Symptom Burden in Glioblastoma: A Prospective Pilot Study from Diagnosis to First Progression.

INTRODUCTION: The evaluation of symptom burden, performance status, and neurological function is still challenging in glioblastoma (GBM) patients. Patients may suffer from a wide spectrum of neurological symptoms like cognitive deficits, aphasia, or hemiparesis, which interfere to report to comprehensive questionnaires. However, an integrated and reliable neuro-oncological assessment is the key in the clinical management and in the evaluation of treatment benefits for GBM patients. METHODS: We implemented an easy-to-use clinical toolkit for the prospective assessment and follow-up evaluation of GBM patients using the Karnofsky performance status (KPS), the National Institute of Health Stroke Scale (NIH-SS), and simple scores for the evaluation of key symptoms like fatigue, depression, and headache. RESULTS: We prospectively followed 50 patients. The composite score (headache, depression, and fatigue), fatigue alone, the NIHSS, and the KPS were suitable biomarkers to evaluate symptom burden in GBM patients and indicate clinical disease progression. DISCUSSION/CONCLUSION: The proposed clinical toolkit seems feasible in routine clinical practice and reflects changes in symptom burden in different stages of the postsurgical course of GBM patients in this monocentric clinical pilot trial.

State of affairs regarding targeted pharmacological therapy of cancers metastasized to the brain.

In 1999 a visionary short article by The Wall Street Journal writers Robert Langreth and Michael Waldholz popularized the new term "personalized medicine," that is to say, the targeting of drugs to each unique genetic profile. From today's perspective, targeted approaches have clearly found the widest use in the antineoplastic domain. The current review was initiated to review the progress that has been made regarding the treatment of patients with advanced cancer and brain metastases. PubMed was searched for the terms brain metastasis, brain metastases, or metastatic brain in the Title/Abstract. Selection was limited to randomized controlled trial (RCT) and publication date January 2010 to February 2022. Following visual review, 51 papers on metastatic lung cancer, 12 on metastatic breast cancer, and 9 on malignant melanoma were retained and underwent full analysis. Information was extracted from the papers giving specific numbers for intracranial response rate and/or overall survival. Since most pharmacological trials on advanced cancers excluded patients with brain metastases and since hardly any information on adjuvant radiotherapy and radiosurgery is available from the pharmacological trials, precise assessment of the effect of targeted medication for the subgroups with brain metastases is difficult. Some quantitative information regarding the success of targeted pharmacological therapy is only available for patients with breast and lung cancer and melanoma. Overall, targeted approaches approximately doubled the lifespan in the subgroups of brain metastases from tumors with targetable surface receptors such as anaplastic lymphoma kinase (ALK) fusion receptor in non-small cell lung cancer or human epidermal growth factor receptor 2 (HER2)-positive breast cancer. For these types, overall survival in the situation of brain metastases is now more than a year. For receptor-negative lung cancer and melanoma, introduction of immune checkpoint blockers brought a substantial advance, although overall survival for melanoma metastasized to the brain appears to remain in the range of 6 to 9 months. The outlook for small cell lung cancer metastasized to the brain apparently remains poor. The introduction of targeted therapy roughly doubled survival times of advanced cancers including those metastasized to the brain, but so far, targeted therapy does not differ essentially from chemotherapy, therefore also facing tumors developing escape mechanisms. With the improved perspective of patients suffering from brain metastases, it becomes important to further optimize treatment of this specific patient group within the framework of randomized trials.

Postoperative radiotherapy for meningiomas - a decision-making analysis.

