following severe head injury on neuropsychological testing.

Despite recent advances in the management of severe head injury the mortality and morbidity remains high. Intracranial pressure (ICP) and cerebral perfusion pressure (CPP) are crucial parameters for the correct management at the intensive care unit, due to their therapeutic and prognostic importance. In addition, regional brain tissue oxygenation (ptiO2) seems to be of importance. While different studies demonstrated the impact of cerebral hypoxia on outcome (mortality), no data are available focusing on morbidity (neuropsychological deficits). Therefore, our study is carried out to demonstrate a possible relationship between amount of cerebral oxygenation during acute stage after severe head injury and neuropsychological outcome. Besides ICP and CPP, ptiO2 was monitored in 40 severely head injured patients during the ICU stay from the day of admission until day 10. Monitoring data were stored and amount of hypoxic episodes were calculated. Besides outcome using the Glasgow Outcome Scale neuropsychological testing was performed 2-3 years after injury. Analysing the quality of brain tissue oxygenation, a relationship to the performance in neuropsychological tests could be found. Patients with low brain tissue oxygenation had a worse outcome in neuropsychological testing, especially concerning intelligence and memory. Associated with these deficits patients showed a reduced performance in their profession. Our data suggest a possible predictive value of brain tissue oxygen on morbidity analysing neurocognitive function after head injury. This may implicate monitoring and treatment of cerebral hypoxia.

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

OBJECTIVE: To evaluate the effects of a brain tissue oxygen (P(ti)O(2)) guided treatment in patients with traumatic brain injury. METHODS: P(ti)O(2) 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 P(ti)O(2) above 1.33 kPa (10 mm Hg) (P(ti)O(2) guided group). RESULTS: Cerebral hypoxic phases with P(ti)O(2) values below 1.33 kPa occurred significantly less often in the P(ti)O(2) guided group. P(ti)O(2) 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 P(ti)O(2) guided group. CONCLUSIONS: Cerebral hypoxic events can be reduced significantly by increasing cerebral perfusion pressure as required. To show a clear beneficial effect of P(ti)O(2) guided cerebral perfusion pressure management on outcome, a multicentre randomised trial needs to be undertaken.

Therapeutic aspects of brain tissue pO2 monitoring after subarachnoid hemorrhage.

Prolonged phases of brain tissue hypoxia (ptiO2 < 10 mmHg) lead to cerebral infarction. Therefore, the present study investigates the role of ptiO2--monitoring to guide hypervolemic hypertensive therapy in patients suffering from severe subarachnoid hemorrhage (SAH). Besides transcranial doppler, neuromonitoring of ICP/CPP was supplemented by ptiO2 monitoring. The ptiO2 catheter was inserted into viable tissue in the vascular territory with the highest risk for vasospasm. Patients were divided in an infarction (n = 21) and a non-infarction group (n = 11). Critical CPP (< 70 mmHg) as well as hypoxic ptiO2 (< 10 mmHg) was significantly more frequent in the infarction group (CPP: 25 vs 13%, p < 0.001; ptiO2: 16 vs 7%, p < 0.001). In both groups, over 25% of the critical ptiO2 values occurred at a CPP > 90 mmHg. In the infarction group, 13 patients showed transient phases of hypoxia which normalized under induced hypervolemic hypertension and 5 patients developed persistent hypoxia. In the non-infarction group 6 patients showed transient hypoxia and in 5 patients no hypoxic values could be found. In conclusion, monitoring of ptiO2 provides an additional independent parameter to detect hypoxic events and to guide therapy.

Extraneural metastases of primary brain tumors.

Extraneural metastasis (ENM) of primary brain tumors is arare occurence. Based on acritical analysis of the literature the present review focuses on illustrating special common features of these tumors with regard to immunological, cytokinetical and tumorbiological issues. In this respect much can be learned from the specific conditions following organ transplantation which is extensively discussed.

Medulloblastoma displays distinct regional matrix metalloprotease expression.