BACKGROUND: The management of meningiomas is challenging, and the role of postoperative radiotherapy is not standardized. METHODS: Radiation oncology experts in Swiss centres were asked to participate in this decision-making analysis on the use of postoperative radiotherapy (RT) for meningiomas. Experts from ten Swiss centres agreed to participate and provided their treatment algorithms. Their input was converted into decision trees based on the objective consensus methodology. The decision trees were used as a basis to identify consensus and discrepancies in clinical routine. RESULTS: Several criteria used for decision-making in postoperative RT in meningiomas were identified: histological grading, resection status, recurrence, location of the tumour, zugzwang (therapeutic need to treat and/or severity of symptoms), size, and cell division rate. Postoperative RT is recommended by all experts for WHO grade III tumours as well as for incompletely resected WHO grade II tumours. While most centres do not recommend adjuvant irradiation for WHO grade I meningiomas, some offer this treatment in recurrent situations or routinely for symptomatic tumours in critical locations. The recommendations for postoperative RT for recurrent or incompletely resected WHO grade I and II meningiomas were surprisingly heterogeneous. CONCLUSIONS: Due to limited evidence on the utility of postoperative RT for meningiomas, treatment strategies vary considerably among clinical experts depending on the clinical setting, even in a small country like Switzerland. Clear majorities were identified for postoperative RT in WHO grade III meningiomas and against RT for hemispheric grade I meningiomas outside critical locations. The limited data and variations in clinical recommendations are in contrast with the high prevalence of meningiomas, especially in elderly individuals.

Long-term apparent diffusion coefficient value changes in patients undergoing radiosurgical treatment of meningiomas.

PURPOSE: A noninvasive method to predict the progress or treatment response of meningiomas is desirable to improve the tumor management. Studies showed that apparent diffusion coefficient (ADC) pretreatment values can predict treatment response in brain tumors. The aim of this study was to analyze changes of intratumoral ADC values in patients with meningiomas undergoing conservative or radiosurgery. METHOD: MR images of 51 patients with diagnose of meningiomas were retrospectively reviewed. Twenty-five patients undergoing conservative or radiosurgery treatment, respectively, were included in the study. The follow-up data ranged between 1 and 10 years. Based on ROI analysis, the mean ADC values, ADC10%min, and ADC90%max were evaluated at different time points during follow-up. RESULTS: Baseline ADC values in between both groups were similar. The ADCmean values, ADC10%min, and ADC90%max within the different groups did not show any significant changes during the follow-up times in the untreated (ADCmean over 10 years period: 0.87 ± 0.05 × 10-3 mm2/s) and radiosurgically treated (ADCmean over 4 years period: 1.02 ± 0.12 × 10-3 mm2/s) group. However, statistically significant difference was observed when comparing the ADCmean and ADC90%max values of untreated with radiosurgically treated (p < 0.0001) meningiomas. Also, ADC10%min revealed statistically significant difference between the untreated and the radiosurgery group (p < 0.05). CONCLUSIONS: ADC values in conservatively managed meningiomas remain stable during the follow-up. However, meningiomas undergoing radiosurgery reveal significant change of the mean ADC values over time, suggesting that ADC may reflect a change in the biological behavior of the tumor. These observations might suggest the value of ADC changes as an indicator of treatment response.

Changing the paradigm of intracranial hypertension in brain tumor patients: a study based on non-invasive ICP measurements.

BACKGROUND: The ultrasound based non-invasive ICP measurement method has been recently validated. Correlation of symptoms and signs of intracranial hypertension with actual ICP measurements in patients with large intracranial tumors is controversial. The purpose of this study was to assess ICP in patients with brain tumors, presenting with neurological signs and symptoms of elevated ICP and to further evaluate the value and utility of non-invasive ICP monitoring. METHODS: Twenty patients underwent non-invasive ICP measurement using a two-depth transcranial Doppler ultrasound designed to simultaneously compare pulse dynamics in the proximal (intracranial), and the distal (extracranial) intraorbital segments of the ophthalmic artery through the closed eyelid. RESULTS: Forty-eight measurements were analyzed. Radiological characteristics included tumor volume (range = 5.45-220.27cm3, mean = 48.81 cm3), perilesional edema (range = 0-238.27cm3, mean = 74.40 cm3), and midline shift (mean = 3.99 mm). All ICP measurements were in the normal range of 7-16 mmHg (ICPmean: 9.19 mmHg). The correlation of demographics, clinical and radiological variables in a bivariate association, showed a statistically significant correlation with neurological deficits and ICPmax (p = 0.02) as well as ICPmean (p = 0.01). The correlation between ICP and neurological deficits, showed a negative value of the estimate. The ICP was not increased in all cases, whether ipsilateral nor contralateral to the tumor. The multivariate model analysis demonstrated that neurological deficits were associated with lower ICPmax values, whereas maximum tumor diameter was associated with larger ICPmax values. CONCLUSIONS: This study demonstrated that ICP in patients with intracranial tumors and mass effect is not necessarily increased. Therefore, clinical signs of intracranial hypertension do not necessarily reflect increased ICP.