Matrix metalloproteases (MMPs) play an important role in tissue remodeling and neoangiogenesis during tumor progression. Little is known about the presence and regional distribution of MMPs in medulloblastomas. Based on immunohistochemical, immunocytochemical and zymographical analysis is the present study illustrates the differential pattern of MMP expression for the medulloblastoma compared to that of glioma and ependymoma. In 10 examined medulloblastoma tumors gelatinase-A was strongly expressed by clusters of tumor cells. Gelatinase-B was, similar to glioma and ependymoma, predominantly found around endothelial cells. The DAB signal for macrophage metalloelastase was seen around macrophages and matrilysin was expressed by single tumor cells. Stromelysin-1 protein was detected in medulloblastoma but not in glioma or ependymoma. From the presented data it follows that each tumor entity might display its own characteristic MMP expression pattern.

New ultrasound techniques and their application in neurosurgical intra-operative sonography.

We describe a variety of new ultrasound techniques by their physical background, potentials and applications regarding usefulness during intra-operative neurosurgical procedures. Transducers like high-frequency and small rotating probes fitting into neuroendoscopes, imaging techniques as extended field-of-view technique, harmonic imaging, echo-enhancers, 3-D imaging and the real-time integration of neurosonography with pre-operative CT- or MR-data are mentioned. The technical or physical principles are explained, followed by a discussion of these techniques from available literature dealing with their intra-operative neurosurgical applications and the experience of the authors with the techniques. With higher frequencies micromillimeter imaging is possible and small probe allows endoneurosonography. Echo-enhancers and harmonic imaging improve the signal-to-noise ratio and 3-D imaging and extended field-of-view techniques allows a better understanding of the pathoanatomy. With the real-time integration of intra-operative ultrasound images and pre-operative CT or MR images additional information, like hemodynamic pattern, are available for the neurosurgeon. Although until now only a limited number of reports about new sonographic techniques during intra-operative application in neurosurgery exist, the methods seem to be promising in creating images easier to understand, incorporating more information about pathoanatomy and supplying the neurosurgeon with information additional to that provided by CT and MRI.

Combined intra-operative monitoring of hearing by means of auditory brainstem responses (ABR) and transtympanic electrocochleography (ECochG) during surgery of intra- and extrameatal acoustic neurinomas.

BACKGROUND: Although being established as a standard procedure in intra-operative monitoring in acoustic neurinoma surgery, auditory brainstem responses (ABR) represent a far-field technique bearing some technical limitations. This prospective study was designed to evaluate electrocochleography (ECochG) as a supplementary tool for hearing preservation. METHOD: 84 patients with unilateral intra-/extrameatal acoustic neurinomas (extrameatal diameter: 5-55 mm) preserving serviceable hearing, were operated on using a combined (neuro-/otosurgical) suboccipital approach. ECochG was recorded simultaneously to ABR following transtympanic insertion of a steel needle electrode into the promontory under otoscopic view. FINDINGS: Serviceable hearing (Class 1-3 according to Gardner/Robertson) was preserved in 43 out of 84 patients (51.2%), of whom 40 showed both ECochG and ABR being preserved. All 24 patients with loss of both modalities became deaf. Hearing preservation was observed in 4 out of 12 patients with preserved ECochG but loss of ABR (waves III-V). The reverse was observed in 2 cases with postoperative deafness. While both ECochG and ABR amplitudes were significantly correlated with pre- and postoperative hearing, latencies of ECochG summating (SP) and action potential (AP) proved to be more reliable indicators for preserved hearing than ABR (peak I/III/V) latencies. The predictive value of baseline ABR amplitudes for postoperative hearing, however, was superior to ECochG parameters. Only in large neurinomas (extrameatal diameter: >2 cm) tumour size was found to be a significant predictor for the preservation of hearing. Apart from three cases with postoperative otoliquorrhea and one further case presenting with local bleeding within the external acoustic meatus, no side effects were observed. CONCLUSIONS: In combination with ABR monitoring, ECochG proved to be a useful supplementary tool for hearing preservation in acoustic neurinoma surgery. It is particularly helpful during electrocautery and drilling, since no averaging is required. Special applications are: (1) small tumours with good serviceable hearing; (2) and/or a large intrameatal portion; (3) cases with lost or endangered contralateral hearing (e.g. bilateral acoustic neurinomas), when the preservation of poor or even non-functional hearing is desirable.

Surgical management of tethered spinal cord in adults: report of 54 cases.