Spinal Metastases of Supratentorial Glioblastoma with Primitive Neuronal Component.

BACKGROUND: Glioblastoma multiforme with a primitive neuronal component is a rare entity, with few cases reported in the literature. CASE DESCRIPTION: A patient who had a supratentorial glioblastoma multiforme with a primitive neuronal component developed spinal metastasis during the disease course. With his history of leukemia during childhood, he was likely exposed to therapeutic ionizing brain radiation, which could have increased the risk of developing brain cancer in adulthood. CONCLUSIONS: The range of incidence rates of dissemination in the literature is 2%-4%, typically in cases of cerebellar glioblastoma multiforme, but as high as 25% in autopsy series. Our case highlights several other topics in the literature, such as immunohistochemical patterns that differ between the primary tumor and spinal metastases and dissemination locations, typically leptomeningeal or ventricular invasion.

Longitudinal Imaging of Tumor Volume, Diffusivity, and Perfusion After Preoperative Endovascular Embolization in Supratentorial Hemispheric Meningiomas.

OBJECTIVE: To describe longitudinal image changes in supratentorial hemispheric meningiomas based on magnetic resonance imaging after preoperative embolization using calibrated microspheres. METHODS: A total of 14 patients with symptomatic supratentorial meningiomas were included in a prospective, mono-centric, mono-arm study. Magnetic resonance imaging changes on diffusion-weighted imaging, dynamic contrast susceptibility-perfusion-weighted imaging, susceptibility-weighted imaging, and magnetization-prepared rapid acquisition gradient-echo sequence T1-weighted postcontrast sequences 6 and 48 hours after embolization were evaluated and correlated with angiographic and clinical data. RESULTS: The mean age of the patients was 63 ± 12.7 years with an equal female/male ratio. Twelve meningiomas were World Health Organization grade I and II tumors. After embolization, baseline apparent diffusion coefficient (901 ± 166 mm2/s) decreased significantly within 6 hours (696 ± 115 mm2/s, P = 0.0008) as well within 48 hours (752 ± 134 mm2/s; P = 0.0147). Baseline mean ratio of relative cerebral blood volume (rCBV)tumor/rCBVwhite matter (3.67 ± 1.83) and relative cerebral blood flow (rCBF)tumor/rCBFwhite matter (2.89 ± 1.57) significantly decreased after embolization within 6 hours (rCBVtumor/rCBVwhite matter of 1.45 ± 0.9; P = 0.0007, rCBF of 1.16 ± 0.68; P = 0.0029) and 48 hours (rCBV of 1.50 ± 1.07; P = 0.0009, rCBFtumor/rCBFwhite matter of 1.19 ± 0.8; P = 0.003). The viable enhanced baseline mean tumor volume (54.3 ± 34.9 mm3) was sustainably and significantly diminished within 6 hours (26.6 ± 20.8 mm3; P = 0.02) and 48 hours (29.7 ± 22.5 mm3; P = 0.035) after embolization. There was a good correlation between angiographic devascularization rate and the embolized tumor volume at 6 hours (r = 0.7; P = 0.03) and 48 hours (r = 0.78; P = 0.041). CONCLUSIONS: Preoperative meningioma embolization with calibrated microspheres is safe and effectively induces a significant and sustainable tissue transformation over 48 hours.

Percent reduction of growth hormone levels correlates closely with percent resected tumor volume in acromegaly.