OBJECT: The clinical features specific to tethered cord syndrome (TCS) in adults as well as factors determining outcome and prognosis have rarely been addressed systematically. The authors studied 56 patients, 54 of whom were treated surgically over the last 16 years. METHODS: In 17 patients who had been asymptomatic during childhood, TCS was diagnosed 8 years after onset of symptoms. Tethered cord syndrome was diagnosed 4 years after worsening in 39 patients with neurological signs or symptoms since childhood. The patients were followed for an average of 8 years. Features specific to adult-age presentation included nondermatomal pain aggravated by movement in 34 patients and conditions such as pregnancy and childbirth (in five of 11 pregnant patients). The most frequent tethering lesions were lipoma in 32, tight terminal filum in 28, and split cord malformation and secondary adhesions in 12 patients, respectively. Improvement or stabilization of symptoms at 6 months after surgery was noted in 46 (85%) of 54 patients. Improvement in pain status was most frequent (86%) followed by improvements in spasticity (71%), bladder dysfunction (44%), and sensorimotor deficits (35%). Factors associated with adverse outcome included preoperative duration of neurological deficits more than 5 years and incomplete untethering. On average, 8 (80%) of 10 patients with incomplete untethering developed recurrent symptoms 5 years after surgery compared with only seven (16%) of 44 patients in whom complete untethering was achieved. Seven patients underwent reoperation and in five of them stabilization of symptoms was attained. At a mean follow up of 8 years, 46 (85%) of the 54 surgically treated patients were in stable neurological condition, including those in whom reoperation was performed. CONCLUSIONS: Surgery for TCS is as beneficial in adults as it is in children. Its success depends on early diagnosis and complete untethering of the spinal cord.

Intra-operative electromyographic monitoring of the lower cranial motor nerves (LCN IX-XII) in skull base surgery.

The functional preservation of lower (motor) cranial nerves (LCN) is endangered during skull base surgery. Intra-operative EMG monitoring of the LCN IX-XII was investigated in 78 patients undergoing 80 operations on various skull base tumors with regard to technical feasibility and clinical efficacy. Ongoing 'spontaneous muscle activity' (SMA) and 'compound muscle action potentials' (CMAP) following supramaximal bipolar stimulation were intra-operatively recorded applying needle electrodes into the soft palate (CN IX: n=76), the vocal cord (CN X: n=72), the trapezius muscle (CN XI: n=18), and the tongue (CN XII: n=71). From 24/22/8 cases with LCN IX/X/XII deficits (despite monitoring) only 5/6/4 remained unchanged (3-6 months postoperative). An irreversible plegia of the LCN IX/X/XII occurred in three (1/1/1) patients. In 7/6/1 patients postoperative (3-6 months) LCN IX/X/XII function was better than preoperatively. In all patients accessory nerve function remained unchanged. 'Pathological' SMA of the LCN IX/X/XII occurred in 12/16/8 cases, but in only 6/5/3 cases corresponded to postoperative LCN deficits. Corresponding 'pathological' SMA patterns were found in 18/17/5 out of 24/22/8 cases with postoperative LCN IX/X/XII dysfunction. Reproducible CMAP of LCN IX/X/XI/XII could be recorded in 59/56/11/32 patients. Approximate 'normal' values were calculated and compared to (very few) data so far given in the literature. Electromyographic monitoring proved to be a safe tool for the intra-operative identification and localization of the LCN contributing to their anatomical and functional preservation. The predictive value of standard neurophysiological parameters for functional outcome, however, is limited.

Intra-Operative electromyographic monitoring of extra-ocular motor nerves (Nn. III, VI) in skull base surgery.

BACKGROUND: Extraocular motor nerves (Nn. III, IV, VI) are at risk of damage during skull base surgery. A new recording technique was employed in 18 patients suffering from various skull base tumours in order to extend intra-operative EMG monitoring to the extra-ocular muscles. METHODS: Selective intra-operative EMG recordings were obtained from extra-ocular muscles by placement of single-shafted bipolar needle electrodes under the guidance of B-mode ultrasound to visualise the needle tip within the target muscle in the orbital cavity. FINDINGS: Following bipolar electrical stimulation, the oculomotor nerve (N.III) was intra-operatively identified in 5 out of 7 cases, and the abducens nerve (N.VI) in 12 out of 18 cases. Postoperative (3-6 months) oculomotor nerve function remained unchanged in 5 and improved in 2 patients. No permanent deterioration was observed. Abducens nerve function deteriorated in two patients and improved in one case, but remained unchanged in 15 cases. No side effects occurred. There was neither any distinct relation of ocular motor nerve function to the kind and extent of SMA ("spontaneous muscle activity") patterns, nor could such relationship be detected with concern to neurophysiological parameters (latencies, amplitudes) of electrically evoked CMAP ("compound muscle action potentials"). INTERPRETATION: The EMG technique proposed proved to be mainly effective as a mapping tool for intra-operative localisation and identification of ocular motor nerves in skull base surgery. However, the predictive value of conventional neurophysiological parameters for clinical outcome, seems to be rather poor. Further studies on a larger number of patients are therefore required to develop new quantification techniques which enable an intra-operative prediction of ocular motor nerve deficits. Further efforts are also necessary to extend this technique to the trochlear nerve.

Advanced neuromonitoring including cerebral tissue oxygenation and outcome after traumatic brain injury.

For 51 patients suffering from traumatic brain injury (GCS < 9), we compared the prognostic value of critical parameters derived from neuromonitoring of intracranial pressure (ICP), cerebral perfusion pressure (CPP) and brain tissue oxygenation (PiO2) during different time periods after trauma (< or = 12, < or = 24, < or = 48, < or = 72 and < or = 96 h). For patients with good outcome (GOS = 4-5, n = 30) the proportion of critical ICP values (> 40 mmHg) was about 0.2% during all time periods. The corresponding proportions for patients with bad outcome (GOS = 1-3, n = 21) rose from 0.2% to 4.7% during increasing time periods. The frequency of critical ICP values was significantly related to outcome (p < 0.001) for time periods > 48 h after trauma. Differences of critical CPP (< or = 50 mmHg) and hypoxic PiO2 (< or = 5 mmHg) between both outcome groups were less pronounced and for both parameters significant relations to outcome were only obtained for the longest time period (< or = 96 h, p < or = 0.05). Higher thresholds for CPP (< or = 60 mmHg, < or = 70 mmHg) did not reveal any relation to outcome. For all neuromonitoring parameters significant relations between the frequency of critical values and outcome could be determined. Critical ICP values provide the earliest and highest prognostic power, while critical CPP and hypoxic PiO2 only showed prognostic power in later time periods.

Clinical cerebral microdialysis: brain metabolism and brain tissue oxygenation after acute brain injury.

While continuous monitoring of brain tissue oxygenation (P(ti)O2) is known as a practicable, safe and reliable monitoring technology supplementing traditional ICP-CPP-monitoring, the impact of cerebral microdialysis, now available bedside, is not proven extensively. Therefore our studies focused on the practicability, complications and clinical impact of microdialysis during long term monitoring after acute brain injury, especially the analysis of the correlation between changes of local brain oxygenation and metabolism. Advanced neuromonitoring including ICP-CPP-p(ti)O2 was performed in 20 patients suffering from acute brain injury. Analysis of the extracellular fluid metabolites (glucose, lactate, pyruvate, glutamate) were performed bedside hourly. No catheter associated complications, like infection and bleeding, occurred. However, longterm monitoring was limited in 5 out of 20 patients caused by obliteration of the microdialysis catheter after 3-4 days. In the individual patients partly a correlation between increased lactate levels as well as lactate pyruvate ratios and hypoxic brain tissue oxygenation could be found. Analysing the data sets of all patients only a low correlation was detected indicating physiological and increased lactate and lactate/pyruvate ratio during sufficient brain oxygenation. Additionally, concentrations of excitatory amino acid glutamate were found in normal and elevated range during periods of hypoxic oxygenation (P(ti)O2 < 10 mmHg) and intracranial hypertension. Our data strongly suggest partly evidence of correlation between hypoxic oxygenation and metabolic disturbances after brain injury. On the other hand brain metabolism is altered without changes of cerebral oxygenation. Further studies are indicated to improve our pathophysiological knowledge before microdialysis is routinely useful in neurointensive care.

Ultrasound-guided neuronavigation of deep-seated cavernous haemangiomas: clinical results and navigation techniques.