OBJECT: Correlation between tumor volume and hormone levels in individual patients would permit calculation of the fraction of tumor removed by surgery, by measuring postoperative hormone levels. The goals of this study were to examine the relationship between tumor volume, growth hormone (GH), and insulin-like growth factor-1 (IGF-1) levels, and to assess the correlation between percent tumor removal and the reduction in plasma GH and IGF-1 in patients with acromegaly. METHODS: The 3D region of interest-based volumetric method was used to measure tumor volume via MRI before and after surgery in 11 patients with GH-secreting adenomas. The volume of residual tumor as a fraction of preoperative tumor volume was correlated with GH levels before and after surgery. Examination of this potential correlation required selection of patients with acromegaly who 1) had incomplete tumor removal, 2) had precise measurements of initial and residual tumor, and 3) were not on medical therapy. RESULTS: Densely granulated tumors produced more peripheral GH per mass of tumor than sparsely granulated tumors (p = 0.04). There was a correlation between GH and IGF-1 levels (p = 0.001). Although there was no close correlation between tumor size and peripheral GH levels, after normalizing each tumor to its own plasma GH level and tumor volume, a comparison of percent tumor resection with percent drop in plasma GH yielded a high correlation coefficient (p = 0.006). CONCLUSIONS: Densely granulated somatotropinomas produce more GH per mass of tumor than do sparsely granulated tumors. Each GH-secreting tumor has its own intrinsic level of GH production per mass of tumor, which is homogeneous over the tumor mass, and which varies greatly between tumors. In most patients the fraction of a GH-secreting tumor removed by surgery can be accurately estimated by simply comparing plasma GH levels after surgery to those before surgery.

Quality of life and outcome after treatment of ruptured cerebral aneurysms: results of a single center in Switzerland.

OBJECT: To evaluate the subjective outcome and quality of life (QoL) of patients who suffered from aneurysmal subarachnoid hemorrhage and underwent endovascular coiling or microsurgical clipping in a single center. METHODS: For this retrospective single-center study, we included patients who underwent aneurysm occlusion at the Cantonal Hospital of Aarau between January 2000 and December 2006. The QoL, the functional status, and the level of independence were assessed by means of the Short Form (SF)-12 Health Survey, the modified Rankin Scale (mRS), and the Barthel Index. The questionnaires were sent to and completed by the patients. A total of 104 patients with a mean age of 53.14 years (range, 18-80 years) were included in the study. In 63 (60.6 %) of the cases, the aneurysm was clipped; in 41 (39.4 %) of the cases, endovascular coiling was performed. RESULTS: The SF-12 scores for the PCS (Physical Component Summary) and MCS (Mental Component Summary) were similar for both clipped (PCS 45.35; MCS 46.55) and coiled (PCS 46.31; MCS 47.87) patients. The mean values were, on average, 4.17 points lower for the PCS and 2.79 points lower for the MCS when compared with the mean of the US population, with a mean of 50 (standard deviation (SD) 10). The mean Barthel Index for the entire group was 92.26 (SD 16.8) and was almost identical for both the clipped (92.54; SD 16.21) and coiled (91.83; SD 17.9) patients (p = 0.56). The mean mRS did not differ between the coiled and clipped patients (coiled 1.63; clipped 1.56; p = 0.97) CONCLUSIONS: There were no significant differences in the functional and mental health scores between the two groups of clipped and coiled patients who were treated at our center, but both groups were lower than population-based scores. Although the neurologic condition and the imaging results on admission were worse in the coiled group, the long-term results did not differ significantly.

Use of fluorescence to guide resection or biopsy of primary brain tumors and brain metastases.

OBJECT: The accurate discrimination between tumor and normal tissue is crucial for determining how much to resect and therefore for the clinical outcome of patients with brain tumors. In recent years, guidance with 5-aminolevulinic acid (5-ALA)-induced intraoperative fluorescence has proven to be a useful surgical adjunct for gross-total resection of high-grade gliomas. The clinical utility of 5-ALA in resection of brain tumors other than glioblastomas has not yet been established. The authors assessed the frequency of positive 5-ALA fluorescence in a cohort of patients with primary brain tumors and metastases. METHODS: The authors conducted a single-center retrospective analysis of 531 patients with intracranial tumors treated by 5-ALA-guided resection or biopsy. They analyzed patient characteristics, preoperative and postoperative liver function test results, intraoperative tumor fluorescence, and histological data. They also screened discharge summaries for clinical adverse effects resulting from the administration of 5-ALA. Intraoperative qualitative 5-ALA fluorescence (none, mild, moderate, and strong) was documented by the surgeon and dichotomized into negative and positive fluorescence. RESULTS: A total of 458 cases qualified for final analysis. The highest percentage of 5-ALA-positive fluorescence in open resection was found in glioblastomas (96%, n = 99/103). Among other tumors, 5-ALA-positive fluorescence was detected in 88% (n = 21/32) of anaplastic gliomas (WHO Grade III), 40% (n = 8/19) of low-grade gliomas (WHO Grade II), no (n = 0/3) WHO Grade I gliomas, and 77% (n = 85/110) of meningiomas. Among metastases, the highest percentage of 5-ALA-positive fluorescence was detected in adenocarcinomas (48%, n = 13/27). Low rates or absence of positive fluorescence was found among pituitary adenomas (8%, n = 1/12) and schwannomas (0%, n = 0/7). Biopsies of high-grade primary brain tumors showed positive rates of fluorescence similar to those recorded for open resection. No clinical adverse effects associated with use of 5-ALA were observed. Only 1 patient had clinically silent transient elevation of liver enzymes. CONCLUSIONS: Study findings suggest that the administration of 5-ALA as a surgical adjunct for resection and biopsy of primary brain tumors and brain metastases is safe. In light of the high rate of positive fluorescence in high-grade gliomas other than glioblastomas, meningiomas, and a variety of metastatic cancers, 5-ALA seems to be a promising tool for enhancing intraoperative identification of neoplastic tissue and optimizing the extent of resection.

First noninvasive thermal ablation of a brain tumor with MR-guided focused ultrasound.

Magnetic resonance-guided focused ultrasound surgery (MRgFUS) allows for precise thermal ablation of target tissues. While this emerging modality is increasingly used for the treatment of various types of extracranial soft tissue tumors, it has only recently been acknowledged as a modality for noninvasive neurosurgery. MRgFUS has been particularly successful for functional neurosurgery, whereas its clinical application for tumor neurosurgery has been delayed for various technical and procedural reasons. Here, we report the case of a 63-year-old patient presenting with a centrally located recurrent glioblastoma who was included in our ongoing clinical phase I study aimed at evaluating the feasibility and safety of transcranial MRgFUS for brain tumor ablation. Applying 25 high-power sonications under MR imaging guidance, partial tumor ablation could be achieved without provoking neurological deficits or other adverse effects in the patient. This proves, for the first time, the feasibility of using transcranial MR-guided focused ultrasound to safely ablate substantial volumes of brain tumor tissue.

Cortical hemosiderin is associated with seizures in patients with newly diagnosed malignant brain tumors.

Hemorrhage is common in brain tumors. Due to characteristic magnetic field changes induced by hemosiderin it can be detected using susceptibility weighted MRI (SWI). Its relevance to clinical syndromes is unclear. Here we investigated the patterns of intra-tumoral SWI positivity (SWI(pos)) as a surrogate for hemosiderin with regard to the prevalence of epilepsy. We report on 105 patients with newly diagnosed supra-tentorial gliomas and brain metastasis. The following parameters were recorded from pre-operative MRI: (1) SWI(pos) defined as dot-like or fine linear signal changes; (2) allocation of SWI(pos) to tumor compartments (contrast enhancement, central hypointensity, non-enhancing area outside contrast-enhancement); (3) allocation of SWI(pos) to include the cortex, or SWI(pos) in subcortical tumor parts only; (4) tumor size on T2 weighted and gadolinium-enhanced T1 images. 80 tumors (76 %) showed SWI(pos) (4/14 diffuse astrocytoma WHO II, 5/9 anaplastic astrocytoma WHO III, 41/46 glioblastoma WHO IV, 30/36 metastasis). The presence of SWI(pos) depended on tumor size but not on patient's age, medication with antiplatelet drugs or anticoagulation. Seizures occurred in 60 % of patients. Cortical SWI(pos) significantly correlated with seizures in brain metastasis (p = 0.044), and as a trend in glioblastoma (p = 0.062). Cortical SWI(pos) may confer a risk for seizures in patients with newly diagnosed brain metastasis and glioblastoma. Whether development of cortical SWI(pos) induced by treatment or by the natural course of tumors also leads to the new onset of seizures has to be addressed in longitudinal studies in larger patient cohorts.

Radiation-induced imaging changes following Gamma Knife surgery for cerebral arteriovenous malformations.