The aim of this study was to evaluate guidance techniques and patient outcomes of ultrasound-guided neuronavigation of deep-seated intracerebral cavernous hemangiomas (CAs). Thirty-five patients with deep-seated intracerebral CAs with sizes ranging between 7 and 45 mm were operated upon only with ultrasound-guidance. Twenty-seven were located in or near eloquent regions. In 30 patients dissection to the lesion was performed through sulci and fissures. The best approach to a lesion based on surface anatomy and depth was determined using sonographic information. Navigation was done sonographically. In five patients the shortest approach via a corticotomy was determined sonographically. Twenty-six patients had no neurological deficit postoperatively. Preoperative deficits improved in seven of nine patients. Fifteen of 19 patients suffering epileptic seizures had no seizures postoperatively. Intraoperative sonography revealed residual CA tissue after microsurgical extirpation in two cases. This report shows that intraoperative sonographic navigation provides safe guidance to deep-seated CAs with good clinical outcome independent of size.

Is there a benefit of preoperative meningioma embolization?

OBJECTIVE: To evaluate the effect of preoperative embolization of meningiomas on surgery and outcomes. METHODS: In a prospective study, 60 consecutive patients with intracranial meningiomas who were treated in two neurosurgical centers were included. In Center A, embolization was performed for none of the patients (n = 30). In Center B, 30 consecutive patients with embolized meningiomas were treated. Preoperatively, tumor size and location, neurological status, and Barthel scale score were recorded. In Center B, the extent of tumor devascularization was evaluated using angiography and postembolization magnetic resonance imaging. Intraoperatively, blood loss, the numbers of blood units transfused, and the observations of the neurosurgeon concerning hemostasis, tumor consistency, and intratumoral necrosis were recorded. Postoperatively, the neurological status and duration of hospitalization were recorded. Six months after surgery, the outcomes were assessed using the Barthel scale and neurological examinations. RESULTS: The mean tumor sizes were 22.9 cc in Center A and 29.6 cc in Center B (P > 0.1). The mean blood losses did not differ significantly (646 ml in Center A versus 636 ml in Center B; P > 0.5). However, for a subgroup of patients with subtotal devascularization (>90% of the tumor) on postembolization magnetic resonance imaging scans in Center B, blood loss was less, compared with the entire group in Center A (P < 0.05). The observations of the neurosurgeon regarding hemostasis, tumor consistency, and intratumoral necrosis did not differ significantly. There were no surgery-related deaths in either center. The rates of surgical morbidity, with permanent neurological worsening, were 20% (n = 6) in Center A and 16% (n = 5) in Center B. There was one permanent neurological deficit (3%) caused by embolization. CONCLUSION: In this preliminary study, only complete embolization had an effect on blood loss. The value of preoperative embolization for all meningiomas must be reconsidered, especially in view of the high costs and risks of embolization.

Vascular endothelial growth factor-driven glioma growth and vascularization in an orthotopic rat model monitored by magnetic resonance imaging.

OBJECTIVE: The goal of the present study was to develop an orthotopic in vivo model for the investigation of vascular endothelial growth factor (VEGF)-dependent glioma growth and vascularization. METHODS: C6 glioma cells were infected with viruses encoding sense or antisense VEGF. Expression of the transgene was controlled by Northern blot analysis, Western blot analysis, and immunohistochemistry. Spheroids generated from both clones as well as from wild-type and mock-transfected cells were implanted in the brains of Sprague-Dawley rats. Growth and vascularization were assessed using magnetic resonance imaging after 7 and 11 days. Histology was studied using hematoxylin and eosin staining, immunohistochemistry with anti-von Willebrand staining, anti-VEGF, anti-CD8, and assessment of vessel density. RESULTS: Cell proliferation, migration, and invasion in vitro were very similar in all cell clones. Sense gliomas demonstrated by far the fastest growth in vivo, with intense contrast enhancement meeting criteria for highly malignant tumors. Histological examination revealed masses of von Willebrand- and VEGF-positive tumor vessels with a high vessel density. Antisense gliomas depicted the radiological features of low-grade gliomas, with slow growth and poor vascularization, although they were highly infiltrative. Wild-type and mock-transfected gliomas demonstrated similar growth and vascularization patterns intermediate between sense and antisense gliomas. Any influence of the allogeneic response of the hosts on different tumor sizes could be excluded. CONCLUSION: Our model elucidates glioma growth and vascularization as strongly VEGF dependent, which is consistent with human gliomas. Thus, this model is suitable for testing antiangiogenic strategies to interfere with the VEGF/VEGF receptor system, as well as for exploring VEGF-independent mechanisms using the antisense-transfected clone.