OBJECT: The objective of this study was to evaluate the incidence, severity, clinical manifestations, and risk factors of radiation-induced imaging changes (RIICs) following Gamma Knife surgery (GKS) for cerebral arteriovenous malformations (AVMs). METHODS: A total of 1426 GKS procedures performed for AVMs with imaging follow-up available were analyzed. Radiation-induced imaging changes were defined as newly developed increased T2 signal surrounding the treated AVM nidi. A grading system was developed to categorize the severity of RIICs. Grade I RIICs were mild imaging changes imposing no mass effect on the surrounding brain. Grade II RIICs were moderate changes causing effacement of the sulci or compression of the ventricles. Grade III RIICs were severe changes causing midline shift of the brain. Univariate and multivariate logistic regression analyses were applied to test factors potentially affecting the occurrence, severity, and associated symptoms of RIICs. RESULTS: A total of 482 nidi (33.8%) developed RIICs following GKS, with 281 classified as Grade I, 164 as Grade II, and 37 as Grade III. The median duration from GKS to the development of RIICs was 13 months (range 2-124 months). The imaging changes disappeared completely within 2-128 months (median 22 months) following the development of RIICs. The RIICs were symptomatic in 122 patients, yielding an overall incidence of symptomatic RIICs of 8.6%. Twenty-six patients (1.8%) with RIICs had permanent deficits. A negative history of prior surgery, no prior hemorrhage, large nidus, and a single draining vein were associated with a higher risk of RIICs. CONCLUSIONS: Radiation-induced imaging changes are the most common adverse effects following GKS. Fortunately, few of the RIICs are symptomatic and most of the symptoms are reversible. Patients with a relatively healthy brain and nidi that are large, or with a single draining vein, are more likely to develop RIICs.

Long-term results of gamma knife surgery for partially embolized arteriovenous malformations.

BACKGROUND: The effectiveness and risk of gamma knife surgery (GKS) in the management of partially embolized cerebral arteriovenous malformations (AVMs) remain to be elucidated. OBJECTIVE: To evaluate the long-term imaging and clinical outcomes of GKS in AVM patients who had undergone previous partial embolization and compare the results with patients treated with GKS alone. METHODS: A total of 215 embolized AVMs were analyzed. The mean patient age was 32.9 years. The mean volume of the nidus was 4.6 mL (range, 0.1-29.4 mL), and the mean prescription dose was 19.6 Gy (range, 4-28 Gy). This group was compared with 729 nonembolized AVMs. RESULTS: After embolization and GKS, angiographically confirmed total obliteration of the AVMs was significantly lower (33%) compared with patients in whom GKS was used alone (60.9%; P < .001). However, the mean nidus size was larger and the Spetzler-Martin grade was higher for the embolized AVMs compared with the nonembolized AVMs. Radiation-induced changes occurred more often in the embolized (43.4%) than the nonembolized (33.4%) AVMs (P = .028). Permanent neurological deficits associated with radiation-induced changes occurred in 2.7% of the embolized compared with 1.3% of the nonembolized patients (P = .14). CONCLUSION: In our retrospective and historical series, the long-term results suggest that the obliteration rate is significantly lower in embolized AVMs compared with nonembolized AVMs, also because of the fact that the combined treatment is applied to higher grade AVMs; the percentage of grade III-V AVMs was 58.6% and 48.8% for nonembolized AVMs.

Hemorrhage risk of cerebral arteriovenous malformations before and during the latency period after GAMMA knife radiosurgery.