Near-infrared spectroscopy--not useful to monitor cerebral oxygenation after severe brain injury.

Since its development more than twenty years ago, non-invasive near-infrared-spectroscopy (NIRS) has been widely used to monitor cerebral oxygenation. Despite of its growing number of users, the diagnostic value of near-infrared spectroscopy still remains unclear, especially in case of acute brain injury and long-term neuromonitoring, necessary during intensive care therapy. To evaluate quality and sensitivity of NIRS measurements compared to invasive ICP-, CPP- and regional brain tissue--pO2 (p(ti)O2) monitoring, 31 patients, suffering from severe brain injury due to subarachnoid hemorrhage or severe head injury, were studied. NIRS measurements were only possible in 80% (using the INVOS oximeter) and in 46% (using the CRITIKON monitor), while good data quality was obtained in 100% from ICP, CPP and p(ti)O2. Major reasons for the failure of NIRS measurements were: (1) a wet chamber between sensor and skin, (2) galea hematoma or (3) subdural air after craniotomy. Different tests were performed to compare the sensitivity of regular oxygen saturation (NIRS) with the sensitivity of invasively determined p(ti)O2. Only induced hyperoxia (FiO2 = 1.0) revealed a significant correlation between both parameters (r = 0.67, p < 0.01). Lower or no correlation was found after changing paCO2 and administration of mannitol. The high failure rate and the limited sensitivity does not make the clinical use of near-infrared spectroscopy suitable as a part of neuromonitoring after acute brain injury at the present time.

Inhibition of Ras farnesylation by lovastatin leads to downregulation of proliferation and migration in primary cultured human glioblastoma cells.

BACKGROUND: Malignant astrocytomas are the most common primary intracranial human tumors. All therapeutic approaches are limited due to their high proliferative capacity and their ability to diffusely invade the brain. Amplification of tyrosine kinase receptors and their signaling pathways have been implicated as contributing to the molecular pathogenesis of astrocytomas, providing possible new targets for therapeutic intervention. In particular, astrocytomas, although lacking oncogenic Ras mutations, have elevated levels of activated Ras. Lovastatin, an inhibitor of the beta-hydroxy-beta-methylglutary CoA reductase (HMG-CoA-reductase), is currently used to treat patients with hypercholesterolemia. In addition, it inhibits isoprenylation of several members of the Ras superfamily of proteins and therefore has multiple cellular effects including the reduction of proliferation. MATERIALS AND METHODS: In this study, we investigated the impact of lovastatin on two human glioma cell lines and on 15 primary cell cultures established from biopsies of patients with glioblastoma multiforme (GBM,) Proliferation of glioma cell lines and primary tumor cells was determined by cell counting and by using the MTT assay. The cell morphology was analyzed by staining of actin filaments with phalloidin. Apoptosis was measured using the TUNEL assay. To investigate the influence of this drug on glioma cell motility, tumor cell migration was investigated using three dimensional spheroid disintegration assays. In addition, tumor cell invasion was analyzed with a confrontational assay between tumor spheroids and rat brain aggregates. RESULTS: Inhibition of farnesyl biosynthesis using lovastatin led to a block in Ras mediated signaling, indicated by lower MAPK activity. Consequently, tumor cell proliferation was reduced up to 80%. Lovastatin appeared to decrease glioma viability by inducing apoptosis, as indicated by morphological changes and increase of TUNEL positive cells. Lovastatin acts through isoprenoid depletion, because supplementation of the media with 50-100 microM mevalonate restored all tau eta epsilon effects. Invasion of tumor cells into brain tissue was not effected while migration was reduced beta upsilon about 30-40% in cells treated with high concentrations (> or = 100 microM) of lovastatin. This was surprising because drug treatment at lower concentrations led to a disruption of the actin cytoskeleton, as indicated by Phalloidin staining. CONCLUSION: Our data strongly suggest that inhibition of elevated Ras activity by lovastatin effectively targets the MAPK and probably other signaling pathways thus offering a pharmacological based approach for a potential treatment of human astrocytomas.

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.