BACKGROUND AND PURPOSE: To evaluate the hemorrhage rates of cerebral arteriovenous malformations (AVM) and the risk factors of hemorrhage before and after Gamma Knife radiosurgery (GKS). METHODS: The annual hemorrhage rate was calculated as the number of hemorrhages divided by the patient-years at risk. Characteristics of patients and AVM related to hemorrhagic or nonhemorrhagic presentation were evaluated by logistic regression. Risk factors predicting AVM hemorrhage during the period from the diagnosis to GKS of AVM and during the latency period after radiosurgery were evaluated using Cox regression hazards model. RESULTS: The annual hemorrhage rate before GKS was 2.0% assuming patients were at risk for hemorrhage since their birth. The hemorrhage rate calculated between the diagnosis and GKS of AVM was 6.6% and reduced to 2.5% after GKS until obliteration of the AVM. Although small and deep nidi and those with deep and single draining veins tended to present themselves with hemorrhage, only nidi with single draining veins and those ruptured before were more likely to bleed once the AVM had been diagnosed. These factors no longer predisposed the nidus to a rupture after radiosurgery and the only predicting factor for hemorrhage was a low radiosurgical prescription dose to the margin of nidus. CONCLUSIONS: The AVM hemorrhage rate seems to reduce after GKS. After radiosurgery, none of the patients or nidus-related risk factors remained relevant to the occurrence of hemorrhage. The nidus treated with a high radiosurgical dose is less likely to bleed.

Early draining vein occlusion after gamma knife surgery for arteriovenous malformations.

BACKGROUND: Increased signals on T2-weighted magnetic resonance imaging usually interpreted as radiation-induced changes or brain edema is a common short- to mid-term complication after Gamma Knife surgery (GKS) for intracranial arteriovenous malformations (AVMs), although its nature remains to be clarified. Early draining vein occlusion with resultant brain edema or hemorrhage, although well established in surgical series, was not described in radiosurgical literature until recently. OBJECTIVE: To outline the incidence, clinical manifestations, and outcomes of this unusual complication in our series of 1256 AVM patients treated with GKS. METHODS: From 1989 to 2008, 1400 patients underwent GKS for cerebral AVMs or dural arteriovenous fistulae at the University of Virginia. In 1256 patients, magnetic resonance imaging after GKS was available for analysis of radiation-induced changes and early draining vein occlusion. RESULTS: After GKS, 456 patients (36%) developed radiation-induced changes surrounding the treated nidi. Among these patients, 12 had early thrombosis of the draining vein accompanied by radiation-induced changes. Venous thrombosis occurred 6 to 25 months (median 11.6 months) after GKS. Three patients were asymptomatic on the image findings of venous occlusion and brain edema, 3 experienced headache, 1 had seizure and headache, and neurological deficits developed in 5. Patients with neurological deficits were treated with corticosteroids; 2 of the patients recovered completely, 1 still had slight hemiparesis, 1 had short-term memory deficits, and 1 died of massive intracerebral hemorrhage. CONCLUSION: Although venous structures are considered more radioresistant, endothelial damage accompanied by venous flow stasis might cause early venous thrombosis and premature venous occlusion after radiosurgery for AVMs. In our series, all patients had a favorable outcome except 1 with a fatal hemorrhage.

Physiological and morphological plasticity induced by chronic treatment with NT-3 or NT-4/5 in hippocampal slice cultures.

Expression of neurotrophins (NTs) and their receptors is elevated in the adult CNS under several neuropathological conditions. We have investigated the anatomical and electrophysiological consequences of chronic NT-3 or NT-4/5 treatment on established organotypic hippocampal slice cultures maintained in vitro for > 14 days. Both NT-3 and NT-4/5 increased spontaneous, action potential-dependent excitatory synaptic activity (sEPSCs), but only NT-3 increased inhibitory synaptic activity (sIPSCs) in CA3 pyramidal cells. Both NTs strongly promoted spontaneous synaptic bursting activity. Spontaneous bursts of EPSCs were observed after either NT treatment but only NT-3-treated cultures exhibited an increase in spontaneous bursts of IPSCs. In addition, sIPSC bursts were eliminated by blocking glutamatergic excitation. The frequency of miniature inhibitory postsynaptic currents, but not miniature excitatory postsynaptic currents, was also increased by both NT-3 and NT-4/5. Furthermore, NT-3 and NT-4/5 induced an up-regulation of the growth-associated protein GAP-43, suggesting that neurotrophins may be able to induce axonal reorganization in established neuronal networks. CA1 pyramidal cells exhibited slight alterations in dendritic branching after NT-4/5, but not NT-3 treatment. We conclude that chronic treatment with NT-3 or NT-4/5 can affect an established hippocampal network by elevating spontaneous inhibitory and excitatory synaptic activity and inducing coordinated pre- and postsynaptic structural changes.